Lung Cancer

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

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

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

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

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

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

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

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

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

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

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

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

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

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

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

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

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

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

Pulmonology Data Trends 2024 is a supplement to CHEST Physician highlighting the latest breakthroughs in pulmonology research and treatments through a series of infographics.

Read more: 

Artificial Intelligence in Sleep Apnea
Ritwick Agrawal, MD, MS, FCCP

RSV Updates: Prophylaxis Approval and Hospitalization for Severe RSV
Riddhi Upadhyay, MD

Biologics in Asthma: Changing the Severe Asthma Paradigm
Shyam Subramanian, MD, FCCP

Updates in COPD Guidelines and Treatment
Dharani K. Narendra, MD, FCCP

Targeted Therapies and Surgical Resection for Lung Cancer: Evolving Treatment Options
Saadia A. Faiz, MD, FCCP

Closing the GAP in Idiopathic Pulmonary Fibrosis
Humayun Anjum, MD, FCCP

Severe Community-Acquired Pneumonia: Diagnostic Criteria, Treatment, and COVID-19
Sujith V. Cherian, MD, FCCP

Pulmonary Hypertension: Comorbidities and Novel Therapies
Mary Jo S. Farmer, MD, PhD, FCCP

The Genetic Side of Interstitial Lung Disease
Priya Balakrishnan, MD, MS, FCCP

Noninvasive Ventilation in Neuromuscular Disease
Sreelatha Naik, MD, FCCP, and Kelly Lobrutto, CRNP

Pulmonology Data Trends 2024 is a supplement to CHEST Physician highlighting the latest breakthroughs in pulmonology research and treatments through a series of infographics.

Read more: 

Artificial Intelligence in Sleep Apnea
Ritwick Agrawal, MD, MS, FCCP

RSV Updates: Prophylaxis Approval and Hospitalization for Severe RSV
Riddhi Upadhyay, MD

Biologics in Asthma: Changing the Severe Asthma Paradigm
Shyam Subramanian, MD, FCCP

Updates in COPD Guidelines and Treatment
Dharani K. Narendra, MD, FCCP

Targeted Therapies and Surgical Resection for Lung Cancer: Evolving Treatment Options
Saadia A. Faiz, MD, FCCP

Closing the GAP in Idiopathic Pulmonary Fibrosis
Humayun Anjum, MD, FCCP

Severe Community-Acquired Pneumonia: Diagnostic Criteria, Treatment, and COVID-19
Sujith V. Cherian, MD, FCCP

Pulmonary Hypertension: Comorbidities and Novel Therapies
Mary Jo S. Farmer, MD, PhD, FCCP

The Genetic Side of Interstitial Lung Disease
Priya Balakrishnan, MD, MS, FCCP

Noninvasive Ventilation in Neuromuscular Disease
Sreelatha Naik, MD, FCCP, and Kelly Lobrutto, CRNP

Pulmonology Data Trends 2024 is a supplement to CHEST Physician highlighting the latest breakthroughs in pulmonology research and treatments through a series of infographics.

Read more: 

Artificial Intelligence in Sleep Apnea
Ritwick Agrawal, MD, MS, FCCP

RSV Updates: Prophylaxis Approval and Hospitalization for Severe RSV
Riddhi Upadhyay, MD

Biologics in Asthma: Changing the Severe Asthma Paradigm
Shyam Subramanian, MD, FCCP

Updates in COPD Guidelines and Treatment
Dharani K. Narendra, MD, FCCP

Targeted Therapies and Surgical Resection for Lung Cancer: Evolving Treatment Options
Saadia A. Faiz, MD, FCCP

Closing the GAP in Idiopathic Pulmonary Fibrosis
Humayun Anjum, MD, FCCP

Severe Community-Acquired Pneumonia: Diagnostic Criteria, Treatment, and COVID-19
Sujith V. Cherian, MD, FCCP

Pulmonary Hypertension: Comorbidities and Novel Therapies
Mary Jo S. Farmer, MD, PhD, FCCP

The Genetic Side of Interstitial Lung Disease
Priya Balakrishnan, MD, MS, FCCP

Noninvasive Ventilation in Neuromuscular Disease
Sreelatha Naik, MD, FCCP, and Kelly Lobrutto, CRNP

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Each year in the United States, approximately 1.7 million Americans are diagnosed with a potentially lethal malignancy. Typical therapies of choice include surgery, radiation, and occasionally, toxic chemotherapy (chemo) — approaches that eliminate the cancer in about 1,000,000 of these cases. The remaining 700,000 or so often proceed to chemotherapy either immediately or upon cancer recurrence, spread, or newly recognized metastases. “Cures” after that point are rare.

I’m speaking in generalities, understanding that each cancer and each patient is unique.
 

Chemotherapy

Chemotherapy alone can cure a small number of cancer types. When added to radiation or surgery, chemotherapy can help to cure a wider range of cancer types. As an add-on, chemotherapy can extend the length and quality of life for many patients with cancer. Since chemotherapy is by definition “toxic,” it can also shorten the duration or harm the quality of life and provide false hope. The Table summarizes what chemotherapy can and cannot achieve in selected cancer types.

