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Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

A version of this article first appeared on Medscape.com.

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

A version of this article first appeared on Medscape.com.

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

A version of this article first appeared on Medscape.com.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Adjuvant radiotherapy after radical prostatectomy provided no meaningful benefit in patients with prostate cancer but increased the risk for urinary and bowel morbidity, compared with men followed with observation alone, according to the latest results from the phase 3 RADICALS-RT trial.

The new findings showed no difference in the rate of 10-year freedom from distant metastases or overall survival in patients who received adjuvant radiotherapy vs. those who underwent observation with salvage radiotherapy if their disease progressed and provided further confirmation of earlier results reported in The Lancet in 2020.

Observation with early salvage radiotherapy in cases of biochemical failure should be the standard of care, concluded study coauthor Noel Clarke, MBBS, who presented the results at the annual meeting of the European Society for Medical Oncology.

Invited discussant and session cochair Shahneed Sandhu, MBBS, said that the findings definitively confirm the value of observation with salvage radiotherapy over adjuvant radiotherapy in this patient population.

“The approach of early salvage radiotherapy spared morbidity [from] radiation in the vast majority of patients, and further bowel and bladder toxicity is reduced in the setting of salvage radiotherapy,” said Dr. Sandhu, an associate professor and consultant medical oncologist at Peter MacCallum Cancer Centre, Victoria, Australia.

The aim of the RADICALS-RT study was to clarify the optimal timing for radiotherapy after radical prostatectomy in men with prostate cancer, which previously had been uncertain.

In the study, 697 patients were randomly assigned to adjuvant radiotherapy and 699 to observation with salvage radiotherapy. Participants had undergone radical prostatectomy; had a postoperative prostate-specific antigen (PSA) level ≤ 0.2 ng/mL; and at least one risk factor for cancer relapse, including pathologic T-stage III or IV, Gleason score of 7-10, positive margins, or preoperative PSA ≥ 10 ng/mL.

Patients in the observation arm received salvage radiotherapy if they experienced two consecutive PSA increases ≥ 0.1 ng/mL or three consecutive rises.

Overall, the investigators found similar rates of 10-year freedom from distant metastases in both arms: 93% in the adjuvant radiotherapy group vs. 90% in the observation group (hazard ratio, 0.68; P = .095). The 10-year overall survival rates were similar as well: 88% in the adjuvant radiotherapy group and 87% in the observation group (HR, 0.98; P = .92).

However, self-reported urinary and fecal incontinence rates at 1 year were significantly higher in the adjuvant radiotherapy group vs. the observation group, 60% of whom had not received salvage radiotherapy at that time.

Secondary outcome measures, including biochemical progression-free survival and time to further hormone therapy, were also similar in the treatment and observation arms.

Overall, the trial results “support the use of early salvage radiotherapy for PSA failure after radical prostatectomy rather than early adjuvant intervention, “ concluded Dr. Clarke, a professor and consultant urologist at the Christie Hospital and Salford Royal Hospital, Manchester, England.

And when biochemical recurrence does occur, Dr. Sandhu noted that prostate-specific membrane antigen PET is increasingly used in practice to help “define the extent of disease” and “tailor radiation fields.”

Dr. Clarke reported serving on advisory boards for Janssen, Astellas, and Bayer. Dr. Sandhu reported receiving research grant support and/or serving as a consultant or adviser for Advanced Accelerator Application (a Novartis company), AstraZeneca, Merck Sharp and Dohme, Roche/Genentech, Amgen, Pfizer, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, and Sehnwa.

A version of this article first appeared on Medscape.com.

Adjuvant radiotherapy after radical prostatectomy provided no meaningful benefit in patients with prostate cancer but increased the risk for urinary and bowel morbidity, compared with men followed with observation alone, according to the latest results from the phase 3 RADICALS-RT trial.

The new findings showed no difference in the rate of 10-year freedom from distant metastases or overall survival in patients who received adjuvant radiotherapy vs. those who underwent observation with salvage radiotherapy if their disease progressed and provided further confirmation of earlier results reported in The Lancet in 2020.

Observation with early salvage radiotherapy in cases of biochemical failure should be the standard of care, concluded study coauthor Noel Clarke, MBBS, who presented the results at the annual meeting of the European Society for Medical Oncology.

Invited discussant and session cochair Shahneed Sandhu, MBBS, said that the findings definitively confirm the value of observation with salvage radiotherapy over adjuvant radiotherapy in this patient population.

“The approach of early salvage radiotherapy spared morbidity [from] radiation in the vast majority of patients, and further bowel and bladder toxicity is reduced in the setting of salvage radiotherapy,” said Dr. Sandhu, an associate professor and consultant medical oncologist at Peter MacCallum Cancer Centre, Victoria, Australia.

The aim of the RADICALS-RT study was to clarify the optimal timing for radiotherapy after radical prostatectomy in men with prostate cancer, which previously had been uncertain.

In the study, 697 patients were randomly assigned to adjuvant radiotherapy and 699 to observation with salvage radiotherapy. Participants had undergone radical prostatectomy; had a postoperative prostate-specific antigen (PSA) level ≤ 0.2 ng/mL; and at least one risk factor for cancer relapse, including pathologic T-stage III or IV, Gleason score of 7-10, positive margins, or preoperative PSA ≥ 10 ng/mL.

Patients in the observation arm received salvage radiotherapy if they experienced two consecutive PSA increases ≥ 0.1 ng/mL or three consecutive rises.

Overall, the investigators found similar rates of 10-year freedom from distant metastases in both arms: 93% in the adjuvant radiotherapy group vs. 90% in the observation group (hazard ratio, 0.68; P = .095). The 10-year overall survival rates were similar as well: 88% in the adjuvant radiotherapy group and 87% in the observation group (HR, 0.98; P = .92).

However, self-reported urinary and fecal incontinence rates at 1 year were significantly higher in the adjuvant radiotherapy group vs. the observation group, 60% of whom had not received salvage radiotherapy at that time.

Secondary outcome measures, including biochemical progression-free survival and time to further hormone therapy, were also similar in the treatment and observation arms.

Overall, the trial results “support the use of early salvage radiotherapy for PSA failure after radical prostatectomy rather than early adjuvant intervention, “ concluded Dr. Clarke, a professor and consultant urologist at the Christie Hospital and Salford Royal Hospital, Manchester, England.

And when biochemical recurrence does occur, Dr. Sandhu noted that prostate-specific membrane antigen PET is increasingly used in practice to help “define the extent of disease” and “tailor radiation fields.”

Dr. Clarke reported serving on advisory boards for Janssen, Astellas, and Bayer. Dr. Sandhu reported receiving research grant support and/or serving as a consultant or adviser for Advanced Accelerator Application (a Novartis company), AstraZeneca, Merck Sharp and Dohme, Roche/Genentech, Amgen, Pfizer, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, and Sehnwa.

A version of this article first appeared on Medscape.com.

Adjuvant radiotherapy after radical prostatectomy provided no meaningful benefit in patients with prostate cancer but increased the risk for urinary and bowel morbidity, compared with men followed with observation alone, according to the latest results from the phase 3 RADICALS-RT trial.

The new findings showed no difference in the rate of 10-year freedom from distant metastases or overall survival in patients who received adjuvant radiotherapy vs. those who underwent observation with salvage radiotherapy if their disease progressed and provided further confirmation of earlier results reported in The Lancet in 2020.

Observation with early salvage radiotherapy in cases of biochemical failure should be the standard of care, concluded study coauthor Noel Clarke, MBBS, who presented the results at the annual meeting of the European Society for Medical Oncology.

Invited discussant and session cochair Shahneed Sandhu, MBBS, said that the findings definitively confirm the value of observation with salvage radiotherapy over adjuvant radiotherapy in this patient population.

“The approach of early salvage radiotherapy spared morbidity [from] radiation in the vast majority of patients, and further bowel and bladder toxicity is reduced in the setting of salvage radiotherapy,” said Dr. Sandhu, an associate professor and consultant medical oncologist at Peter MacCallum Cancer Centre, Victoria, Australia.

The aim of the RADICALS-RT study was to clarify the optimal timing for radiotherapy after radical prostatectomy in men with prostate cancer, which previously had been uncertain.

In the study, 697 patients were randomly assigned to adjuvant radiotherapy and 699 to observation with salvage radiotherapy. Participants had undergone radical prostatectomy; had a postoperative prostate-specific antigen (PSA) level ≤ 0.2 ng/mL; and at least one risk factor for cancer relapse, including pathologic T-stage III or IV, Gleason score of 7-10, positive margins, or preoperative PSA ≥ 10 ng/mL.

Patients in the observation arm received salvage radiotherapy if they experienced two consecutive PSA increases ≥ 0.1 ng/mL or three consecutive rises.

Overall, the investigators found similar rates of 10-year freedom from distant metastases in both arms: 93% in the adjuvant radiotherapy group vs. 90% in the observation group (hazard ratio, 0.68; P = .095). The 10-year overall survival rates were similar as well: 88% in the adjuvant radiotherapy group and 87% in the observation group (HR, 0.98; P = .92).

However, self-reported urinary and fecal incontinence rates at 1 year were significantly higher in the adjuvant radiotherapy group vs. the observation group, 60% of whom had not received salvage radiotherapy at that time.

