Breast Cancer

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The Clinical Treatment Score post 5 years (CTS5) has been validated for the prediction of late distant recurrences in a large contemporary cohort of breast cancer patients drawn from the landmark TAILORx study – but only provided they’re over age 50 at the time of their initial breast cancer diagnosis, Ivana Sestak, PhD, reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

“The CTS5 was much less prognostic in younger patients, and we did not observe good discrimination for the CTS5 in this cohort,” she said. “Further evaluation in premenopausal cohorts is needed before CTS5 can be applied to younger patients.”

She and her coworkers developed the CTS5 as a simple, expeditious tool to identify women at high risk of late distance recurrence of estrogen receptor–positive breast cancer after successfully completing 5 years of endocrine therapy. It’s designed to serve as an aid to physicians and patients in clinical decision making: Women who are CTS5 high risk are likely to benefit from extended endocrine therapy beyond the 5-year mark, while those at low risk are not.

“Trials so far have shown only a modest risk reduction of around 5% with extended endocrine therapy. This may be partly due to the fact that none of these trials had specifically selected patients who were at high risk of developing a late recurrence. It is therefore crucial that we identify those patients who are at high risk of late recurrence, as they will benefit most from extended endocrine therapy,” explained Dr. Sestak, a medical statistician at Queen Mary University, London.

The CTS5 calculator is freely available online at www.cts5-calculator.com. Clinicians simply plug in readily available information on four specific variables for their patients who have completed 5 years of endocrine therapy free of distant recurrence: age at breast cancer diagnosis, tumor size in millimeters, tumor grade, and number of involved nodes. The calculator promptly spits out a CTS5 score and the associated risk of distant recurrence during years 5-10 after initial diagnosis. That risk is categorized as low if it’s 5% or less in years 5-10, and high if it’s greater than 10%.

The CTS5 was developed and validated using long-term follow-up data on more than 11,000 postmenopausal breast cancer patients in the ATAC and BIG1-98 randomized trials. The CTS5 performed well in those tests. But those studies were completed more than a decade ago and were limited to postmenopausal patients. Dr. Sestak and coinvestigators wanted to assess the tool’s discriminatory powers in a contemporary population of breast cancer patients that included large numbers of premenopausal women. So they tapped into the National Cancer Institute–sponsored TAILORx study, which included 7,353 breast cancer patients who were distant recurrence free after 5 years. All had early-stage, hormone receptor–positive, HER2-negative, and axillary node–negative breast cancer. And all underwent baseline testing using Genomic Health’s Oncotype DX Breast Recurrence Score to assess expression of 21 genes associated with breast cancer recurrence.

The CTS5 proved to be highly prognostic in the overall TAILORx population. But upon drilling down further, Dr. Sestak and coworkers determined that CTS5 had only marginal prognostic value in the 2,259 women age 50 years or younger. Indeed, not a single patient in that age group was categorized as CTS5 high risk, and the actual distant recurrence rates during years 5-9 weren’t significantly different between the low- and intermediate-risk CTS5 groups.

In contrast, CTS5 performed well as a prognosticator in the 2,257 TAILORx participants over age 50 who received both chemotherapy and endocrine therapy during their first 5 years following diagnosis. For a fast and simple test with zero cost, it displayed impressive discriminatory power: The 63.8% of women classified as CTS5 low risk had a 2.6% distant recurrence rate – and thus constituted a group who could reasonably avoid extended endocrine therapy – while the 3.5% who were CTS5 high risk had a 9.5% event rate, and the intermediate-risk group had a 7.3% event rate. The prognostic power of CTS5 in the 2,837 women aged over 50 years who received only hormonal therapy was less robust, albeit still statistically significant.

In women classified as being at low risk of recurrence based upon an Oncotype DX score of 0-10, the CTS5 was not a significant prognosticator for the prediction of late distant recurrences. However, in those who were at intermediate or high risk as determined by a score of 11-100 on the Oncotype test, CTS5 was highly prognostic.

A significant limitation of this CTS5 validation study in the TAILORx population was that only a median 2.86 years of follow-up data after the 5-year mark was available – not sufficient time for a large number of distant recurrences. The rate was 3.1% in women treated with only endocrine therapy who had an Oncotype DX score of 0-25, and 3.8% in those with a score of 11-100 who received both chemotherapy and endocrine therapy.

Dr. Sestak shrugged off the less than stellar performance of the CTS5 in women aged age 50 years or younger in the TAILORx analysis.

“We developed the CTS5 specifically in postmenopausal women, so we’re not really surprised that it’s less prognostic in young women,” she said.

Her group next plans to evaluate the CTS5 in another large premenopausal cohort of breast cancer patients.

“If it’s not prognostic there, then we’ll have to adjust the algorithm and recalibrate it specifically for younger patients,” according to Dr. Sestak.

The TAILORx validation study was supported by Breast Cancer Now, Cancer Research UK, Exact Sciences, and the University of London. Dr. Sestak reported having received honoraria from Myriad Genetics, Nanostring Technology, and Pfizer Oncology.

SOURCE: Sestak I et al. SABCS 2019, Abstract GS4-03.

SAN ANTONIO – The Clinical Treatment Score post 5 years (CTS5) has been validated for the prediction of late distant recurrences in a large contemporary cohort of breast cancer patients drawn from the landmark TAILORx study – but only provided they’re over age 50 at the time of their initial breast cancer diagnosis, Ivana Sestak, PhD, reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

“The CTS5 was much less prognostic in younger patients, and we did not observe good discrimination for the CTS5 in this cohort,” she said. “Further evaluation in premenopausal cohorts is needed before CTS5 can be applied to younger patients.”

She and her coworkers developed the CTS5 as a simple, expeditious tool to identify women at high risk of late distance recurrence of estrogen receptor–positive breast cancer after successfully completing 5 years of endocrine therapy. It’s designed to serve as an aid to physicians and patients in clinical decision making: Women who are CTS5 high risk are likely to benefit from extended endocrine therapy beyond the 5-year mark, while those at low risk are not.

“Trials so far have shown only a modest risk reduction of around 5% with extended endocrine therapy. This may be partly due to the fact that none of these trials had specifically selected patients who were at high risk of developing a late recurrence. It is therefore crucial that we identify those patients who are at high risk of late recurrence, as they will benefit most from extended endocrine therapy,” explained Dr. Sestak, a medical statistician at Queen Mary University, London.

The CTS5 calculator is freely available online at www.cts5-calculator.com. Clinicians simply plug in readily available information on four specific variables for their patients who have completed 5 years of endocrine therapy free of distant recurrence: age at breast cancer diagnosis, tumor size in millimeters, tumor grade, and number of involved nodes. The calculator promptly spits out a CTS5 score and the associated risk of distant recurrence during years 5-10 after initial diagnosis. That risk is categorized as low if it’s 5% or less in years 5-10, and high if it’s greater than 10%.

The CTS5 was developed and validated using long-term follow-up data on more than 11,000 postmenopausal breast cancer patients in the ATAC and BIG1-98 randomized trials. The CTS5 performed well in those tests. But those studies were completed more than a decade ago and were limited to postmenopausal patients. Dr. Sestak and coinvestigators wanted to assess the tool’s discriminatory powers in a contemporary population of breast cancer patients that included large numbers of premenopausal women. So they tapped into the National Cancer Institute–sponsored TAILORx study, which included 7,353 breast cancer patients who were distant recurrence free after 5 years. All had early-stage, hormone receptor–positive, HER2-negative, and axillary node–negative breast cancer. And all underwent baseline testing using Genomic Health’s Oncotype DX Breast Recurrence Score to assess expression of 21 genes associated with breast cancer recurrence.

The CTS5 proved to be highly prognostic in the overall TAILORx population. But upon drilling down further, Dr. Sestak and coworkers determined that CTS5 had only marginal prognostic value in the 2,259 women age 50 years or younger. Indeed, not a single patient in that age group was categorized as CTS5 high risk, and the actual distant recurrence rates during years 5-9 weren’t significantly different between the low- and intermediate-risk CTS5 groups.