• Lack of response (the tumor failed to shrink).
• Progression (the cancer may have grown or spread further).
• Adverse side effects were too severe to continue.

The drugs used in second-line chemo will typically be different from those used in first line, sometimes because cancer cells can develop resistance to chemotherapy drugs over time. Moreover, the goal of second-line chemo may differ from that of first-line therapy. Rather than chiefly aiming for a cure, second-line treatment might focus on slowing cancer growth, managing symptoms, or improving quality of life. Unfortunately, not every type of cancer has a readily available second-line option.

Third-line treatment. Third-line options come into play when both the initial course of chemo (first line) and the subsequent treatment (second line) have failed to achieve remission or control the cancer’s spread. Owing to the progressive nature of advanced cancers, patients might not be eligible or healthy enough for third-line therapy. Depending on cancer type, the patient’s general health, and response to previous treatments, third-line options could include:

• New or different chemotherapy drugs compared with prior lines.
• Surgery to debulk the tumor.
• Radiation for symptom control.
• Targeted therapy: drugs designed to target specific vulnerabilities in cancer cells.
• Immunotherapy: agents that help the body’s immune system fight cancer cells.
• Clinical trials testing new or investigational treatments, which may be applicable at any time, depending on the questions being addressed.

The goals of third-line therapy may shift from aiming for a cure to managing symptoms, improving quality of life, and potentially slowing cancer growth. The decision to pursue third-line therapy involves careful consideration by the doctor and patient, weighing the potential benefits and risks of treatment considering the individual’s overall health and specific situation.

It’s important to have realistic expectations about the potential outcomes of third-line therapy. Although remission may be unlikely, third-line therapy can still play a role in managing the disease.

Navigating advanced cancer treatment is very complex. The patient and physician must together consider detailed explanations and clarifications to set expectations and make informed decisions about care.
 

Interventions to Consider Earlier

In traditional clinical oncology practice, other interventions are possible, but these may not be offered until treatment has reached the third line:

• Molecular testing.
• Palliation.
• Clinical trials.
• Innovative testing to guide targeted therapy by ascertaining which agents are most likely (or not likely at all) to be effective.

I would argue that the patient’s interests are better served by considering and offering these other interventions much earlier, even before starting first-line chemotherapy.

Molecular testing. The best time for molecular testing of a new malignant tumor is typically at the time of diagnosis. Here’s why:

• Molecular testing helps identify specific genetic mutations in the cancer cells. This information can be crucial for selecting targeted therapies that are most effective against those specific mutations. Early detection allows for the most treatment options. For example, for non–small cell lung cancer, early is best because treatment and outcomes may well be changed by test results.
• Knowing the tumor’s molecular makeup can help determine whether a patient qualifies for clinical trials of new drugs designed for specific mutations.
• Some molecular markers can offer information about the tumor’s aggressiveness and potential for metastasis so that prognosis can be informed.

Molecular testing can be a valuable tool throughout a cancer patient’s journey. With genetically diverse tumors, the initial biopsy might not capture the full picture. Molecular testing of circulating tumor DNA can be used to monitor a patient’s response to treatment and detect potential mutations that might arise during treatment resistance. Retesting after metastasis can provide additional information that can aid in treatment decisions.

Palliative care. The ideal time to discuss palliative care with a patient with cancer is early in the diagnosis and treatment process. Palliative care is not the same as hospice care; it isn’t just about end-of-life. Palliative care focuses on improving a patient’s quality of life throughout cancer treatment. Palliative care specialists can address a wide range of symptoms a patient might experience from cancer or its treatment, including pain, fatigue, nausea, and anxiety.

Early discussions allow for a more comprehensive care plan. Open communication about all treatment options, including palliative care, empowers patients to make informed decisions about their care goals and preferences.

Specific situations where discussing palliative care might be appropriate are:

• Soon after a cancer diagnosis.
• If the patient experiences significant side effects from cancer treatment.
• When considering different treatment options, palliative care can complement those treatments.
• In advanced stages of cancer, to focus on comfort and quality of life.

Clinical trials. Participation in a clinical trial to explore new or investigational treatments should always be considered.

In theory, clinical trials should be an option at any time in the patient’s course. But the organized clinical trial experience may not be available or appropriate. Then, the individual becomes a de facto “clinical trial with an n of 1.” Read this brief open-access blog post at Cancer Commons to learn more about that circumstance.

Innovative testing. The best choice of chemotherapeutic or targeted therapies is often unclear. The clinician is likely to follow published guidelines, often from the National Comprehensive Cancer Network.

These are evidence based and driven by consensus of experts. But guideline-recommended therapy is not always effective, and weeks or months can pass before this ineffectiveness becomes apparent. Thus, many researchers and companies are seeking methods of testing each patient’s specific cancer to determine in advance, or very quickly, whether a particular drug is likely to be effective.