Secondary outcome measures, including biochemical progression-free survival and time to further hormone therapy, were also similar in the treatment and observation arms.

Overall, the trial results “support the use of early salvage radiotherapy for PSA failure after radical prostatectomy rather than early adjuvant intervention, “ concluded Dr. Clarke, a professor and consultant urologist at the Christie Hospital and Salford Royal Hospital, Manchester, England.

And when biochemical recurrence does occur, Dr. Sandhu noted that prostate-specific membrane antigen PET is increasingly used in practice to help “define the extent of disease” and “tailor radiation fields.”

Dr. Clarke reported serving on advisory boards for Janssen, Astellas, and Bayer. Dr. Sandhu reported receiving research grant support and/or serving as a consultant or adviser for Advanced Accelerator Application (a Novartis company), AstraZeneca, Merck Sharp and Dohme, Roche/Genentech, Amgen, Pfizer, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, and Sehnwa.

A version of this article first appeared on Medscape.com.

Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.

Although the trial did not produce the desired result, it still provided important impetus for researchers to do better, said lead investigator Luca Gianni, MD, chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.

“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.

Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.

NeoTRIP results

Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.

“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.

At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.

In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.

A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.

Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.

At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076­­ for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.

Pathologic complete responses key

In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.

Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).

Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.

The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.

“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.

Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.

Why no benefit to the ICI?

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.

For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.

In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.

“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.

Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.

The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.

Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.

Although the trial did not produce the desired result, it still provided important impetus for researchers to do better, said lead investigator Luca Gianni, MD, chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.

“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.

Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.

NeoTRIP results

Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.

“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.

At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.

In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.

A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.

Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.

At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076­­ for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.

Pathologic complete responses key

In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.

Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).

Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.

The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.

“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.

Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.

Why no benefit to the ICI?

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.

For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.

In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.

“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.

Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.

The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.

Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.

Although the trial did not produce the desired result, it still provided important impetus for researchers to do better, said lead investigator Luca Gianni, MD, chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.

“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.

Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.

NeoTRIP results

Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.

“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.

At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.

In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.

A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.

Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.

At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076­­ for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.

Pathologic complete responses key

In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.

Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).

Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.

The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.

“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.

Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.

Why no benefit to the ICI?

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.

For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.

In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.

“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.

Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.

The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.

During treatment for metastatic cancer, remote monitoring of symptoms using electronic patient-reported outcomes (ePROs) reduced health care visits and improved patients’ physical function and quality of life, but did not impact overall survival, according to findings from the PRO-TECT trial.

“Although survival was not impacted in this trial, patients found the intervention to be valuable and experienced improved quality of life and decreased hospitalizations,” said Ethan Basch, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, who presented the findings at the annual meeting of the European Society for Medical Oncology.

Jiyoung Ahn, PhD, professor of population health at NYU Langone Health and associate director of population science, NYU Langone Perlmutter Cancer Center, both in New York, said this study “provides exciting scientific evidence” supporting real-time, remote monitoring of PROs. Dr. Ahn was not involved with the PRO-TECT trial.

Symptoms among patients with advanced cancer receiving treatment are “exceedingly common,” Dr. Basch explained, but “unfortunately, evidence demonstrates that we as clinicians miss up to 50% of our patients’ symptoms with potential serious downstream consequences.”

Remote monitoring with ePROs can help clinicians detect patients’ symptoms early so they can intervene early.

In the PRO-TECT cluster-randomized trial, 52 oncology practices in the United States were randomly assigned (1:1) to remote monitoring with ePRO surveys or usual care. The cohort included 1,191 patients with metastatic cancer – with 593 patients at PRO practices and 598 patients at control practices. Participating practices could enroll up to 50 patients with any type of metastatic cancer, except for indolent lymphoma or acute leukemia, who were receiving systemic treatment.

Patients in the ePRO practices completed weekly surveys either online or using an automated telephone system for up to 1 year. The survey included questions related to nine common symptoms, performance status, and falls.

For symptoms that are severe or worsening, a real-time alert goes to the care team through the electronic health record or by an email, Dr. Basch explained. Similarly, reports highlighting the longitudinal trajectory of symptoms can be generated at patient visits and reviewed by clinicians, which can bring “the patient and the care team closer together by elevating those issues that are particularly salient to the patient’s experience,” he noted.

Patients completed over 91% of the electronic symptom surveys. After 24 months, the team observed no significant difference in the primary outcome of overall survival – 42.0 months with ePRO vs. 43.5 months with usual care (hazard ratio, 0.99; P = .86).

Dr. Basch and colleagues did, however, observe a 6% reduction in emergency or hospital admissions in the ePRO group, compared with usual care. The ePRO group also had a significantly longer time to first emergency admission (HR, 0.84; P = .03) and a decreased average number of admissions per patient over 1 year (1.48 vs. 1.81; P = .006).

At multiple time points, the team also observed “clinically meaningful and statistically significant” benefits in physical functioning, symptom control, and health-related quality of life, Dr. Basch reported. More patients in the ePRO than the usual-care group experienced benefits in fatigue (odds ratio, 1.77; P < .001), anorexia (OR, 1.32; P = .03), nausea/vomiting (OR, 1.40; P = .01), and sleep (OR, 1.73; P < .001).

Patients’ impressions of the ePRO symptom monitoring system were also “overwhelmingly” positive, Dr. Basch said. Most found the questions relevant and easy to understand and felt that their care team used the information, which made patients feel more in control of their care.

Nurses generally had a favorable impression of the system, with the majority stating that the information was helpful for electronic health record documentation and that it improved discussions with their patients and improved their efficiency.

However, about one-quarter of the nurses expressed reluctance about continuing to use the system, citing the “added work of the ePROs, particularly alerts that were triggered that prompted them to call their patients, particularly during the pandemic when nurses in the United States were pulled in many directions,” Dr. Basch said.

He noted that future ePRO implementations should aim to integrate ePROs into care processes and adjust nurse responsibilities to allow time for ePRO work.

It will also be important to offer a variety of ePRO platforms that are easily accessible for different patient groups. “Notably,” said Dr. Basch, about one-third of the patients selected the automated telephone option. These were largely patients living in rural areas of the United States with lower socioeconomic status and lower health literacy, “suggesting that we need to think about our technologies to meet patients where they are,” he said.

Despite the positive outcomes, there are “challenges to widespread adoption,” agreed NYU’s Dr. Ahn.

These challenges include the need for physician adaptation to new technologies, data security, and ensuring patient engagement and compliance with remote monitoring systems.

“Successfully addressing these challenges is crucial for optimizing the integration of ePROs into cancer care,” Dr. Ahn said.

ESMO’s invited discussant, Anne Letsch, MD, noted that “cancer therapies are getting more complex, and it’s important that patients are well informed and empowered to get together with the treatment teams throughout therapy.”

The high completion rate with ePRO symptom surveys was “quite remarkable,” said Dr. Letsch, head of the Cancer Center at the University Hospital Schleswig Holstein, Kiel, Germany.

But, Dr. Letsch said, it’s “a pity” that there was no overall survival benefit among patients in the ePRO group. Perhaps overall survival is not what matters most in this context, she said. Instead, she asked, “are other outcomes, like health-related quality of life, symptom control and treatment safety, much more important?”

Dr. Basch also questioned whether the survival differences between the two groups may have been blunted because a substantial portion of the trial was conducted during the COVID-19 pandemic, when medical resources and treatments were delayed and diverted.

Dr. Basch pointed to a 2017 study he and colleagues conducted at a single tertiary care medical center, in which patients monitored with ePROs did demonstrate an overall survival benefit, compared with usual care.

Overall, though, the study demonstrated that “symptom monitoring with ePROs is feasible during routine treatment for advanced cancers across diverse practices in the U.S.” and improved patients’ quality of life, Dr. Basch said.

Funding for the study was provided by a grant from the Patient-Centered Outcomes Research Institute. Dr. Basch has disclosed relationships with Resilience Health, Sivan Health, Navigating Cancer, and AstraZeneca. Dr. Letsch and Dr. Ahn report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

During treatment for metastatic cancer, remote monitoring of symptoms using electronic patient-reported outcomes (ePROs) reduced health care visits and improved patients’ physical function and quality of life, but did not impact overall survival, according to findings from the PRO-TECT trial.

“Although survival was not impacted in this trial, patients found the intervention to be valuable and experienced improved quality of life and decreased hospitalizations,” said Ethan Basch, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, who presented the findings at the annual meeting of the European Society for Medical Oncology.

Jiyoung Ahn, PhD, professor of population health at NYU Langone Health and associate director of population science, NYU Langone Perlmutter Cancer Center, both in New York, said this study “provides exciting scientific evidence” supporting real-time, remote monitoring of PROs. Dr. Ahn was not involved with the PRO-TECT trial.

Symptoms among patients with advanced cancer receiving treatment are “exceedingly common,” Dr. Basch explained, but “unfortunately, evidence demonstrates that we as clinicians miss up to 50% of our patients’ symptoms with potential serious downstream consequences.”

Remote monitoring with ePROs can help clinicians detect patients’ symptoms early so they can intervene early.