In contrast, CTS5 performed well as a prognosticator in the 2,257 TAILORx participants over age 50 who received both chemotherapy and endocrine therapy during their first 5 years following diagnosis. For a fast and simple test with zero cost, it displayed impressive discriminatory power: The 63.8% of women classified as CTS5 low risk had a 2.6% distant recurrence rate – and thus constituted a group who could reasonably avoid extended endocrine therapy – while the 3.5% who were CTS5 high risk had a 9.5% event rate, and the intermediate-risk group had a 7.3% event rate. The prognostic power of CTS5 in the 2,837 women aged over 50 years who received only hormonal therapy was less robust, albeit still statistically significant.

In women classified as being at low risk of recurrence based upon an Oncotype DX score of 0-10, the CTS5 was not a significant prognosticator for the prediction of late distant recurrences. However, in those who were at intermediate or high risk as determined by a score of 11-100 on the Oncotype test, CTS5 was highly prognostic.

A significant limitation of this CTS5 validation study in the TAILORx population was that only a median 2.86 years of follow-up data after the 5-year mark was available – not sufficient time for a large number of distant recurrences. The rate was 3.1% in women treated with only endocrine therapy who had an Oncotype DX score of 0-25, and 3.8% in those with a score of 11-100 who received both chemotherapy and endocrine therapy.

Dr. Sestak shrugged off the less than stellar performance of the CTS5 in women aged age 50 years or younger in the TAILORx analysis.

“We developed the CTS5 specifically in postmenopausal women, so we’re not really surprised that it’s less prognostic in young women,” she said.

Her group next plans to evaluate the CTS5 in another large premenopausal cohort of breast cancer patients.

“If it’s not prognostic there, then we’ll have to adjust the algorithm and recalibrate it specifically for younger patients,” according to Dr. Sestak.

The TAILORx validation study was supported by Breast Cancer Now, Cancer Research UK, Exact Sciences, and the University of London. Dr. Sestak reported having received honoraria from Myriad Genetics, Nanostring Technology, and Pfizer Oncology.

SOURCE: Sestak I et al. SABCS 2019, Abstract GS4-03.

SAN ANTONIO – The Clinical Treatment Score post 5 years (CTS5) has been validated for the prediction of late distant recurrences in a large contemporary cohort of breast cancer patients drawn from the landmark TAILORx study – but only provided they’re over age 50 at the time of their initial breast cancer diagnosis, Ivana Sestak, PhD, reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

“The CTS5 was much less prognostic in younger patients, and we did not observe good discrimination for the CTS5 in this cohort,” she said. “Further evaluation in premenopausal cohorts is needed before CTS5 can be applied to younger patients.”

She and her coworkers developed the CTS5 as a simple, expeditious tool to identify women at high risk of late distance recurrence of estrogen receptor–positive breast cancer after successfully completing 5 years of endocrine therapy. It’s designed to serve as an aid to physicians and patients in clinical decision making: Women who are CTS5 high risk are likely to benefit from extended endocrine therapy beyond the 5-year mark, while those at low risk are not.

“Trials so far have shown only a modest risk reduction of around 5% with extended endocrine therapy. This may be partly due to the fact that none of these trials had specifically selected patients who were at high risk of developing a late recurrence. It is therefore crucial that we identify those patients who are at high risk of late recurrence, as they will benefit most from extended endocrine therapy,” explained Dr. Sestak, a medical statistician at Queen Mary University, London.

The CTS5 calculator is freely available online at www.cts5-calculator.com. Clinicians simply plug in readily available information on four specific variables for their patients who have completed 5 years of endocrine therapy free of distant recurrence: age at breast cancer diagnosis, tumor size in millimeters, tumor grade, and number of involved nodes. The calculator promptly spits out a CTS5 score and the associated risk of distant recurrence during years 5-10 after initial diagnosis. That risk is categorized as low if it’s 5% or less in years 5-10, and high if it’s greater than 10%.

The CTS5 was developed and validated using long-term follow-up data on more than 11,000 postmenopausal breast cancer patients in the ATAC and BIG1-98 randomized trials. The CTS5 performed well in those tests. But those studies were completed more than a decade ago and were limited to postmenopausal patients. Dr. Sestak and coinvestigators wanted to assess the tool’s discriminatory powers in a contemporary population of breast cancer patients that included large numbers of premenopausal women. So they tapped into the National Cancer Institute–sponsored TAILORx study, which included 7,353 breast cancer patients who were distant recurrence free after 5 years. All had early-stage, hormone receptor–positive, HER2-negative, and axillary node–negative breast cancer. And all underwent baseline testing using Genomic Health’s Oncotype DX Breast Recurrence Score to assess expression of 21 genes associated with breast cancer recurrence.

The CTS5 proved to be highly prognostic in the overall TAILORx population. But upon drilling down further, Dr. Sestak and coworkers determined that CTS5 had only marginal prognostic value in the 2,259 women age 50 years or younger. Indeed, not a single patient in that age group was categorized as CTS5 high risk, and the actual distant recurrence rates during years 5-9 weren’t significantly different between the low- and intermediate-risk CTS5 groups.

In contrast, CTS5 performed well as a prognosticator in the 2,257 TAILORx participants over age 50 who received both chemotherapy and endocrine therapy during their first 5 years following diagnosis. For a fast and simple test with zero cost, it displayed impressive discriminatory power: The 63.8% of women classified as CTS5 low risk had a 2.6% distant recurrence rate – and thus constituted a group who could reasonably avoid extended endocrine therapy – while the 3.5% who were CTS5 high risk had a 9.5% event rate, and the intermediate-risk group had a 7.3% event rate. The prognostic power of CTS5 in the 2,837 women aged over 50 years who received only hormonal therapy was less robust, albeit still statistically significant.

In women classified as being at low risk of recurrence based upon an Oncotype DX score of 0-10, the CTS5 was not a significant prognosticator for the prediction of late distant recurrences. However, in those who were at intermediate or high risk as determined by a score of 11-100 on the Oncotype test, CTS5 was highly prognostic.

A significant limitation of this CTS5 validation study in the TAILORx population was that only a median 2.86 years of follow-up data after the 5-year mark was available – not sufficient time for a large number of distant recurrences. The rate was 3.1% in women treated with only endocrine therapy who had an Oncotype DX score of 0-25, and 3.8% in those with a score of 11-100 who received both chemotherapy and endocrine therapy.

Dr. Sestak shrugged off the less than stellar performance of the CTS5 in women aged age 50 years or younger in the TAILORx analysis.

“We developed the CTS5 specifically in postmenopausal women, so we’re not really surprised that it’s less prognostic in young women,” she said.

Her group next plans to evaluate the CTS5 in another large premenopausal cohort of breast cancer patients.

“If it’s not prognostic there, then we’ll have to adjust the algorithm and recalibrate it specifically for younger patients,” according to Dr. Sestak.

The TAILORx validation study was supported by Breast Cancer Now, Cancer Research UK, Exact Sciences, and the University of London. Dr. Sestak reported having received honoraria from Myriad Genetics, Nanostring Technology, and Pfizer Oncology.

SOURCE: Sestak I et al. SABCS 2019, Abstract GS4-03.

SAN ANTONIO – Residual cancer burden (RCB) is poised to alter American Joint Committee on Cancer (AJCC) staging standards in breast cancer, according to investigators.

Will Pass/MDedge News

A meta-analysis showed that RCB – which is calculated in the neoadjuvant setting through a combination of primary tumor bed cellularity, lymph node positivity, and size of largest metastasis – was significantly associated with long-term survival of more than 5,000 breast cancer patients, reported principal investigator W. Fraser Symmans, MD, of MD Anderson Cancer Center, Houston, who presented the findings at the San Antonio Breast Cancer Symposium.

Will Pass/MDedge News

Coinvestigator Laura J. Esserman, MD, of the University of California, San Francisco, who was in attendance at Dr. Symmans’ presentation, put the study in context.

“The reason we did this meta-analysis was to really change the joint commission – the AJCC staging – and we expect that will happen on the basis of these results,” Dr. Esserman said. “[RBC] is, moving forward, the standard of care.”