In the PRO-TECT cluster-randomized trial, 52 oncology practices in the United States were randomly assigned (1:1) to remote monitoring with ePRO surveys or usual care. The cohort included 1,191 patients with metastatic cancer – with 593 patients at PRO practices and 598 patients at control practices. Participating practices could enroll up to 50 patients with any type of metastatic cancer, except for indolent lymphoma or acute leukemia, who were receiving systemic treatment.

Patients in the ePRO practices completed weekly surveys either online or using an automated telephone system for up to 1 year. The survey included questions related to nine common symptoms, performance status, and falls.

For symptoms that are severe or worsening, a real-time alert goes to the care team through the electronic health record or by an email, Dr. Basch explained. Similarly, reports highlighting the longitudinal trajectory of symptoms can be generated at patient visits and reviewed by clinicians, which can bring “the patient and the care team closer together by elevating those issues that are particularly salient to the patient’s experience,” he noted.

Patients completed over 91% of the electronic symptom surveys. After 24 months, the team observed no significant difference in the primary outcome of overall survival – 42.0 months with ePRO vs. 43.5 months with usual care (hazard ratio, 0.99; P = .86).

Dr. Basch and colleagues did, however, observe a 6% reduction in emergency or hospital admissions in the ePRO group, compared with usual care. The ePRO group also had a significantly longer time to first emergency admission (HR, 0.84; P = .03) and a decreased average number of admissions per patient over 1 year (1.48 vs. 1.81; P = .006).

At multiple time points, the team also observed “clinically meaningful and statistically significant” benefits in physical functioning, symptom control, and health-related quality of life, Dr. Basch reported. More patients in the ePRO than the usual-care group experienced benefits in fatigue (odds ratio, 1.77; P < .001), anorexia (OR, 1.32; P = .03), nausea/vomiting (OR, 1.40; P = .01), and sleep (OR, 1.73; P < .001).

Patients’ impressions of the ePRO symptom monitoring system were also “overwhelmingly” positive, Dr. Basch said. Most found the questions relevant and easy to understand and felt that their care team used the information, which made patients feel more in control of their care.

Nurses generally had a favorable impression of the system, with the majority stating that the information was helpful for electronic health record documentation and that it improved discussions with their patients and improved their efficiency.

However, about one-quarter of the nurses expressed reluctance about continuing to use the system, citing the “added work of the ePROs, particularly alerts that were triggered that prompted them to call their patients, particularly during the pandemic when nurses in the United States were pulled in many directions,” Dr. Basch said.

He noted that future ePRO implementations should aim to integrate ePROs into care processes and adjust nurse responsibilities to allow time for ePRO work.

It will also be important to offer a variety of ePRO platforms that are easily accessible for different patient groups. “Notably,” said Dr. Basch, about one-third of the patients selected the automated telephone option. These were largely patients living in rural areas of the United States with lower socioeconomic status and lower health literacy, “suggesting that we need to think about our technologies to meet patients where they are,” he said.

Despite the positive outcomes, there are “challenges to widespread adoption,” agreed NYU’s Dr. Ahn.

These challenges include the need for physician adaptation to new technologies, data security, and ensuring patient engagement and compliance with remote monitoring systems.

“Successfully addressing these challenges is crucial for optimizing the integration of ePROs into cancer care,” Dr. Ahn said.

ESMO’s invited discussant, Anne Letsch, MD, noted that “cancer therapies are getting more complex, and it’s important that patients are well informed and empowered to get together with the treatment teams throughout therapy.”

The high completion rate with ePRO symptom surveys was “quite remarkable,” said Dr. Letsch, head of the Cancer Center at the University Hospital Schleswig Holstein, Kiel, Germany.

But, Dr. Letsch said, it’s “a pity” that there was no overall survival benefit among patients in the ePRO group. Perhaps overall survival is not what matters most in this context, she said. Instead, she asked, “are other outcomes, like health-related quality of life, symptom control and treatment safety, much more important?”

Dr. Basch also questioned whether the survival differences between the two groups may have been blunted because a substantial portion of the trial was conducted during the COVID-19 pandemic, when medical resources and treatments were delayed and diverted.

Dr. Basch pointed to a 2017 study he and colleagues conducted at a single tertiary care medical center, in which patients monitored with ePROs did demonstrate an overall survival benefit, compared with usual care.

Overall, though, the study demonstrated that “symptom monitoring with ePROs is feasible during routine treatment for advanced cancers across diverse practices in the U.S.” and improved patients’ quality of life, Dr. Basch said.

Funding for the study was provided by a grant from the Patient-Centered Outcomes Research Institute. Dr. Basch has disclosed relationships with Resilience Health, Sivan Health, Navigating Cancer, and AstraZeneca. Dr. Letsch and Dr. Ahn report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

During treatment for metastatic cancer, remote monitoring of symptoms using electronic patient-reported outcomes (ePROs) reduced health care visits and improved patients’ physical function and quality of life, but did not impact overall survival, according to findings from the PRO-TECT trial.

“Although survival was not impacted in this trial, patients found the intervention to be valuable and experienced improved quality of life and decreased hospitalizations,” said Ethan Basch, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, who presented the findings at the annual meeting of the European Society for Medical Oncology.

Jiyoung Ahn, PhD, professor of population health at NYU Langone Health and associate director of population science, NYU Langone Perlmutter Cancer Center, both in New York, said this study “provides exciting scientific evidence” supporting real-time, remote monitoring of PROs. Dr. Ahn was not involved with the PRO-TECT trial.

Symptoms among patients with advanced cancer receiving treatment are “exceedingly common,” Dr. Basch explained, but “unfortunately, evidence demonstrates that we as clinicians miss up to 50% of our patients’ symptoms with potential serious downstream consequences.”

Remote monitoring with ePROs can help clinicians detect patients’ symptoms early so they can intervene early.

In the PRO-TECT cluster-randomized trial, 52 oncology practices in the United States were randomly assigned (1:1) to remote monitoring with ePRO surveys or usual care. The cohort included 1,191 patients with metastatic cancer – with 593 patients at PRO practices and 598 patients at control practices. Participating practices could enroll up to 50 patients with any type of metastatic cancer, except for indolent lymphoma or acute leukemia, who were receiving systemic treatment.

Patients in the ePRO practices completed weekly surveys either online or using an automated telephone system for up to 1 year. The survey included questions related to nine common symptoms, performance status, and falls.

For symptoms that are severe or worsening, a real-time alert goes to the care team through the electronic health record or by an email, Dr. Basch explained. Similarly, reports highlighting the longitudinal trajectory of symptoms can be generated at patient visits and reviewed by clinicians, which can bring “the patient and the care team closer together by elevating those issues that are particularly salient to the patient’s experience,” he noted.

Patients completed over 91% of the electronic symptom surveys. After 24 months, the team observed no significant difference in the primary outcome of overall survival – 42.0 months with ePRO vs. 43.5 months with usual care (hazard ratio, 0.99; P = .86).

Dr. Basch and colleagues did, however, observe a 6% reduction in emergency or hospital admissions in the ePRO group, compared with usual care. The ePRO group also had a significantly longer time to first emergency admission (HR, 0.84; P = .03) and a decreased average number of admissions per patient over 1 year (1.48 vs. 1.81; P = .006).

At multiple time points, the team also observed “clinically meaningful and statistically significant” benefits in physical functioning, symptom control, and health-related quality of life, Dr. Basch reported. More patients in the ePRO than the usual-care group experienced benefits in fatigue (odds ratio, 1.77; P < .001), anorexia (OR, 1.32; P = .03), nausea/vomiting (OR, 1.40; P = .01), and sleep (OR, 1.73; P < .001).

Patients’ impressions of the ePRO symptom monitoring system were also “overwhelmingly” positive, Dr. Basch said. Most found the questions relevant and easy to understand and felt that their care team used the information, which made patients feel more in control of their care.

Nurses generally had a favorable impression of the system, with the majority stating that the information was helpful for electronic health record documentation and that it improved discussions with their patients and improved their efficiency.

However, about one-quarter of the nurses expressed reluctance about continuing to use the system, citing the “added work of the ePROs, particularly alerts that were triggered that prompted them to call their patients, particularly during the pandemic when nurses in the United States were pulled in many directions,” Dr. Basch said.

He noted that future ePRO implementations should aim to integrate ePROs into care processes and adjust nurse responsibilities to allow time for ePRO work.

It will also be important to offer a variety of ePRO platforms that are easily accessible for different patient groups. “Notably,” said Dr. Basch, about one-third of the patients selected the automated telephone option. These were largely patients living in rural areas of the United States with lower socioeconomic status and lower health literacy, “suggesting that we need to think about our technologies to meet patients where they are,” he said.

Despite the positive outcomes, there are “challenges to widespread adoption,” agreed NYU’s Dr. Ahn.

These challenges include the need for physician adaptation to new technologies, data security, and ensuring patient engagement and compliance with remote monitoring systems.

“Successfully addressing these challenges is crucial for optimizing the integration of ePROs into cancer care,” Dr. Ahn said.

ESMO’s invited discussant, Anne Letsch, MD, noted that “cancer therapies are getting more complex, and it’s important that patients are well informed and empowered to get together with the treatment teams throughout therapy.”

The high completion rate with ePRO symptom surveys was “quite remarkable,” said Dr. Letsch, head of the Cancer Center at the University Hospital Schleswig Holstein, Kiel, Germany.

But, Dr. Letsch said, it’s “a pity” that there was no overall survival benefit among patients in the ePRO group. Perhaps overall survival is not what matters most in this context, she said. Instead, she asked, “are other outcomes, like health-related quality of life, symptom control and treatment safety, much more important?”

Dr. Basch also questioned whether the survival differences between the two groups may have been blunted because a substantial portion of the trial was conducted during the COVID-19 pandemic, when medical resources and treatments were delayed and diverted.

Dr. Basch pointed to a 2017 study he and colleagues conducted at a single tertiary care medical center, in which patients monitored with ePROs did demonstrate an overall survival benefit, compared with usual care.

Overall, though, the study demonstrated that “symptom monitoring with ePROs is feasible during routine treatment for advanced cancers across diverse practices in the U.S.” and improved patients’ quality of life, Dr. Basch said.

Funding for the study was provided by a grant from the Patient-Centered Outcomes Research Institute. Dr. Basch has disclosed relationships with Resilience Health, Sivan Health, Navigating Cancer, and AstraZeneca. Dr. Letsch and Dr. Ahn report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Short-term fasting during chemotherapy enhances health-related quality of life in patients with early breast cancer, with no untoward effects, according to late-breaking research presented on day 1 of the annual meeting of the European Society for Medical Oncology.

“Strikingly,” fasting also appeared to prevent fatigue, something patients with breast cancer struggle with, Daniela A. Koppold, MD, Charité University Medicine Berlin, noted in her oral presentation.

The study adds to other evidence suggesting that fasting around chemotherapy cycles may reduce toxicity and adverse effects associated with chemotherapy.

The invited discussant, Jann Arends, MD, with Freiburg (Germany) University Medical Center, said that the findings fit “very well” with previous observations. “Short-term fasting in subjects not at risk for malnutrition is feasible, well tolerated, and appears to improve several parameters of quality of life,” Dr. Arends said.
 

Promising supportive therapy

The randomized controlled trial assessed the feasibility and impact of short-term fasting on health-related quality of life, compared with a plant-based, low-sugar diet (active comparator) in 106 women with early breast cancer.

The chemotherapy regimens in the trial included four cycles of doxorubicin or epirubicin, followed by taxane therapy. The interventions for both groups occurred about 2 days before chemotherapy plus 24 hours after each cycle ended (about 60-72 hours total).

For the fasting group, this meant about 200 kcal/day through vegetable juices and vegetable broths. In between chemotherapy sessions, both groups were advised to eat a more vegetarian-focused diet, but that was not mandatory.

Health-related quality of life assessments occurred at baseline and after each chemotherapy session (cycle four at day 7) as well as after 4 and 6 months.

The investigators assessed health-related quality of life using the 27-item Functional Assessment of Cancer Therapy-General (FACT-G) that measured the domains of physical, social/familial, emotional, and functional well-being.

At baseline, the two groups had similar FACT-G scores (fasting, 82.9 vs. plant diet, 81.9; P = .523). By day 7, the short-term–fasting group had a significantly better FACT-G score, compared with the plant-based–diet group (fasting, 78.3 vs. plant, 69.5; P = .021).

Although the two groups “started out from the same point, the fasting group had an incremental effect, which quite startled us,” Dr. Koppold told the audience. “Over the course of the chemotherapies, [fasting] had additive effects” and by cycle four of chemotherapy, the difference became statistically and clinically significant, indicating “much better” quality of life in the short-term–fasting group.

What was “even more striking,” said Dr. Koppold, was the impact fasting had on the secondary outcome of fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue).

“Short-term fasting not only had a protective effect on fatigue, compared to the control group, but the short-term–fasting group didn’t develop any clinically visible fatigue,” Dr. Koppold said. “They were in a normal range by cycle four while the control group developed fatigue as we would have expected.”

Importantly, she noted, fasting had no significant impact on weight. The study excluded women who were underweight or had a history of eating disorder or relevant psychopathology.

Summing up, Dr. Koppold said that short-term fasting represents a “promising” supportive therapy during breast cancer chemotherapy to enhance quality of life.

Commenting on the study, Rebecca Guterman, a registered dietitian at Perlmutter Cancer Center at NYU Langone Health, New York, said that it’s well known that a healthy diet plays “a key role during anticancer treatments.” Dietary changes can, for instance, help alleviate common chemotherapy side effects such as loss of appetite, nausea, fatigue, or diarrhea, she said.

These new findings support fasting for 60-72 hours around chemotherapy for some patients with breast cancer who may experience more rapid recovery and better quality of life, said Ms. Guterman.

However, she noted, the results should not be applied to patient populations outside of breast cancer or treatment regimens outside this study. And, she noted, “how the patient feels during the 60-72 hour fast also has to be considered.”

An individual’s “nutritional status must be considered. If a patient has poor appetite and loses weight between treatments, fasting should not be done before next treatment,” Ms. Guterman said.

The study was funded by a private sponsor (G. Müller, Munich, Germany) and a grant from the Günter and Regine KelmFoundation (Zurich). Dr. Koppold is a member of the steering board of ÄGHE e.V. (German-speaking Medical Association for Fasting and Nutrition); cofounder of the Academy for Integrative Fasting GbR; and consults for a mobile app on intermittent fasting (Fastic) as well as a company producing plant-based supplements (EVERYYIN). Dr. Arends has disclosed relationships with Baxter. Ms. Guterman has no relevant disclosures.

A version of this article first appeared on Medscape.com.

Short-term fasting during chemotherapy enhances health-related quality of life in patients with early breast cancer, with no untoward effects, according to late-breaking research presented on day 1 of the annual meeting of the European Society for Medical Oncology.

“Strikingly,” fasting also appeared to prevent fatigue, something patients with breast cancer struggle with, Daniela A. Koppold, MD, Charité University Medicine Berlin, noted in her oral presentation.

The study adds to other evidence suggesting that fasting around chemotherapy cycles may reduce toxicity and adverse effects associated with chemotherapy.

The invited discussant, Jann Arends, MD, with Freiburg (Germany) University Medical Center, said that the findings fit “very well” with previous observations. “Short-term fasting in subjects not at risk for malnutrition is feasible, well tolerated, and appears to improve several parameters of quality of life,” Dr. Arends said.
 

Promising supportive therapy

The randomized controlled trial assessed the feasibility and impact of short-term fasting on health-related quality of life, compared with a plant-based, low-sugar diet (active comparator) in 106 women with early breast cancer.

The chemotherapy regimens in the trial included four cycles of doxorubicin or epirubicin, followed by taxane therapy. The interventions for both groups occurred about 2 days before chemotherapy plus 24 hours after each cycle ended (about 60-72 hours total).

For the fasting group, this meant about 200 kcal/day through vegetable juices and vegetable broths. In between chemotherapy sessions, both groups were advised to eat a more vegetarian-focused diet, but that was not mandatory.

Health-related quality of life assessments occurred at baseline and after each chemotherapy session (cycle four at day 7) as well as after 4 and 6 months.

The investigators assessed health-related quality of life using the 27-item Functional Assessment of Cancer Therapy-General (FACT-G) that measured the domains of physical, social/familial, emotional, and functional well-being.

At baseline, the two groups had similar FACT-G scores (fasting, 82.9 vs. plant diet, 81.9; P = .523). By day 7, the short-term–fasting group had a significantly better FACT-G score, compared with the plant-based–diet group (fasting, 78.3 vs. plant, 69.5; P = .021).

Although the two groups “started out from the same point, the fasting group had an incremental effect, which quite startled us,” Dr. Koppold told the audience. “Over the course of the chemotherapies, [fasting] had additive effects” and by cycle four of chemotherapy, the difference became statistically and clinically significant, indicating “much better” quality of life in the short-term–fasting group.

What was “even more striking,” said Dr. Koppold, was the impact fasting had on the secondary outcome of fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue).

“Short-term fasting not only had a protective effect on fatigue, compared to the control group, but the short-term–fasting group didn’t develop any clinically visible fatigue,” Dr. Koppold said. “They were in a normal range by cycle four while the control group developed fatigue as we would have expected.”

Importantly, she noted, fasting had no significant impact on weight. The study excluded women who were underweight or had a history of eating disorder or relevant psychopathology.

Summing up, Dr. Koppold said that short-term fasting represents a “promising” supportive therapy during breast cancer chemotherapy to enhance quality of life.

Commenting on the study, Rebecca Guterman, a registered dietitian at Perlmutter Cancer Center at NYU Langone Health, New York, said that it’s well known that a healthy diet plays “a key role during anticancer treatments.” Dietary changes can, for instance, help alleviate common chemotherapy side effects such as loss of appetite, nausea, fatigue, or diarrhea, she said.

These new findings support fasting for 60-72 hours around chemotherapy for some patients with breast cancer who may experience more rapid recovery and better quality of life, said Ms. Guterman.

However, she noted, the results should not be applied to patient populations outside of breast cancer or treatment regimens outside this study. And, she noted, “how the patient feels during the 60-72 hour fast also has to be considered.”