The investigators analyzed individual-level data from 5,160 patients treated at multiple institutions. For each patient, RCB, which is scored from 0 to III, from pathologic complete response (0) to high disease burden (III), was compared with event-free survival (EFS) and disease relapse-free survival (DRFS).

Will Pass/MDedge News

“I ask my pathologist to give me the RCB score,” Dr. Kaklamani said. “The question is, what do I do with the results? It’s a little limited. In triple-negative patients I may consider giving capecitabine in the adjuvant setting, or obviously enrolling them in clinical trials. In my HER2-positive patients, I will look at the results from the KATHERINE trial and the ExteNET trial to guide me. In my HR-positive patients, I’m still waiting for results from other trials to see how these results can be interpreted. What we’ve [found] is in many trials, achieving a pathologic complete response in HR-positive patients may not be as important, but as you can see here, it looks like RCB really is.”

The investigators disclosed relationships with Seattle Genetics, Almac, Syndax, and others.
 

SOURCE: Yau et al. SABCS. 2019 Dec 13. Abstract GS5-01.

SAN ANTONIO – Residual cancer burden (RCB) is poised to alter American Joint Committee on Cancer (AJCC) staging standards in breast cancer, according to investigators.

Will Pass/MDedge News

A meta-analysis showed that RCB – which is calculated in the neoadjuvant setting through a combination of primary tumor bed cellularity, lymph node positivity, and size of largest metastasis – was significantly associated with long-term survival of more than 5,000 breast cancer patients, reported principal investigator W. Fraser Symmans, MD, of MD Anderson Cancer Center, Houston, who presented the findings at the San Antonio Breast Cancer Symposium.

Will Pass/MDedge News

Coinvestigator Laura J. Esserman, MD, of the University of California, San Francisco, who was in attendance at Dr. Symmans’ presentation, put the study in context.

“The reason we did this meta-analysis was to really change the joint commission – the AJCC staging – and we expect that will happen on the basis of these results,” Dr. Esserman said. “[RBC] is, moving forward, the standard of care.”

The investigators analyzed individual-level data from 5,160 patients treated at multiple institutions. For each patient, RCB, which is scored from 0 to III, from pathologic complete response (0) to high disease burden (III), was compared with event-free survival (EFS) and disease relapse-free survival (DRFS).

Will Pass/MDedge News

“I ask my pathologist to give me the RCB score,” Dr. Kaklamani said. “The question is, what do I do with the results? It’s a little limited. In triple-negative patients I may consider giving capecitabine in the adjuvant setting, or obviously enrolling them in clinical trials. In my HER2-positive patients, I will look at the results from the KATHERINE trial and the ExteNET trial to guide me. In my HR-positive patients, I’m still waiting for results from other trials to see how these results can be interpreted. What we’ve [found] is in many trials, achieving a pathologic complete response in HR-positive patients may not be as important, but as you can see here, it looks like RCB really is.”

The investigators disclosed relationships with Seattle Genetics, Almac, Syndax, and others.
 

SOURCE: Yau et al. SABCS. 2019 Dec 13. Abstract GS5-01.

SAN ANTONIO – Residual cancer burden (RCB) is poised to alter American Joint Committee on Cancer (AJCC) staging standards in breast cancer, according to investigators.

Will Pass/MDedge News

A meta-analysis showed that RCB – which is calculated in the neoadjuvant setting through a combination of primary tumor bed cellularity, lymph node positivity, and size of largest metastasis – was significantly associated with long-term survival of more than 5,000 breast cancer patients, reported principal investigator W. Fraser Symmans, MD, of MD Anderson Cancer Center, Houston, who presented the findings at the San Antonio Breast Cancer Symposium.

Will Pass/MDedge News

Coinvestigator Laura J. Esserman, MD, of the University of California, San Francisco, who was in attendance at Dr. Symmans’ presentation, put the study in context.

“The reason we did this meta-analysis was to really change the joint commission – the AJCC staging – and we expect that will happen on the basis of these results,” Dr. Esserman said. “[RBC] is, moving forward, the standard of care.”

The investigators analyzed individual-level data from 5,160 patients treated at multiple institutions. For each patient, RCB, which is scored from 0 to III, from pathologic complete response (0) to high disease burden (III), was compared with event-free survival (EFS) and disease relapse-free survival (DRFS).

Will Pass/MDedge News

“I ask my pathologist to give me the RCB score,” Dr. Kaklamani said. “The question is, what do I do with the results? It’s a little limited. In triple-negative patients I may consider giving capecitabine in the adjuvant setting, or obviously enrolling them in clinical trials. In my HER2-positive patients, I will look at the results from the KATHERINE trial and the ExteNET trial to guide me. In my HR-positive patients, I’m still waiting for results from other trials to see how these results can be interpreted. What we’ve [found] is in many trials, achieving a pathologic complete response in HR-positive patients may not be as important, but as you can see here, it looks like RCB really is.”

The investigators disclosed relationships with Seattle Genetics, Almac, Syndax, and others.
 

SOURCE: Yau et al. SABCS. 2019 Dec 13. Abstract GS5-01.

SAN ANTONIO – For patients with early triple-negative breast cancer (TNBC), adding capecitabine to standard adjuvant chemotherapy may extend disease-free survival (DFS), based results of a phase 3 trial conducted in China.

Will Pass/MDedge News

Although capecitabine boosted DFS by approximately 6%, overall survival remained unchanged, reported lead author Junjie Li, MD, of Fudan University in Shanghai, China.

In a presentation at the San Antonio Breast Cancer Symposium, Dr. Li explained that these findings provide much-needed support for the concomitant use of capecitabine in breast cancer.

“Capecitabine has been proven [effective] in advanced breast cancer, while in earlier stage disease, available data are still inconsistent,” Dr. Li said.

To help resolve some of this uncertainty, Dr. Li and colleagues conducted an open-label, phase 3 trial involving 585 patients with TNBC who were either node positive or negative and had tumors more than 1 cm in diameter. Patients were randomized in a 1:1 ratio to receive either standard therapy with three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil; or three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine.

After a median follow-up of 67 months, 288 patients had received the capecitabine regimen and 273 had undergone standard therapy. The 5-year DFS was significantly longer in the capecitabine group, at 86.26%, than the control group, at 80.23% (hazard ratio, 0.66; P = .038). This benefit extended across subgroups, Dr. Li noted. While a slight numerical difference in overall survival was seen between capecitabine and control arms, this was not statistically significant (93.27% vs. 90.55%).

The investigators described safety profiles between treatment arms as “generally comparable.” In the capecitabine group, more than one-third of patients (38.89%) had dose reductions, while 8.42% reported grade 3-4 hand-foot syndrome. Grade 3-4 toxicities were more common in the capecitabine group, including neutropenia (45.79% vs. 41.32%) and febrile neutropenia (16.5% vs. 15.97%).

“Capecitabine concomitant use with docetaxel and epirubicin may significantly improve disease-free survival in early triple-negative patients,” Dr. Li concluded. He suggested that the study regimen be viewed as an alternative adjuvant regimen, as it provided clinically meaningful improvements in survival while maintaining tolerability.

Conference attendee Mohamed El-Naghy, MD, PhD, a practicing oncologist in Oneida, N.Y., expressed concern for one aspect of the trial methodology during the question and answer session following Dr. Li’s presentation: Although all patients in the trial were considered triple negative, 10 patients had estrogen receptor/progesterone receptor (ER/PR) expression ranging from 1 to 9%, which conflicts with the definition of TNBCr provided by current guidelines, according to Dr. Li.

“It is always important to have common language,” Dr. El-Naghy said. “And if you define [TNBC by] ER/PR negativity, and still you have 10% [expression], that is unacceptable. The whole point is, I looked at your numbers – 10 patients in the whole study – maybe you say they are triple negative, but these [patients] are contamination to your sample.”

Responding to this comment, Dr. Li said that the data from these patients had a minimal impact on the study results.

“We did another analysis to exclude these 10 patients, but still the result is quite similar, because they are just 10 patients – 5 in each group,” Dr. Li said.

Will Pass/MDedge News

Invited discussant Priyanka Sharma, MD, of the University of Kansas Medical Center, Kansas City, offered some additional viewpoints on the trial.