An individual’s “nutritional status must be considered. If a patient has poor appetite and loses weight between treatments, fasting should not be done before next treatment,” Ms. Guterman said.

The study was funded by a private sponsor (G. Müller, Munich, Germany) and a grant from the Günter and Regine KelmFoundation (Zurich). Dr. Koppold is a member of the steering board of ÄGHE e.V. (German-speaking Medical Association for Fasting and Nutrition); cofounder of the Academy for Integrative Fasting GbR; and consults for a mobile app on intermittent fasting (Fastic) as well as a company producing plant-based supplements (EVERYYIN). Dr. Arends has disclosed relationships with Baxter. Ms. Guterman has no relevant disclosures.

A version of this article first appeared on Medscape.com.

Short-term fasting during chemotherapy enhances health-related quality of life in patients with early breast cancer, with no untoward effects, according to late-breaking research presented on day 1 of the annual meeting of the European Society for Medical Oncology.

“Strikingly,” fasting also appeared to prevent fatigue, something patients with breast cancer struggle with, Daniela A. Koppold, MD, Charité University Medicine Berlin, noted in her oral presentation.

The study adds to other evidence suggesting that fasting around chemotherapy cycles may reduce toxicity and adverse effects associated with chemotherapy.

The invited discussant, Jann Arends, MD, with Freiburg (Germany) University Medical Center, said that the findings fit “very well” with previous observations. “Short-term fasting in subjects not at risk for malnutrition is feasible, well tolerated, and appears to improve several parameters of quality of life,” Dr. Arends said.
 

Promising supportive therapy

The randomized controlled trial assessed the feasibility and impact of short-term fasting on health-related quality of life, compared with a plant-based, low-sugar diet (active comparator) in 106 women with early breast cancer.

The chemotherapy regimens in the trial included four cycles of doxorubicin or epirubicin, followed by taxane therapy. The interventions for both groups occurred about 2 days before chemotherapy plus 24 hours after each cycle ended (about 60-72 hours total).

For the fasting group, this meant about 200 kcal/day through vegetable juices and vegetable broths. In between chemotherapy sessions, both groups were advised to eat a more vegetarian-focused diet, but that was not mandatory.

Health-related quality of life assessments occurred at baseline and after each chemotherapy session (cycle four at day 7) as well as after 4 and 6 months.

The investigators assessed health-related quality of life using the 27-item Functional Assessment of Cancer Therapy-General (FACT-G) that measured the domains of physical, social/familial, emotional, and functional well-being.

At baseline, the two groups had similar FACT-G scores (fasting, 82.9 vs. plant diet, 81.9; P = .523). By day 7, the short-term–fasting group had a significantly better FACT-G score, compared with the plant-based–diet group (fasting, 78.3 vs. plant, 69.5; P = .021).

Although the two groups “started out from the same point, the fasting group had an incremental effect, which quite startled us,” Dr. Koppold told the audience. “Over the course of the chemotherapies, [fasting] had additive effects” and by cycle four of chemotherapy, the difference became statistically and clinically significant, indicating “much better” quality of life in the short-term–fasting group.

What was “even more striking,” said Dr. Koppold, was the impact fasting had on the secondary outcome of fatigue (Functional Assessment of Chronic Illness Therapy–Fatigue).

“Short-term fasting not only had a protective effect on fatigue, compared to the control group, but the short-term–fasting group didn’t develop any clinically visible fatigue,” Dr. Koppold said. “They were in a normal range by cycle four while the control group developed fatigue as we would have expected.”

Importantly, she noted, fasting had no significant impact on weight. The study excluded women who were underweight or had a history of eating disorder or relevant psychopathology.

Summing up, Dr. Koppold said that short-term fasting represents a “promising” supportive therapy during breast cancer chemotherapy to enhance quality of life.

Commenting on the study, Rebecca Guterman, a registered dietitian at Perlmutter Cancer Center at NYU Langone Health, New York, said that it’s well known that a healthy diet plays “a key role during anticancer treatments.” Dietary changes can, for instance, help alleviate common chemotherapy side effects such as loss of appetite, nausea, fatigue, or diarrhea, she said.

These new findings support fasting for 60-72 hours around chemotherapy for some patients with breast cancer who may experience more rapid recovery and better quality of life, said Ms. Guterman.

However, she noted, the results should not be applied to patient populations outside of breast cancer or treatment regimens outside this study. And, she noted, “how the patient feels during the 60-72 hour fast also has to be considered.”

An individual’s “nutritional status must be considered. If a patient has poor appetite and loses weight between treatments, fasting should not be done before next treatment,” Ms. Guterman said.

The study was funded by a private sponsor (G. Müller, Munich, Germany) and a grant from the Günter and Regine KelmFoundation (Zurich). Dr. Koppold is a member of the steering board of ÄGHE e.V. (German-speaking Medical Association for Fasting and Nutrition); cofounder of the Academy for Integrative Fasting GbR; and consults for a mobile app on intermittent fasting (Fastic) as well as a company producing plant-based supplements (EVERYYIN). Dr. Arends has disclosed relationships with Baxter. Ms. Guterman has no relevant disclosures.

A version of this article first appeared on Medscape.com.

MADRID – More than one-third of patients with locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery, findings from the Dutch SANO trial suggest.

After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.

Overall, patients who underwent active surveillance had “noninferior overall survival at 2 years,” said Berend J. Van der Wilk, PhD candidate, Erasmus University, Rotterdam, the Netherlands, who presented the findings at the annual meeting of the European Society for Medical Oncology.

Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery, Mr. Van der Wilk said.

Magnus Nilsson, MD, PhD, the invited discussant, who was not involved in the research, said performing such a conceptually important and complex trial was a “huge achievement.” However, Dr. Nilsson highlighted some “major concerns” with the trial design, which could affect the generalizability of the findings.

Avoiding surgery?

Esophagectomy remains the “keystone of curative treatment for esophageal cancer,” Mr. Van der Wilks explained. However, this operation is a “major surgical procedure” that comes with a mortality rate of up to 5%. As many as 59% of patients experience complications.

The CROSS trial, which included more than 360 patients with esophageal or esophagogastric junction cancer, found that neoadjuvant chemoradiotherapy improved survival among patients with potentially curable disease; 29% of patients achieved a pathologic complete response.

Mr. Van der Wilk said those strong outcomes create some uncertainty as to whether all patients need standard surgery after chemoradiotherapy.

In other words, Mr. Van der Wilk asked, “Should we be willing to follow an active surveillance, organ-sparing strategy for patients with a clinical response?”

An active surveillance strategy, he said, would require frequent evaluations of the patient’s clinical response. Surgery would be performed only in cases of proven residual tumor in which there were no distant metastases. The potential pitfall of an active surveillance approach is that patients may develop unresectable tumor regrowths, “possibly resulting in inferior overall survival.”

To compare active surveillance with standard surgery, the team conducted a phase 3 noninferiority stepped-wedge cluster randomized trial involving patients with locally advanced esophageal cancer.

Patients received neoadjuvant chemoradiotherapy with carboplatin and paclitaxel for 5 weeks. Concurrent radiotherapy was delivered at 41.4 Gy in 23 fractions, 5 days per week, as in the CROSS trial.

More than 300 patients who achieved a complete clinical response 12 weeks after completing chemoradiotherapy were randomly assigned to undergo standard surgery or active surveillance. Surgery was performed for those with subsequent tumor regrowth.

Overall, 198 patients underwent active surveillance, and 111 patients underwent standard surgery. The two groups were well balanced in terms of median age, sex distribution, proportion of adenocarcinomas, and World Health Organization performance scores. At the last patient assessment, on July 6, 2023, the median follow-up was 38 months.

Overall, 101 of 111 patients in the standard surgery arm and 83 of 198 (42%) in the active surveillance group had surgery. The time to surgery in the active surveillance arm was 5.9 months, compared with 0.7 months with standard surgery. For both groups, the R0 resection rate was 98%.

Mr. Van der Wilk reported no significant difference in overall survival between the active surveillance and standard surgery groups (hazard ratio for death, 1.14; 95% confidence interval, 0.74-0.78; P = .55). Overall survival in the active surveillance group was noninferior to that in the standard surgery group at 2 years. Noninferiority was defined as an overall survival difference between the two arms of less than 15%.

Mr. Van der Wilk also reported no significant difference in disease-free survival between the active surveillance and the standard surgery groups – 35 months with active surveillance, and 49 months with surgery (HR, 1.35; P = .15). At 30 months following neoadjuvant chemoradiotherapy, 43% of patients on active surveillance and 34% with standard surgery developed distant metastases, but the difference was not significant (odds ratio, 1.45; P = .18).

Among the patients in the active surveillance arm who had a complete response, 35% (n = 69) had a persistent clinical response, while 17% (33 patients) developed distant metastases, and 48% (n = 96) experienced locoregional growth. The postoperative 90-day mortality was 4% in the active surveillance group and 5% in the surgery group.

Health-related quality of life was significantly better at 6 and 9 months in the active surveillance group, Mr. Van der Wilk noted.

Although Dr. Nilsson, the invited discussant, highlighted the importance of the trial, he also expressed concern over the trial design.