“A large proportion of patients had non–grade III disease, and one could say that the dose of docetaxel monotherapy in the control arm was not the traditional 100 mg/m², and that could have negatively impacted the outcomes in the control arm,” Dr. Sharma said. “In addition, the trial is representative of patients only from China, and whether these findings would hold true in other ethnic and racial groups is not known. Furthermore, there seemed to be limited efficacy in patients with N0 disease, which comprised two-thirds of the trial.”

Despite these potential limitations, based on the trial results and other evidence, Dr. Sharma suggested that adding capecitabine to standard systemic therapy may be considered a viable option for patients with early TNBC.

The investigators reported no disclosures.

SOURCE: Li J et al. SABCS 2019, Abstract GS1-08.

SAN ANTONIO – For patients with early triple-negative breast cancer (TNBC), adding capecitabine to standard adjuvant chemotherapy may extend disease-free survival (DFS), based results of a phase 3 trial conducted in China.

Will Pass/MDedge News

Although capecitabine boosted DFS by approximately 6%, overall survival remained unchanged, reported lead author Junjie Li, MD, of Fudan University in Shanghai, China.

In a presentation at the San Antonio Breast Cancer Symposium, Dr. Li explained that these findings provide much-needed support for the concomitant use of capecitabine in breast cancer.

“Capecitabine has been proven [effective] in advanced breast cancer, while in earlier stage disease, available data are still inconsistent,” Dr. Li said.

To help resolve some of this uncertainty, Dr. Li and colleagues conducted an open-label, phase 3 trial involving 585 patients with TNBC who were either node positive or negative and had tumors more than 1 cm in diameter. Patients were randomized in a 1:1 ratio to receive either standard therapy with three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil; or three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine.

After a median follow-up of 67 months, 288 patients had received the capecitabine regimen and 273 had undergone standard therapy. The 5-year DFS was significantly longer in the capecitabine group, at 86.26%, than the control group, at 80.23% (hazard ratio, 0.66; P = .038). This benefit extended across subgroups, Dr. Li noted. While a slight numerical difference in overall survival was seen between capecitabine and control arms, this was not statistically significant (93.27% vs. 90.55%).

The investigators described safety profiles between treatment arms as “generally comparable.” In the capecitabine group, more than one-third of patients (38.89%) had dose reductions, while 8.42% reported grade 3-4 hand-foot syndrome. Grade 3-4 toxicities were more common in the capecitabine group, including neutropenia (45.79% vs. 41.32%) and febrile neutropenia (16.5% vs. 15.97%).

“Capecitabine concomitant use with docetaxel and epirubicin may significantly improve disease-free survival in early triple-negative patients,” Dr. Li concluded. He suggested that the study regimen be viewed as an alternative adjuvant regimen, as it provided clinically meaningful improvements in survival while maintaining tolerability.

Conference attendee Mohamed El-Naghy, MD, PhD, a practicing oncologist in Oneida, N.Y., expressed concern for one aspect of the trial methodology during the question and answer session following Dr. Li’s presentation: Although all patients in the trial were considered triple negative, 10 patients had estrogen receptor/progesterone receptor (ER/PR) expression ranging from 1 to 9%, which conflicts with the definition of TNBCr provided by current guidelines, according to Dr. Li.

“It is always important to have common language,” Dr. El-Naghy said. “And if you define [TNBC by] ER/PR negativity, and still you have 10% [expression], that is unacceptable. The whole point is, I looked at your numbers – 10 patients in the whole study – maybe you say they are triple negative, but these [patients] are contamination to your sample.”

Responding to this comment, Dr. Li said that the data from these patients had a minimal impact on the study results.

“We did another analysis to exclude these 10 patients, but still the result is quite similar, because they are just 10 patients – 5 in each group,” Dr. Li said.

Will Pass/MDedge News

Invited discussant Priyanka Sharma, MD, of the University of Kansas Medical Center, Kansas City, offered some additional viewpoints on the trial.

“A large proportion of patients had non–grade III disease, and one could say that the dose of docetaxel monotherapy in the control arm was not the traditional 100 mg/m², and that could have negatively impacted the outcomes in the control arm,” Dr. Sharma said. “In addition, the trial is representative of patients only from China, and whether these findings would hold true in other ethnic and racial groups is not known. Furthermore, there seemed to be limited efficacy in patients with N0 disease, which comprised two-thirds of the trial.”

Despite these potential limitations, based on the trial results and other evidence, Dr. Sharma suggested that adding capecitabine to standard systemic therapy may be considered a viable option for patients with early TNBC.

The investigators reported no disclosures.

SOURCE: Li J et al. SABCS 2019, Abstract GS1-08.

SAN ANTONIO – For patients with early triple-negative breast cancer (TNBC), adding capecitabine to standard adjuvant chemotherapy may extend disease-free survival (DFS), based results of a phase 3 trial conducted in China.

Will Pass/MDedge News

Although capecitabine boosted DFS by approximately 6%, overall survival remained unchanged, reported lead author Junjie Li, MD, of Fudan University in Shanghai, China.

In a presentation at the San Antonio Breast Cancer Symposium, Dr. Li explained that these findings provide much-needed support for the concomitant use of capecitabine in breast cancer.

“Capecitabine has been proven [effective] in advanced breast cancer, while in earlier stage disease, available data are still inconsistent,” Dr. Li said.

To help resolve some of this uncertainty, Dr. Li and colleagues conducted an open-label, phase 3 trial involving 585 patients with TNBC who were either node positive or negative and had tumors more than 1 cm in diameter. Patients were randomized in a 1:1 ratio to receive either standard therapy with three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil; or three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine.

After a median follow-up of 67 months, 288 patients had received the capecitabine regimen and 273 had undergone standard therapy. The 5-year DFS was significantly longer in the capecitabine group, at 86.26%, than the control group, at 80.23% (hazard ratio, 0.66; P = .038). This benefit extended across subgroups, Dr. Li noted. While a slight numerical difference in overall survival was seen between capecitabine and control arms, this was not statistically significant (93.27% vs. 90.55%).

The investigators described safety profiles between treatment arms as “generally comparable.” In the capecitabine group, more than one-third of patients (38.89%) had dose reductions, while 8.42% reported grade 3-4 hand-foot syndrome. Grade 3-4 toxicities were more common in the capecitabine group, including neutropenia (45.79% vs. 41.32%) and febrile neutropenia (16.5% vs. 15.97%).

“Capecitabine concomitant use with docetaxel and epirubicin may significantly improve disease-free survival in early triple-negative patients,” Dr. Li concluded. He suggested that the study regimen be viewed as an alternative adjuvant regimen, as it provided clinically meaningful improvements in survival while maintaining tolerability.

Conference attendee Mohamed El-Naghy, MD, PhD, a practicing oncologist in Oneida, N.Y., expressed concern for one aspect of the trial methodology during the question and answer session following Dr. Li’s presentation: Although all patients in the trial were considered triple negative, 10 patients had estrogen receptor/progesterone receptor (ER/PR) expression ranging from 1 to 9%, which conflicts with the definition of TNBCr provided by current guidelines, according to Dr. Li.

“It is always important to have common language,” Dr. El-Naghy said. “And if you define [TNBC by] ER/PR negativity, and still you have 10% [expression], that is unacceptable. The whole point is, I looked at your numbers – 10 patients in the whole study – maybe you say they are triple negative, but these [patients] are contamination to your sample.”

Responding to this comment, Dr. Li said that the data from these patients had a minimal impact on the study results.

“We did another analysis to exclude these 10 patients, but still the result is quite similar, because they are just 10 patients – 5 in each group,” Dr. Li said.

Will Pass/MDedge News

Invited discussant Priyanka Sharma, MD, of the University of Kansas Medical Center, Kansas City, offered some additional viewpoints on the trial.

“A large proportion of patients had non–grade III disease, and one could say that the dose of docetaxel monotherapy in the control arm was not the traditional 100 mg/m², and that could have negatively impacted the outcomes in the control arm,” Dr. Sharma said. “In addition, the trial is representative of patients only from China, and whether these findings would hold true in other ethnic and racial groups is not known. Furthermore, there seemed to be limited efficacy in patients with N0 disease, which comprised two-thirds of the trial.”