The intention-to-treat analysis was contaminated, Dr. Nilsson said, because the trial design allowed for one crossover, but patients in the trial crossed over at two time points – 35 patients who were initially assigned to standard surgery crossed over to the active surveillance arm, and later, seven patients from a preSANO trial were included in the active surveillance arm.

Dr. Nilsson also expressed concern about mixing squamous cell carcinoma and adenocarcinoma histologies in the study. If the authors had distinguished patients with squamous cell carcinoma and those with adenocarcinoma in each arm, there may have a difference in overall survival, given that squamous cell carcinoma is much easier to treat.

The study also included some patients who did not have a complete clinical response and whose surgery was delayed by more than 10 weeks – a practice that, Dr. Nilsson said, “does not really seem to be safe.” A recent study led by Dr. Nilsson found that delaying surgery for 10-12 weeks in comparison with 4-6 weeks did not improve histologic complete response or other pathologic endpoints and may have led to worse survival.

“I’m afraid it’s not really certain that it’s safe to prolong surgery more than 10 weeks or longer in the clinical noncomplete responders,” said Dr. Nilsson, from the department of clinical science, intervention, and technology, Karolinska Institute, Stockholm.

Overall, he said, the study “suggests that survival may be noninferior” among patients on active surveillance in comparison with those who undergo immediate surgery, but the findings need to be confirmed in a trial with a more stringent intention-to-treat analysis that is stratified by histologic subtypes.

The study was funded by the Dutch Cancer Society and the Netherlands Organisation for Health Research and Development (ZonMw). Mr. Van der Wilk has disclosed no relevant financial relationships. Dr. Nilsson has relationships with Medtronic, Intuitive Surgical, Bristol-Myers Squibb, and Merck Sharp & Dohme, from which he received no personal financial benefit.

A version of this article first appeared on Medscape.com.

MADRID – More than one-third of patients with locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery, findings from the Dutch SANO trial suggest.

After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.

Overall, patients who underwent active surveillance had “noninferior overall survival at 2 years,” said Berend J. Van der Wilk, PhD candidate, Erasmus University, Rotterdam, the Netherlands, who presented the findings at the annual meeting of the European Society for Medical Oncology.

Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery, Mr. Van der Wilk said.

Magnus Nilsson, MD, PhD, the invited discussant, who was not involved in the research, said performing such a conceptually important and complex trial was a “huge achievement.” However, Dr. Nilsson highlighted some “major concerns” with the trial design, which could affect the generalizability of the findings.

Avoiding surgery?

Esophagectomy remains the “keystone of curative treatment for esophageal cancer,” Mr. Van der Wilks explained. However, this operation is a “major surgical procedure” that comes with a mortality rate of up to 5%. As many as 59% of patients experience complications.

The CROSS trial, which included more than 360 patients with esophageal or esophagogastric junction cancer, found that neoadjuvant chemoradiotherapy improved survival among patients with potentially curable disease; 29% of patients achieved a pathologic complete response.

Mr. Van der Wilk said those strong outcomes create some uncertainty as to whether all patients need standard surgery after chemoradiotherapy.

In other words, Mr. Van der Wilk asked, “Should we be willing to follow an active surveillance, organ-sparing strategy for patients with a clinical response?”

An active surveillance strategy, he said, would require frequent evaluations of the patient’s clinical response. Surgery would be performed only in cases of proven residual tumor in which there were no distant metastases. The potential pitfall of an active surveillance approach is that patients may develop unresectable tumor regrowths, “possibly resulting in inferior overall survival.”

To compare active surveillance with standard surgery, the team conducted a phase 3 noninferiority stepped-wedge cluster randomized trial involving patients with locally advanced esophageal cancer.

Patients received neoadjuvant chemoradiotherapy with carboplatin and paclitaxel for 5 weeks. Concurrent radiotherapy was delivered at 41.4 Gy in 23 fractions, 5 days per week, as in the CROSS trial.

More than 300 patients who achieved a complete clinical response 12 weeks after completing chemoradiotherapy were randomly assigned to undergo standard surgery or active surveillance. Surgery was performed for those with subsequent tumor regrowth.

Overall, 198 patients underwent active surveillance, and 111 patients underwent standard surgery. The two groups were well balanced in terms of median age, sex distribution, proportion of adenocarcinomas, and World Health Organization performance scores. At the last patient assessment, on July 6, 2023, the median follow-up was 38 months.

Overall, 101 of 111 patients in the standard surgery arm and 83 of 198 (42%) in the active surveillance group had surgery. The time to surgery in the active surveillance arm was 5.9 months, compared with 0.7 months with standard surgery. For both groups, the R0 resection rate was 98%.

Mr. Van der Wilk reported no significant difference in overall survival between the active surveillance and standard surgery groups (hazard ratio for death, 1.14; 95% confidence interval, 0.74-0.78; P = .55). Overall survival in the active surveillance group was noninferior to that in the standard surgery group at 2 years. Noninferiority was defined as an overall survival difference between the two arms of less than 15%.

Mr. Van der Wilk also reported no significant difference in disease-free survival between the active surveillance and the standard surgery groups – 35 months with active surveillance, and 49 months with surgery (HR, 1.35; P = .15). At 30 months following neoadjuvant chemoradiotherapy, 43% of patients on active surveillance and 34% with standard surgery developed distant metastases, but the difference was not significant (odds ratio, 1.45; P = .18).

Among the patients in the active surveillance arm who had a complete response, 35% (n = 69) had a persistent clinical response, while 17% (33 patients) developed distant metastases, and 48% (n = 96) experienced locoregional growth. The postoperative 90-day mortality was 4% in the active surveillance group and 5% in the surgery group.

Health-related quality of life was significantly better at 6 and 9 months in the active surveillance group, Mr. Van der Wilk noted.

Although Dr. Nilsson, the invited discussant, highlighted the importance of the trial, he also expressed concern over the trial design.

The intention-to-treat analysis was contaminated, Dr. Nilsson said, because the trial design allowed for one crossover, but patients in the trial crossed over at two time points – 35 patients who were initially assigned to standard surgery crossed over to the active surveillance arm, and later, seven patients from a preSANO trial were included in the active surveillance arm.

Dr. Nilsson also expressed concern about mixing squamous cell carcinoma and adenocarcinoma histologies in the study. If the authors had distinguished patients with squamous cell carcinoma and those with adenocarcinoma in each arm, there may have a difference in overall survival, given that squamous cell carcinoma is much easier to treat.

The study also included some patients who did not have a complete clinical response and whose surgery was delayed by more than 10 weeks – a practice that, Dr. Nilsson said, “does not really seem to be safe.” A recent study led by Dr. Nilsson found that delaying surgery for 10-12 weeks in comparison with 4-6 weeks did not improve histologic complete response or other pathologic endpoints and may have led to worse survival.

“I’m afraid it’s not really certain that it’s safe to prolong surgery more than 10 weeks or longer in the clinical noncomplete responders,” said Dr. Nilsson, from the department of clinical science, intervention, and technology, Karolinska Institute, Stockholm.

Overall, he said, the study “suggests that survival may be noninferior” among patients on active surveillance in comparison with those who undergo immediate surgery, but the findings need to be confirmed in a trial with a more stringent intention-to-treat analysis that is stratified by histologic subtypes.

The study was funded by the Dutch Cancer Society and the Netherlands Organisation for Health Research and Development (ZonMw). Mr. Van der Wilk has disclosed no relevant financial relationships. Dr. Nilsson has relationships with Medtronic, Intuitive Surgical, Bristol-Myers Squibb, and Merck Sharp & Dohme, from which he received no personal financial benefit.

A version of this article first appeared on Medscape.com.

MADRID – More than one-third of patients with locally advanced esophageal cancer who have a complete clinical response to neoadjuvant chemoradiotherapy may be able to safely avoid major surgery, findings from the Dutch SANO trial suggest.

After 2 years, researchers found no significant differences in overall and disease-free survival between patients on active surveillance and those who received surgery either immediately following neoadjuvant chemoradiotherapy or who switched from active surveillance to surgery.

Overall, patients who underwent active surveillance had “noninferior overall survival at 2 years,” said Berend J. Van der Wilk, PhD candidate, Erasmus University, Rotterdam, the Netherlands, who presented the findings at the annual meeting of the European Society for Medical Oncology.

Over the 2-year follow-up, at least 35% of patients on active surveillance were spared surgery. Patients on active surveillance who experienced locoregional regrowth could still undergo surgery, Mr. Van der Wilk said.

Magnus Nilsson, MD, PhD, the invited discussant, who was not involved in the research, said performing such a conceptually important and complex trial was a “huge achievement.” However, Dr. Nilsson highlighted some “major concerns” with the trial design, which could affect the generalizability of the findings.

Avoiding surgery?

Esophagectomy remains the “keystone of curative treatment for esophageal cancer,” Mr. Van der Wilks explained. However, this operation is a “major surgical procedure” that comes with a mortality rate of up to 5%. As many as 59% of patients experience complications.

The CROSS trial, which included more than 360 patients with esophageal or esophagogastric junction cancer, found that neoadjuvant chemoradiotherapy improved survival among patients with potentially curable disease; 29% of patients achieved a pathologic complete response.

Mr. Van der Wilk said those strong outcomes create some uncertainty as to whether all patients need standard surgery after chemoradiotherapy.

In other words, Mr. Van der Wilk asked, “Should we be willing to follow an active surveillance, organ-sparing strategy for patients with a clinical response?”

An active surveillance strategy, he said, would require frequent evaluations of the patient’s clinical response. Surgery would be performed only in cases of proven residual tumor in which there were no distant metastases. The potential pitfall of an active surveillance approach is that patients may develop unresectable tumor regrowths, “possibly resulting in inferior overall survival.”

To compare active surveillance with standard surgery, the team conducted a phase 3 noninferiority stepped-wedge cluster randomized trial involving patients with locally advanced esophageal cancer.

Patients received neoadjuvant chemoradiotherapy with carboplatin and paclitaxel for 5 weeks. Concurrent radiotherapy was delivered at 41.4 Gy in 23 fractions, 5 days per week, as in the CROSS trial.

More than 300 patients who achieved a complete clinical response 12 weeks after completing chemoradiotherapy were randomly assigned to undergo standard surgery or active surveillance. Surgery was performed for those with subsequent tumor regrowth.

Overall, 198 patients underwent active surveillance, and 111 patients underwent standard surgery. The two groups were well balanced in terms of median age, sex distribution, proportion of adenocarcinomas, and World Health Organization performance scores. At the last patient assessment, on July 6, 2023, the median follow-up was 38 months.

Overall, 101 of 111 patients in the standard surgery arm and 83 of 198 (42%) in the active surveillance group had surgery. The time to surgery in the active surveillance arm was 5.9 months, compared with 0.7 months with standard surgery. For both groups, the R0 resection rate was 98%.

Mr. Van der Wilk reported no significant difference in overall survival between the active surveillance and standard surgery groups (hazard ratio for death, 1.14; 95% confidence interval, 0.74-0.78; P = .55). Overall survival in the active surveillance group was noninferior to that in the standard surgery group at 2 years. Noninferiority was defined as an overall survival difference between the two arms of less than 15%.

Mr. Van der Wilk also reported no significant difference in disease-free survival between the active surveillance and the standard surgery groups – 35 months with active surveillance, and 49 months with surgery (HR, 1.35; P = .15). At 30 months following neoadjuvant chemoradiotherapy, 43% of patients on active surveillance and 34% with standard surgery developed distant metastases, but the difference was not significant (odds ratio, 1.45; P = .18).

Among the patients in the active surveillance arm who had a complete response, 35% (n = 69) had a persistent clinical response, while 17% (33 patients) developed distant metastases, and 48% (n = 96) experienced locoregional growth. The postoperative 90-day mortality was 4% in the active surveillance group and 5% in the surgery group.

Health-related quality of life was significantly better at 6 and 9 months in the active surveillance group, Mr. Van der Wilk noted.

Although Dr. Nilsson, the invited discussant, highlighted the importance of the trial, he also expressed concern over the trial design.

The intention-to-treat analysis was contaminated, Dr. Nilsson said, because the trial design allowed for one crossover, but patients in the trial crossed over at two time points – 35 patients who were initially assigned to standard surgery crossed over to the active surveillance arm, and later, seven patients from a preSANO trial were included in the active surveillance arm.

Dr. Nilsson also expressed concern about mixing squamous cell carcinoma and adenocarcinoma histologies in the study. If the authors had distinguished patients with squamous cell carcinoma and those with adenocarcinoma in each arm, there may have a difference in overall survival, given that squamous cell carcinoma is much easier to treat.

The study also included some patients who did not have a complete clinical response and whose surgery was delayed by more than 10 weeks – a practice that, Dr. Nilsson said, “does not really seem to be safe.” A recent study led by Dr. Nilsson found that delaying surgery for 10-12 weeks in comparison with 4-6 weeks did not improve histologic complete response or other pathologic endpoints and may have led to worse survival.

“I’m afraid it’s not really certain that it’s safe to prolong surgery more than 10 weeks or longer in the clinical noncomplete responders,” said Dr. Nilsson, from the department of clinical science, intervention, and technology, Karolinska Institute, Stockholm.

Overall, he said, the study “suggests that survival may be noninferior” among patients on active surveillance in comparison with those who undergo immediate surgery, but the findings need to be confirmed in a trial with a more stringent intention-to-treat analysis that is stratified by histologic subtypes.

The study was funded by the Dutch Cancer Society and the Netherlands Organisation for Health Research and Development (ZonMw). Mr. Van der Wilk has disclosed no relevant financial relationships. Dr. Nilsson has relationships with Medtronic, Intuitive Surgical, Bristol-Myers Squibb, and Merck Sharp & Dohme, from which he received no personal financial benefit.

A version of this article first appeared on Medscape.com.

MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.

Results of a planned 5-year efficacy analysis of the monarchE trial showed that at a median follow-up of 4.5 years, the abemaciclib/endocrine therapy combination was associated with a 7.6% absolute improvement in invasive disease–free survival (IDFS) and 6.7% edge in distant relapse–free survival (DRFS), compared with endocrine therapy alone, reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
 

High recurrence risk

Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.

The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.

A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.

An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.

At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.

In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.

All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
 

Results

At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).

The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).

As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).

There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.

The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.

In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
 

Changing road map

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”

To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.

In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.

To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.

“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.

Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.

The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.

MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.

Results of a planned 5-year efficacy analysis of the monarchE trial showed that at a median follow-up of 4.5 years, the abemaciclib/endocrine therapy combination was associated with a 7.6% absolute improvement in invasive disease–free survival (IDFS) and 6.7% edge in distant relapse–free survival (DRFS), compared with endocrine therapy alone, reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
 

High recurrence risk

Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.

The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.

A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.

An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.

At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.

In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.

All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
 

Results

At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).

The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).

As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).

There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.

The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.

In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
 

Changing road map

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”

To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.

In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.

To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.

“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.

Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.

The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.

MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.

Results of a planned 5-year efficacy analysis of the monarchE trial showed that at a median follow-up of 4.5 years, the abemaciclib/endocrine therapy combination was associated with a 7.6% absolute improvement in invasive disease–free survival (IDFS) and 6.7% edge in distant relapse–free survival (DRFS), compared with endocrine therapy alone, reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
 

High recurrence risk

Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.

The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.

A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.

An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.

At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.

In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.

All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
 

Results

At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).

The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).

As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).

There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.

The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.

In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
 

Changing road map

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”

To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.

In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.

To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.

“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.

Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.

The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.

The Food and Drug Administration is considering banning chemicals used in hair straightening products that have been linked to cancer.

The proposal specifies that formaldehyde would be banned, as well as other chemicals that release formaldehyde, such as methylene glycol. Using hair smoothing products containing formaldehyde and formaldehyde-releasing chemicals “is linked to short-term adverse health effects, such as sensitization reactions and breathing problems, and long-term adverse health effects, including an increased risk of certain cancers,” the proposal states.

One study published last year showed that repeated use of hair straightening products, also called relaxers, could more than double the risk of uterine cancer. Although that study didn’t find that the uterine cancer risk varied based on a person’s race, the researchers noted that women who are Black are among the most likely to use the products and tend to start using them at younger ages, compared with people of other races and ethnicities.

Hair straightening products have also been linked to elevated risks of hormone-sensitive cancers, such as breast cancer and ovarian cancer.

Rep. Ayanna Pressley (D-Mass.) and Rep. Shontel Brown (D-Ohio) applauded the proposed rule in a statement issued jointly on Oct. 6. “The FDA’s proposal to ban these harmful chemicals in hair straighteners and relaxers is a win for public health – especially the health of Black women who are disproportionately put at risk by these products as a result of systemic racism and anti–Black hair sentiment,” Rep. Pressley said The two congresswomen wrote a letter to the FDA earlier this year requesting the topic be investigated.

“Regardless of how we wear our hair, we should be allowed to show up in the world without putting our health at risk. I applaud the FDA for being responsive to our calls and advancing a rule that will help prevent manufacturers from making a profit at the expense of our health,” Rep. Pressley said in the statement. “The administration should finalize this rule without delay.”



A version of this article appeared on WebMD.com

The Food and Drug Administration is considering banning chemicals used in hair straightening products that have been linked to cancer.

The proposal specifies that formaldehyde would be banned, as well as other chemicals that release formaldehyde, such as methylene glycol. Using hair smoothing products containing formaldehyde and formaldehyde-releasing chemicals “is linked to short-term adverse health effects, such as sensitization reactions and breathing problems, and long-term adverse health effects, including an increased risk of certain cancers,” the proposal states.

One study published last year showed that repeated use of hair straightening products, also called relaxers, could more than double the risk of uterine cancer. Although that study didn’t find that the uterine cancer risk varied based on a person’s race, the researchers noted that women who are Black are among the most likely to use the products and tend to start using them at younger ages, compared with people of other races and ethnicities.

Hair straightening products have also been linked to elevated risks of hormone-sensitive cancers, such as breast cancer and ovarian cancer.