Despite these potential limitations, based on the trial results and other evidence, Dr. Sharma suggested that adding capecitabine to standard systemic therapy may be considered a viable option for patients with early TNBC.

The investigators reported no disclosures.

SOURCE: Li J et al. SABCS 2019, Abstract GS1-08.

SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.

Neil Osterweil/MDedge News

Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.

“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.

The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.

Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).

After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.

At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.

When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:

• Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
• Stage IIB: 56.2% versus 48.4%, difference 7.8%.
• Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
• Stage IIIB: 48.6% versus 23.1%, difference 25.6%.

The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.

There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).

pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).

Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).

The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).

“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.

Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.

“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”

“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.

The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.

SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.

SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.

Neil Osterweil/MDedge News

Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.

“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.

The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.

Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).

After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.

At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.

When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:

• Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
• Stage IIB: 56.2% versus 48.4%, difference 7.8%.
• Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
• Stage IIIB: 48.6% versus 23.1%, difference 25.6%.

The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.

There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).

pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).

Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).

The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).

“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.

Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.

“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”

“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.

The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.

SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.

SAN ANTONIO – Adding pembrolizumab to chemotherapy in the neoadjuvant setting increased the likelihood that women with stage III or early node-positive triple-negative breast cancer (TNBC) would have a pathologic complete response and sustained clinical benefit, results of the phase 3 KEYNOTE-522 study showed.

Neil Osterweil/MDedge News

Among 602 patients evaluable in a definitive pathological complete response (pCR) analysis, the pCR rate was 64.8% for those treated with chemotherapy plus pembrolizumab (Keytruda), compared with 51.2% for patients treated with chemotherapy plus placebo, reported Peter Schmid, MD, PhD, from Barts Cancer Institute in London.

“The addition of neoadjuvant pembrolizumab to chemotherapy provided a significant increase in the path CR rate in all patients, but also a larger magnitude of path CR benefit versus chemotherapy alone in patients with higher-risk disease, such as stage III disease or node-positive early triple-negative breast cancer,” he said at the annual San Antonio Breast Cancer Symposium.

The overall pCR results were originally reported at the 2019 annual meeting of the European Society for Medical Oncology. At SABCS 2019, he reported pCR results for specific subgroups in KEYNOTE-522.

Investigators enrolled patients aged 18 years or older with newly diagnosed TNBC of either stage T1cN1-2, or T2-4N0-2 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients also had to have at least two separate tumor cores from the primary tumor for assessment of programmed death–ligand 1 (PD-L1).

After stratification for nodal status, tumor size, and carboplatin schedule (once weekly or every 3 weeks), patients were randomized to receive either pembrolizumab 200 mg every 3 weeks or placebo plus neoadjuvant carboplatin and paclitaxel for four 3-week cycles, followed by four cycles of chemotherapy with either doxorubicin or epirubicin plus cyclophosphamide (AC or EC). Patients went on to surgery, then received adjuvant therapy for nine cycles with either pembrolizumab at the neoadjuvant dose and schedule or placebo.

At the first preplanned interim analysis for event-free survival (EFS) based on 1,174 patients followed for a median of 15.5 months, events had occurred in 7.4% of patients on pembro/chemo, compared with 11.8% on placebo/chemo, but this difference did not meet the prespecified P value boundary of .000051 for significance, Dr. Schmid acknowledged.

When the investigators looked at pCR by disease stage, however, they saw the following benefits across all stages in the study:

• Stage IIA: 73.1% with pembrolizumab versus 62.1% with placebo, difference 11%.
• Stage IIB: 56.2% versus 48.4%, difference 7.8%.
• Stage IIIA: 66.7% versus 42.1%, difference 24.6%.
• Stage IIIB: 48.6% versus 23.1%, difference 25.6%.

The greatest benefit for the addition of pembrolizumab to chemotherapy appeared to be in the higher disease stages, Dr. Schmid said.

There was also a benefit from pembrolizumab for patients with both node-negative disease (pCR, 64.9% vs. 58.6% in the placebo arm) and node-positive disease (64.8% vs. 44.1%, respectively).

pCR rates were also superior with pembrolizumab versus placebo in patients who were PD-L1 negative, defined as a combined positive score (CPS) less than 1 (45.3% vs. 30.3%), as well as PD-L1–positive patients at each of three cutoff values: CPS 1 or greater (68.9% vs. 54.9%), CPS 10 or greater (77.9% vs. 59.8%), and CPS 20 or greater (81.7% vs. 62.5%).

Interestingly, adding pembrolizumab boosted pCR rates both in patients with exposure to a full planned course of chemotherapy (69.7% vs. 55.3% with placebo) and in those who received less than the full course (51.1% vs. 35.7%).

The most common immune-mediated adverse events with the largest between-group differences involved the thyroid, including hypothyroidism (in 14.9% of patients on pembrolizumab and 5.7% of those on placebo), hyperthyroidism (5.1% vs. 1.8%), and thyroiditis (1.7% vs. 1.0%).

“Immune-mediated adverse events are consistent with the known profiles of each regimen, and there’s no new safety signal, no new safety concern at this point in time,” Dr. Schmid said.

Further follow-up will be needed to determine EFS benefit and long-term safety. Investigators plan to perform additional biomarker analyses, including tumor-infiltrating lymphocytes and BRCA, he added.

“Will the KEYNOTE-522 regimen be the new standard of care if approved?” asked invited discussant Kevin Kalinsky, MD, MS, from Columbia University Irving Medical Center in New York. “These are exciting data, both in pCR and early event-free survival. But there’s a risk: a risk of overtreatment, as well as potentially [serious] toxicity in patients with curable disease.”

“The take-home is that this regimen will likely be practice changing in some patients, and with the absence of having a predictor, the benefit may outweigh the risk most in patients with high clinical risk,” he added.

The study was funded by Merck Sharp & Dohme. Dr. Schmid reported advising/consulting for and receiving honoraria from Merck. Dr. Kalinsky disclosed has disclosed that he receives salary from Array Biopharma, has received fees from various companies (not including Merck), and has contracted research with multiple companies, not including Merck.

SOURCE: Schmid P et al. SABCS 2019, Abstract GS3-03.

SAN ANTONIO – The combination of ribociclib and letrozole proved to be an attractive alternative to standard multidrug neoadjuvant chemotherapy for women with high-risk luminal B breast cancer in the exploratory phase 2 SOLTI-1402/CORALLEEN trial.

Bruce Jancin/MDedge News

Neoadjuvant therapy with ribociclib (Kisqali), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), in combination with the aromatase inhibitor letrozole (Femara) proved as effective for presurgical molecular disease downstaging as standard multiagent chemotherapy, but with considerably less toxicity, Joaquín Gavilá, MD, reported at the San Antonio Breast Cancer Symposium.

“We believe that these results suggest that in clinically high-risk luminal B disease, a chemotherapy-free treatment strategy based upon CDK4/6 inhibition is worth exploring in future neoadjuvant trials,” declared Dr. Gavilá, a medical oncologist at the Valencia (Spain) Institute of Oncology.

SOLTI-1402/CORALLEEN was an open-label, multicenter trial involving 106 postmenopausal women with hormone receptor–positive and HER2-negative stage I-IIIA breast cancer, an operable tumor size of at least 2 cm measured by MRI, and high-risk luminal B subtype disease as defined via the Prosigna genomic tumor profiling test, also known as PAM50, on which they had a baseline median Risk of Recurrence (ROR) score of 74 out of a possible 100 points. The luminal B subtype accounts for 30%-40% of all hormone receptor–positive/HER2-negative breast cancer and carries a greater than 10% risk of distant recurrence at 10 years.

The women were randomized to 6 months of neoadjuvant therapy involving one of two regimens: six 28-day cycles of oral ribociclib at 600 mg once daily for 3 weeks followed by 1 week off plus daily oral letrozole at 2.5 mg/day; or four cycles of intravenous doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² every 21 days, then weekly intravenous paclitaxel at 80 mg/m² for 12 weeks.