Rep. Ayanna Pressley (D-Mass.) and Rep. Shontel Brown (D-Ohio) applauded the proposed rule in a statement issued jointly on Oct. 6. “The FDA’s proposal to ban these harmful chemicals in hair straighteners and relaxers is a win for public health – especially the health of Black women who are disproportionately put at risk by these products as a result of systemic racism and anti–Black hair sentiment,” Rep. Pressley said The two congresswomen wrote a letter to the FDA earlier this year requesting the topic be investigated.

“Regardless of how we wear our hair, we should be allowed to show up in the world without putting our health at risk. I applaud the FDA for being responsive to our calls and advancing a rule that will help prevent manufacturers from making a profit at the expense of our health,” Rep. Pressley said in the statement. “The administration should finalize this rule without delay.”



A version of this article appeared on WebMD.com

The Food and Drug Administration is considering banning chemicals used in hair straightening products that have been linked to cancer.

The proposal specifies that formaldehyde would be banned, as well as other chemicals that release formaldehyde, such as methylene glycol. Using hair smoothing products containing formaldehyde and formaldehyde-releasing chemicals “is linked to short-term adverse health effects, such as sensitization reactions and breathing problems, and long-term adverse health effects, including an increased risk of certain cancers,” the proposal states.

One study published last year showed that repeated use of hair straightening products, also called relaxers, could more than double the risk of uterine cancer. Although that study didn’t find that the uterine cancer risk varied based on a person’s race, the researchers noted that women who are Black are among the most likely to use the products and tend to start using them at younger ages, compared with people of other races and ethnicities.

Hair straightening products have also been linked to elevated risks of hormone-sensitive cancers, such as breast cancer and ovarian cancer.

Rep. Ayanna Pressley (D-Mass.) and Rep. Shontel Brown (D-Ohio) applauded the proposed rule in a statement issued jointly on Oct. 6. “The FDA’s proposal to ban these harmful chemicals in hair straighteners and relaxers is a win for public health – especially the health of Black women who are disproportionately put at risk by these products as a result of systemic racism and anti–Black hair sentiment,” Rep. Pressley said The two congresswomen wrote a letter to the FDA earlier this year requesting the topic be investigated.

“Regardless of how we wear our hair, we should be allowed to show up in the world without putting our health at risk. I applaud the FDA for being responsive to our calls and advancing a rule that will help prevent manufacturers from making a profit at the expense of our health,” Rep. Pressley said in the statement. “The administration should finalize this rule without delay.”



A version of this article appeared on WebMD.com

TOPLINE:

Climbing more than five flights of stairs daily is associated with a reduced risk of atherosclerotic cardiovascular disease (ASCVD) of about 20%, new observational data suggest.

METHODOLOGY:

• The prospective cohort study used data from 458,860 adults in the UK Biobank cohort who were 38-73 years old at baseline (2006-2010).
• Information about stair climbing, sociodemographic, and lifestyle factors was collected at baseline and 5 years later.
• Cases of ASCVD – defined as coronary artery disease (CAD), ischemic stroke, or acute complications – were identified via hospital records and death registry.
• Associations between stair climbing and ASCVD were examined as hazard ratios from Cox proportional hazards model. Analyses were stratified by susceptibility to ASCVD based on family history, genetic risk, and established risk factors.

TAKEAWAY:

• A total of 39,043 ASCVD, 30,718 CAD, and 10,521 ischemic stroke cases were recorded during a median follow-up of 12.5 years.
• Compared with no-stair climbing, climbing 6-10 flights of stairs daily was associated with a 7% lower ASCVD risk (multivariable-adjusted HR, 0.93; 95% confidence interval, 0.90-0.96) and climbing 16-20 flights daily was associated with a 10% lower risk (HR, 0.90; 95% CI, 0.85-0.94).
• The benefits plateaued at 20 flights daily; comparable results were obtained for CAD and ischemic stroke; the protective effect of stair climbing was attenuated by increasing levels of disease susceptibility.
• Adults who stopped climbing stairs daily during the study had a 32% higher risk of ASCVD (HR, 1.32; 95% CI,1.06-1.65), compared with peers who never reported stair climbing.

IN PRACTICE:

“These findings highlight the potential advantages of stair climbing as a primary preventive measure for ASCVD in the general population. Short bursts of high-intensity stair climbing are a time-efficient way to improve cardiorespiratory fitness and lipid profile, especially among those unable to achieve the current physical activity recommendations,” study author Lu Qi, with Tulane University, New Orleans, said in a news release.

SOURCE:

The study was published online in Atherosclerosis.

LIMITATIONS:

The observational design limits causal inferences. Stair climbing was self-reported via questionnaires and recall bias is a possibility. The UK Biobank participants do not represent the entire population of the country, with a healthy volunteer selection bias previously reported.

DISCLOSURES:

The study was supported by grants from the National Key R&D Program of China. The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Climbing more than five flights of stairs daily is associated with a reduced risk of atherosclerotic cardiovascular disease (ASCVD) of about 20%, new observational data suggest.

METHODOLOGY:

• The prospective cohort study used data from 458,860 adults in the UK Biobank cohort who were 38-73 years old at baseline (2006-2010).
• Information about stair climbing, sociodemographic, and lifestyle factors was collected at baseline and 5 years later.
• Cases of ASCVD – defined as coronary artery disease (CAD), ischemic stroke, or acute complications – were identified via hospital records and death registry.
• Associations between stair climbing and ASCVD were examined as hazard ratios from Cox proportional hazards model. Analyses were stratified by susceptibility to ASCVD based on family history, genetic risk, and established risk factors.

TAKEAWAY:

• A total of 39,043 ASCVD, 30,718 CAD, and 10,521 ischemic stroke cases were recorded during a median follow-up of 12.5 years.
• Compared with no-stair climbing, climbing 6-10 flights of stairs daily was associated with a 7% lower ASCVD risk (multivariable-adjusted HR, 0.93; 95% confidence interval, 0.90-0.96) and climbing 16-20 flights daily was associated with a 10% lower risk (HR, 0.90; 95% CI, 0.85-0.94).
• The benefits plateaued at 20 flights daily; comparable results were obtained for CAD and ischemic stroke; the protective effect of stair climbing was attenuated by increasing levels of disease susceptibility.
• Adults who stopped climbing stairs daily during the study had a 32% higher risk of ASCVD (HR, 1.32; 95% CI,1.06-1.65), compared with peers who never reported stair climbing.

IN PRACTICE:

“These findings highlight the potential advantages of stair climbing as a primary preventive measure for ASCVD in the general population. Short bursts of high-intensity stair climbing are a time-efficient way to improve cardiorespiratory fitness and lipid profile, especially among those unable to achieve the current physical activity recommendations,” study author Lu Qi, with Tulane University, New Orleans, said in a news release.

SOURCE:

The study was published online in Atherosclerosis.

LIMITATIONS:

The observational design limits causal inferences. Stair climbing was self-reported via questionnaires and recall bias is a possibility. The UK Biobank participants do not represent the entire population of the country, with a healthy volunteer selection bias previously reported.

DISCLOSURES:

The study was supported by grants from the National Key R&D Program of China. The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

Climbing more than five flights of stairs daily is associated with a reduced risk of atherosclerotic cardiovascular disease (ASCVD) of about 20%, new observational data suggest.

METHODOLOGY:

• The prospective cohort study used data from 458,860 adults in the UK Biobank cohort who were 38-73 years old at baseline (2006-2010).
• Information about stair climbing, sociodemographic, and lifestyle factors was collected at baseline and 5 years later.
• Cases of ASCVD – defined as coronary artery disease (CAD), ischemic stroke, or acute complications – were identified via hospital records and death registry.
• Associations between stair climbing and ASCVD were examined as hazard ratios from Cox proportional hazards model. Analyses were stratified by susceptibility to ASCVD based on family history, genetic risk, and established risk factors.

TAKEAWAY:

• A total of 39,043 ASCVD, 30,718 CAD, and 10,521 ischemic stroke cases were recorded during a median follow-up of 12.5 years.
• Compared with no-stair climbing, climbing 6-10 flights of stairs daily was associated with a 7% lower ASCVD risk (multivariable-adjusted HR, 0.93; 95% confidence interval, 0.90-0.96) and climbing 16-20 flights daily was associated with a 10% lower risk (HR, 0.90; 95% CI, 0.85-0.94).
• The benefits plateaued at 20 flights daily; comparable results were obtained for CAD and ischemic stroke; the protective effect of stair climbing was attenuated by increasing levels of disease susceptibility.
• Adults who stopped climbing stairs daily during the study had a 32% higher risk of ASCVD (HR, 1.32; 95% CI,1.06-1.65), compared with peers who never reported stair climbing.

IN PRACTICE:

“These findings highlight the potential advantages of stair climbing as a primary preventive measure for ASCVD in the general population. Short bursts of high-intensity stair climbing are a time-efficient way to improve cardiorespiratory fitness and lipid profile, especially among those unable to achieve the current physical activity recommendations,” study author Lu Qi, with Tulane University, New Orleans, said in a news release.

SOURCE:

The study was published online in Atherosclerosis.

LIMITATIONS:

The observational design limits causal inferences. Stair climbing was self-reported via questionnaires and recall bias is a possibility. The UK Biobank participants do not represent the entire population of the country, with a healthy volunteer selection bias previously reported.

DISCLOSURES:

The study was supported by grants from the National Key R&D Program of China. The authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.