The primary study endpoint was achievement of a low ROR score at the time of surgery: that is, a score below 40 points if pathologically node-negative at surgery, and below 15 with one to three positive nodes, which are the cutoffs for a less than 10% risk of distant recurrence at 10 years. A low ROR score was accomplished in 47% of the ribociclib/letrozole group and 46% of patients on standard multiagent chemotherapy. The median ROR score improved from 74 points at baseline to 18 in the investigational treatment arm and 25 in the standard chemotherapy arm.

“In other words, we observed that nearly half of the patients were downstaged from high risk to low risk in both treatment arms,” Dr. Gavilá noted.

Another 31% of patients in both treatment arms were ROR-intermediate at surgery.

The reduction in ROR score at day 15 of the study was more pronounced in the ribociclib/letrozole group than in the chemotherapy arm.

Turning to secondary outcomes, Dr. Gavilá noted that a Residual Cancer Burden score of 0 or 1, correlating with a pathologic complete response or minimal residual disease at time of surgery, was documented in 6% of the ribociclib/letrozole group and 12% of the chemotherapy group. A Preoperative Endocrine Prognostic Index (PEPI) score of 0 was attained in 22% of the novel treatment group and similarly in 17% of those on chemotherapy. Median levels of the tumor cell proliferation biomarker Ki 67 improved from 32% at baseline to 3% in the ribociclib/letrozole group and 10% in the chemotherapy arm. Eighty-eight percent of the ribociclib/letrozole group converted from luminal B to the less aggressive luminal A intrinsic subtype, as did 83% of patients following neoadjuvant chemotherapy.

The rate of serious adverse events was 4% in the ribociclib/letrozole group and 15% in the chemotherapy arm. The most common grade 3 or higher adverse event was neutropenia in both study arms, followed by increased transaminase levels in the ribociclib/letrozole group and febrile neutropenia in the chemotherapy arm. Fifty-nine percent of the ribociclib/letrozole group experienced an adverse event leading to dose reduction or temporary interruption of treatment, as did 83% of the chemotherapy group.

The SOLTI-1402/CORALLEEN trial was sponsored by Novartis, the Breast Cancer Research Foundation, The American Association for Cancer Research, and the Breast Cancer Now Career Catalyst. Dr. Gavilá reported serving as a consultant to Novartis, Roche, and MSD.

Simultaneously with Dr. Gavilá’s presentation in San Antonio, the study results were published online in The Lancet Oncology.

In an accompanying editorial, Massimo Cristofanilli, MD, opined that while the novel neoadjuvant treatment strategy tested in SOLTI-1402/CORALLEEN is promising, the most important concept introduced in the study is that a molecular subtyping tool such the Prosigna test can be used to assess the success of neoadjuvant therapy.

“The increasing availability of molecular testing in both the primary and metastatic setting is contributing to a change in the ability to stratify, select, and monitor disease biology and molecular evolution. This is resulting in the introduction of new frameworks in breast cancer treatments with potentially profound effects on patient outcomes and quality of life,” according to Dr. Cristofanilli, professor of medicine at Northwestern University, Chicago.

bjancin@mdedge.com

SOURCE: Gavilá J. SABCS 2019 Abstract GS2-06.

SAN ANTONIO – The combination of ribociclib and letrozole proved to be an attractive alternative to standard multidrug neoadjuvant chemotherapy for women with high-risk luminal B breast cancer in the exploratory phase 2 SOLTI-1402/CORALLEEN trial.

Bruce Jancin/MDedge News

Neoadjuvant therapy with ribociclib (Kisqali), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), in combination with the aromatase inhibitor letrozole (Femara) proved as effective for presurgical molecular disease downstaging as standard multiagent chemotherapy, but with considerably less toxicity, Joaquín Gavilá, MD, reported at the San Antonio Breast Cancer Symposium.

“We believe that these results suggest that in clinically high-risk luminal B disease, a chemotherapy-free treatment strategy based upon CDK4/6 inhibition is worth exploring in future neoadjuvant trials,” declared Dr. Gavilá, a medical oncologist at the Valencia (Spain) Institute of Oncology.

SOLTI-1402/CORALLEEN was an open-label, multicenter trial involving 106 postmenopausal women with hormone receptor–positive and HER2-negative stage I-IIIA breast cancer, an operable tumor size of at least 2 cm measured by MRI, and high-risk luminal B subtype disease as defined via the Prosigna genomic tumor profiling test, also known as PAM50, on which they had a baseline median Risk of Recurrence (ROR) score of 74 out of a possible 100 points. The luminal B subtype accounts for 30%-40% of all hormone receptor–positive/HER2-negative breast cancer and carries a greater than 10% risk of distant recurrence at 10 years.

The women were randomized to 6 months of neoadjuvant therapy involving one of two regimens: six 28-day cycles of oral ribociclib at 600 mg once daily for 3 weeks followed by 1 week off plus daily oral letrozole at 2.5 mg/day; or four cycles of intravenous doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² every 21 days, then weekly intravenous paclitaxel at 80 mg/m² for 12 weeks.

The primary study endpoint was achievement of a low ROR score at the time of surgery: that is, a score below 40 points if pathologically node-negative at surgery, and below 15 with one to three positive nodes, which are the cutoffs for a less than 10% risk of distant recurrence at 10 years. A low ROR score was accomplished in 47% of the ribociclib/letrozole group and 46% of patients on standard multiagent chemotherapy. The median ROR score improved from 74 points at baseline to 18 in the investigational treatment arm and 25 in the standard chemotherapy arm.

“In other words, we observed that nearly half of the patients were downstaged from high risk to low risk in both treatment arms,” Dr. Gavilá noted.

Another 31% of patients in both treatment arms were ROR-intermediate at surgery.

The reduction in ROR score at day 15 of the study was more pronounced in the ribociclib/letrozole group than in the chemotherapy arm.

Turning to secondary outcomes, Dr. Gavilá noted that a Residual Cancer Burden score of 0 or 1, correlating with a pathologic complete response or minimal residual disease at time of surgery, was documented in 6% of the ribociclib/letrozole group and 12% of the chemotherapy group. A Preoperative Endocrine Prognostic Index (PEPI) score of 0 was attained in 22% of the novel treatment group and similarly in 17% of those on chemotherapy. Median levels of the tumor cell proliferation biomarker Ki 67 improved from 32% at baseline to 3% in the ribociclib/letrozole group and 10% in the chemotherapy arm. Eighty-eight percent of the ribociclib/letrozole group converted from luminal B to the less aggressive luminal A intrinsic subtype, as did 83% of patients following neoadjuvant chemotherapy.

The rate of serious adverse events was 4% in the ribociclib/letrozole group and 15% in the chemotherapy arm. The most common grade 3 or higher adverse event was neutropenia in both study arms, followed by increased transaminase levels in the ribociclib/letrozole group and febrile neutropenia in the chemotherapy arm. Fifty-nine percent of the ribociclib/letrozole group experienced an adverse event leading to dose reduction or temporary interruption of treatment, as did 83% of the chemotherapy group.

The SOLTI-1402/CORALLEEN trial was sponsored by Novartis, the Breast Cancer Research Foundation, The American Association for Cancer Research, and the Breast Cancer Now Career Catalyst. Dr. Gavilá reported serving as a consultant to Novartis, Roche, and MSD.

Simultaneously with Dr. Gavilá’s presentation in San Antonio, the study results were published online in The Lancet Oncology.

In an accompanying editorial, Massimo Cristofanilli, MD, opined that while the novel neoadjuvant treatment strategy tested in SOLTI-1402/CORALLEEN is promising, the most important concept introduced in the study is that a molecular subtyping tool such the Prosigna test can be used to assess the success of neoadjuvant therapy.

“The increasing availability of molecular testing in both the primary and metastatic setting is contributing to a change in the ability to stratify, select, and monitor disease biology and molecular evolution. This is resulting in the introduction of new frameworks in breast cancer treatments with potentially profound effects on patient outcomes and quality of life,” according to Dr. Cristofanilli, professor of medicine at Northwestern University, Chicago.

bjancin@mdedge.com

SOURCE: Gavilá J. SABCS 2019 Abstract GS2-06.

SAN ANTONIO – The combination of ribociclib and letrozole proved to be an attractive alternative to standard multidrug neoadjuvant chemotherapy for women with high-risk luminal B breast cancer in the exploratory phase 2 SOLTI-1402/CORALLEEN trial.

Bruce Jancin/MDedge News

Neoadjuvant therapy with ribociclib (Kisqali), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), in combination with the aromatase inhibitor letrozole (Femara) proved as effective for presurgical molecular disease downstaging as standard multiagent chemotherapy, but with considerably less toxicity, Joaquín Gavilá, MD, reported at the San Antonio Breast Cancer Symposium.

“We believe that these results suggest that in clinically high-risk luminal B disease, a chemotherapy-free treatment strategy based upon CDK4/6 inhibition is worth exploring in future neoadjuvant trials,” declared Dr. Gavilá, a medical oncologist at the Valencia (Spain) Institute of Oncology.

SOLTI-1402/CORALLEEN was an open-label, multicenter trial involving 106 postmenopausal women with hormone receptor–positive and HER2-negative stage I-IIIA breast cancer, an operable tumor size of at least 2 cm measured by MRI, and high-risk luminal B subtype disease as defined via the Prosigna genomic tumor profiling test, also known as PAM50, on which they had a baseline median Risk of Recurrence (ROR) score of 74 out of a possible 100 points. The luminal B subtype accounts for 30%-40% of all hormone receptor–positive/HER2-negative breast cancer and carries a greater than 10% risk of distant recurrence at 10 years.

The women were randomized to 6 months of neoadjuvant therapy involving one of two regimens: six 28-day cycles of oral ribociclib at 600 mg once daily for 3 weeks followed by 1 week off plus daily oral letrozole at 2.5 mg/day; or four cycles of intravenous doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² every 21 days, then weekly intravenous paclitaxel at 80 mg/m² for 12 weeks.

The primary study endpoint was achievement of a low ROR score at the time of surgery: that is, a score below 40 points if pathologically node-negative at surgery, and below 15 with one to three positive nodes, which are the cutoffs for a less than 10% risk of distant recurrence at 10 years. A low ROR score was accomplished in 47% of the ribociclib/letrozole group and 46% of patients on standard multiagent chemotherapy. The median ROR score improved from 74 points at baseline to 18 in the investigational treatment arm and 25 in the standard chemotherapy arm.

“In other words, we observed that nearly half of the patients were downstaged from high risk to low risk in both treatment arms,” Dr. Gavilá noted.

Another 31% of patients in both treatment arms were ROR-intermediate at surgery.

The reduction in ROR score at day 15 of the study was more pronounced in the ribociclib/letrozole group than in the chemotherapy arm.

Turning to secondary outcomes, Dr. Gavilá noted that a Residual Cancer Burden score of 0 or 1, correlating with a pathologic complete response or minimal residual disease at time of surgery, was documented in 6% of the ribociclib/letrozole group and 12% of the chemotherapy group. A Preoperative Endocrine Prognostic Index (PEPI) score of 0 was attained in 22% of the novel treatment group and similarly in 17% of those on chemotherapy. Median levels of the tumor cell proliferation biomarker Ki 67 improved from 32% at baseline to 3% in the ribociclib/letrozole group and 10% in the chemotherapy arm. Eighty-eight percent of the ribociclib/letrozole group converted from luminal B to the less aggressive luminal A intrinsic subtype, as did 83% of patients following neoadjuvant chemotherapy.

The rate of serious adverse events was 4% in the ribociclib/letrozole group and 15% in the chemotherapy arm. The most common grade 3 or higher adverse event was neutropenia in both study arms, followed by increased transaminase levels in the ribociclib/letrozole group and febrile neutropenia in the chemotherapy arm. Fifty-nine percent of the ribociclib/letrozole group experienced an adverse event leading to dose reduction or temporary interruption of treatment, as did 83% of the chemotherapy group.

The SOLTI-1402/CORALLEEN trial was sponsored by Novartis, the Breast Cancer Research Foundation, The American Association for Cancer Research, and the Breast Cancer Now Career Catalyst. Dr. Gavilá reported serving as a consultant to Novartis, Roche, and MSD.

Simultaneously with Dr. Gavilá’s presentation in San Antonio, the study results were published online in The Lancet Oncology.

In an accompanying editorial, Massimo Cristofanilli, MD, opined that while the novel neoadjuvant treatment strategy tested in SOLTI-1402/CORALLEEN is promising, the most important concept introduced in the study is that a molecular subtyping tool such the Prosigna test can be used to assess the success of neoadjuvant therapy.

“The increasing availability of molecular testing in both the primary and metastatic setting is contributing to a change in the ability to stratify, select, and monitor disease biology and molecular evolution. This is resulting in the introduction of new frameworks in breast cancer treatments with potentially profound effects on patient outcomes and quality of life,” according to Dr. Cristofanilli, professor of medicine at Northwestern University, Chicago.

bjancin@mdedge.com

SOURCE: Gavilá J. SABCS 2019 Abstract GS2-06.

SAN ANTONIO – Adding pertuzumab to trastuzumab and chemotherapy after surgery for HER2-positive early breast cancer continued to show a slight, but statistically nonsignificant overall survival benefit, compared with placebo, at a preplanned 6-year interim analysis of the phase 3 APHINITY trial.

Sharon Worcester/MDedge News

Invasive disease-free survival (IDFS) was significantly improved with pertuzumab at this second interim analysis, and node-positive patients continued to derive the greatest benefit, as was the case in the primary analysis reported in the New England Journal of Medicine in 2017, Martine Piccart, MD, PhD, reported at the San Antonio Breast Cancer Symposium.

At a median of 74.1 months of follow-up, overall survival (OS) was 94.8% in 2,400 patients in the pertuzumab arm, compared with 93.9% in 2,405 patients in the placebo arm (hazard ratio, 0.85), said Dr. Piccart of Institut Jules Bordet, Brussels.

She noted that a “very stringent” P value of.0012 was required for statistical significance in this interim OS analysis.

IDFS rates at follow-up were 90.6% vs. 87.8% in the intent-to-treat population, a difference caused mainly by a reduction in distant and loco-regional recurrence, she noted.

“[That translates] to a 2.8% absolute improvement with pertuzumab at 6 years,” she said, adding that the risk of both distant and loco-regional recurrences was reduced with pertuzumab. “The rate of [central nervous system] metastases, contralateral invasive breast cancers, and death without a prior event – not different between the two treatment groups.”

In the node-positive cohort, the 6-year IDFS rates were 87.9% vs. 83.4% with pertuzumab vs. placebo (4.5% absolute benefit; HR, 0.72), showing a clear benefit.

“In contrast, no treatment effect is detected in the node-negative population [95.0% and 94.9%, respectively; HR, 1.02],” she said.

Importantly, the clinical benefits were seen regardless of hormone receptor status (HRs, 0.73 and 0.83 for hormone receptor–positive and –negative disease, respectively), she said, noting that this finding differs from the 3-year analysis, which suggested an enhanced benefit only in the hormone receptor–negative cohort.

“These [hormone receptor–negative] patients still benefit from pertuzumab ... but interestingly, now the curves are diverging in the hormone receptor–positive population, and there is a benefit emerging,” she said.

An updated descriptive analysis of cardiac safety was also performed, and no new safety concerns emerged, Dr. Piccart said.

“What is important to remember is the rate of severe cardiac events is below 1% in both groups (0.8% and 0.3% with pertuzumab and placebo),” she said.

APHINITY is a randomized, multicenter, double-blind, placebo-controlled trial which previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest but statistically significant improvement in IDFS, compared with placebo and chemotherapy plus trastuzumab (HR, 0.81; P = .04).

The effect was more pronounced in node-negative patients (HR, 0.77) and hormone receptor–negative patients (HR, 0.76).

Patients with node-positive or high-risk node-negative, HER2-positive, operable early breast cancer were enrolled between November 2011 and August 2013, and the primary analysis was conducted at 45.4 months of follow-up. Based on those findings, pertuzumab in combination with trastuzumab was approved for high-risk early HER2-positive breast cancer patients.

The first interim OS analysis was conducted at that time, and no significant treatment effect was observed, Dr. Piccart said.

The 6-year findings demonstrate that the small OS benefit and the statistically significant IDFS benefit with pertuzumab in this setting is maintained, with the node-positive population deriving the greatest benefit.

“Further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2-positive breast cancer,” she said, noting that a calendar-driven third interim OS analysis is planned in 2.5 years.

The APHINITY trial is funded by Roche. Dr. Piccart reported receiving consulting fees from Roche and research funding to her institution from Roche and several other companies. She also is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, and Immunomedics.

SOURCE: Piccart M et al. SABCS 2019, Abstract GS1-04.

SAN ANTONIO – Adding pertuzumab to trastuzumab and chemotherapy after surgery for HER2-positive early breast cancer continued to show a slight, but statistically nonsignificant overall survival benefit, compared with placebo, at a preplanned 6-year interim analysis of the phase 3 APHINITY trial.

Sharon Worcester/MDedge News

Invasive disease-free survival (IDFS) was significantly improved with pertuzumab at this second interim analysis, and node-positive patients continued to derive the greatest benefit, as was the case in the primary analysis reported in the New England Journal of Medicine in 2017, Martine Piccart, MD, PhD, reported at the San Antonio Breast Cancer Symposium.

At a median of 74.1 months of follow-up, overall survival (OS) was 94.8% in 2,400 patients in the pertuzumab arm, compared with 93.9% in 2,405 patients in the placebo arm (hazard ratio, 0.85), said Dr. Piccart of Institut Jules Bordet, Brussels.

She noted that a “very stringent” P value of.0012 was required for statistical significance in this interim OS analysis.

IDFS rates at follow-up were 90.6% vs. 87.8% in the intent-to-treat population, a difference caused mainly by a reduction in distant and loco-regional recurrence, she noted.

“[That translates] to a 2.8% absolute improvement with pertuzumab at 6 years,” she said, adding that the risk of both distant and loco-regional recurrences was reduced with pertuzumab. “The rate of [central nervous system] metastases, contralateral invasive breast cancers, and death without a prior event – not different between the two treatment groups.”

In the node-positive cohort, the 6-year IDFS rates were 87.9% vs. 83.4% with pertuzumab vs. placebo (4.5% absolute benefit; HR, 0.72), showing a clear benefit.

“In contrast, no treatment effect is detected in the node-negative population [95.0% and 94.9%, respectively; HR, 1.02],” she said.

Importantly, the clinical benefits were seen regardless of hormone receptor status (HRs, 0.73 and 0.83 for hormone receptor–positive and –negative disease, respectively), she said, noting that this finding differs from the 3-year analysis, which suggested an enhanced benefit only in the hormone receptor–negative cohort.

“These [hormone receptor–negative] patients still benefit from pertuzumab ... but interestingly, now the curves are diverging in the hormone receptor–positive population, and there is a benefit emerging,” she said.

An updated descriptive analysis of cardiac safety was also performed, and no new safety concerns emerged, Dr. Piccart said.

“What is important to remember is the rate of severe cardiac events is below 1% in both groups (0.8% and 0.3% with pertuzumab and placebo),” she said.

APHINITY is a randomized, multicenter, double-blind, placebo-controlled trial which previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest but statistically significant improvement in IDFS, compared with placebo and chemotherapy plus trastuzumab (HR, 0.81; P = .04).

The effect was more pronounced in node-negative patients (HR, 0.77) and hormone receptor–negative patients (HR, 0.76).

Patients with node-positive or high-risk node-negative, HER2-positive, operable early breast cancer were enrolled between November 2011 and August 2013, and the primary analysis was conducted at 45.4 months of follow-up. Based on those findings, pertuzumab in combination with trastuzumab was approved for high-risk early HER2-positive breast cancer patients.

The first interim OS analysis was conducted at that time, and no significant treatment effect was observed, Dr. Piccart said.

The 6-year findings demonstrate that the small OS benefit and the statistically significant IDFS benefit with pertuzumab in this setting is maintained, with the node-positive population deriving the greatest benefit.

“Further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2-positive breast cancer,” she said, noting that a calendar-driven third interim OS analysis is planned in 2.5 years.

The APHINITY trial is funded by Roche. Dr. Piccart reported receiving consulting fees from Roche and research funding to her institution from Roche and several other companies. She also is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, and Immunomedics.

SOURCE: Piccart M et al. SABCS 2019, Abstract GS1-04.

SAN ANTONIO – Adding pertuzumab to trastuzumab and chemotherapy after surgery for HER2-positive early breast cancer continued to show a slight, but statistically nonsignificant overall survival benefit, compared with placebo, at a preplanned 6-year interim analysis of the phase 3 APHINITY trial.

Sharon Worcester/MDedge News

Invasive disease-free survival (IDFS) was significantly improved with pertuzumab at this second interim analysis, and node-positive patients continued to derive the greatest benefit, as was the case in the primary analysis reported in the New England Journal of Medicine in 2017, Martine Piccart, MD, PhD, reported at the San Antonio Breast Cancer Symposium.

At a median of 74.1 months of follow-up, overall survival (OS) was 94.8% in 2,400 patients in the pertuzumab arm, compared with 93.9% in 2,405 patients in the placebo arm (hazard ratio, 0.85), said Dr. Piccart of Institut Jules Bordet, Brussels.

She noted that a “very stringent” P value of.0012 was required for statistical significance in this interim OS analysis.

IDFS rates at follow-up were 90.6% vs. 87.8% in the intent-to-treat population, a difference caused mainly by a reduction in distant and loco-regional recurrence, she noted.

“[That translates] to a 2.8% absolute improvement with pertuzumab at 6 years,” she said, adding that the risk of both distant and loco-regional recurrences was reduced with pertuzumab. “The rate of [central nervous system] metastases, contralateral invasive breast cancers, and death without a prior event – not different between the two treatment groups.”

In the node-positive cohort, the 6-year IDFS rates were 87.9% vs. 83.4% with pertuzumab vs. placebo (4.5% absolute benefit; HR, 0.72), showing a clear benefit.

“In contrast, no treatment effect is detected in the node-negative population [95.0% and 94.9%, respectively; HR, 1.02],” she said.

Importantly, the clinical benefits were seen regardless of hormone receptor status (HRs, 0.73 and 0.83 for hormone receptor–positive and –negative disease, respectively), she said, noting that this finding differs from the 3-year analysis, which suggested an enhanced benefit only in the hormone receptor–negative cohort.

“These [hormone receptor–negative] patients still benefit from pertuzumab ... but interestingly, now the curves are diverging in the hormone receptor–positive population, and there is a benefit emerging,” she said.

An updated descriptive analysis of cardiac safety was also performed, and no new safety concerns emerged, Dr. Piccart said.

“What is important to remember is the rate of severe cardiac events is below 1% in both groups (0.8% and 0.3% with pertuzumab and placebo),” she said.

APHINITY is a randomized, multicenter, double-blind, placebo-controlled trial which previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest but statistically significant improvement in IDFS, compared with placebo and chemotherapy plus trastuzumab (HR, 0.81; P = .04).

The effect was more pronounced in node-negative patients (HR, 0.77) and hormone receptor–negative patients (HR, 0.76).

Patients with node-positive or high-risk node-negative, HER2-positive, operable early breast cancer were enrolled between November 2011 and August 2013, and the primary analysis was conducted at 45.4 months of follow-up. Based on those findings, pertuzumab in combination with trastuzumab was approved for high-risk early HER2-positive breast cancer patients.

The first interim OS analysis was conducted at that time, and no significant treatment effect was observed, Dr. Piccart said.

The 6-year findings demonstrate that the small OS benefit and the statistically significant IDFS benefit with pertuzumab in this setting is maintained, with the node-positive population deriving the greatest benefit.

“Further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2-positive breast cancer,” she said, noting that a calendar-driven third interim OS analysis is planned in 2.5 years.

The APHINITY trial is funded by Roche. Dr. Piccart reported receiving consulting fees from Roche and research funding to her institution from Roche and several other companies. She also is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, and Immunomedics.

SOURCE: Piccart M et al. SABCS 2019, Abstract GS1-04.