Read more about these leading innovations:

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

Alibrex: A New Blood Test to Reveal Whether a Cancer Treatment is Working

PARIS Test Uses Lab-Grown Mini-Tumors to Find a Patient’s Best Treatment

Using Live Cells from Patients to Find the Right Cancer Drug

Other innovative therapies under investigation could even be agnostic to cancer type:

Treating Pancreatic Cancer: Could Metabolism — Not Genomics — Be the Key?

High-Energy Blue Light Powers a Promising New Treatment to Destroy Cancer Cells

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

Cancer is a tough nut to crack. Many people and organizations are trying very hard. So much is being learned. Some approaches will be effective. We can all hope.

Dr. Lundberg, editor in chief, Cancer Commons, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Each year in the United States, approximately 1.7 million Americans are diagnosed with a potentially lethal malignancy. Typical therapies of choice include surgery, radiation, and occasionally, toxic chemotherapy (chemo) — approaches that eliminate the cancer in about 1,000,000 of these cases. The remaining 700,000 or so often proceed to chemotherapy either immediately or upon cancer recurrence, spread, or newly recognized metastases. “Cures” after that point are rare.

I’m speaking in generalities, understanding that each cancer and each patient is unique.
 

Chemotherapy

Chemotherapy alone can cure a small number of cancer types. When added to radiation or surgery, chemotherapy can help to cure a wider range of cancer types. As an add-on, chemotherapy can extend the length and quality of life for many patients with cancer. Since chemotherapy is by definition “toxic,” it can also shorten the duration or harm the quality of life and provide false hope. The Table summarizes what chemotherapy can and cannot achieve in selected cancer types.

• Lack of response (the tumor failed to shrink).
• Progression (the cancer may have grown or spread further).
• Adverse side effects were too severe to continue.

The drugs used in second-line chemo will typically be different from those used in first line, sometimes because cancer cells can develop resistance to chemotherapy drugs over time. Moreover, the goal of second-line chemo may differ from that of first-line therapy. Rather than chiefly aiming for a cure, second-line treatment might focus on slowing cancer growth, managing symptoms, or improving quality of life. Unfortunately, not every type of cancer has a readily available second-line option.

Third-line treatment. Third-line options come into play when both the initial course of chemo (first line) and the subsequent treatment (second line) have failed to achieve remission or control the cancer’s spread. Owing to the progressive nature of advanced cancers, patients might not be eligible or healthy enough for third-line therapy. Depending on cancer type, the patient’s general health, and response to previous treatments, third-line options could include:

• New or different chemotherapy drugs compared with prior lines.
• Surgery to debulk the tumor.
• Radiation for symptom control.
• Targeted therapy: drugs designed to target specific vulnerabilities in cancer cells.
• Immunotherapy: agents that help the body’s immune system fight cancer cells.
• Clinical trials testing new or investigational treatments, which may be applicable at any time, depending on the questions being addressed.

The goals of third-line therapy may shift from aiming for a cure to managing symptoms, improving quality of life, and potentially slowing cancer growth. The decision to pursue third-line therapy involves careful consideration by the doctor and patient, weighing the potential benefits and risks of treatment considering the individual’s overall health and specific situation.

It’s important to have realistic expectations about the potential outcomes of third-line therapy. Although remission may be unlikely, third-line therapy can still play a role in managing the disease.

Navigating advanced cancer treatment is very complex. The patient and physician must together consider detailed explanations and clarifications to set expectations and make informed decisions about care.
 

Interventions to Consider Earlier

In traditional clinical oncology practice, other interventions are possible, but these may not be offered until treatment has reached the third line:

• Molecular testing.
• Palliation.
• Clinical trials.
• Innovative testing to guide targeted therapy by ascertaining which agents are most likely (or not likely at all) to be effective.

I would argue that the patient’s interests are better served by considering and offering these other interventions much earlier, even before starting first-line chemotherapy.

Molecular testing. The best time for molecular testing of a new malignant tumor is typically at the time of diagnosis. Here’s why:

• Molecular testing helps identify specific genetic mutations in the cancer cells. This information can be crucial for selecting targeted therapies that are most effective against those specific mutations. Early detection allows for the most treatment options. For example, for non–small cell lung cancer, early is best because treatment and outcomes may well be changed by test results.
• Knowing the tumor’s molecular makeup can help determine whether a patient qualifies for clinical trials of new drugs designed for specific mutations.
• Some molecular markers can offer information about the tumor’s aggressiveness and potential for metastasis so that prognosis can be informed.

Molecular testing can be a valuable tool throughout a cancer patient’s journey. With genetically diverse tumors, the initial biopsy might not capture the full picture. Molecular testing of circulating tumor DNA can be used to monitor a patient’s response to treatment and detect potential mutations that might arise during treatment resistance. Retesting after metastasis can provide additional information that can aid in treatment decisions.

Palliative care. The ideal time to discuss palliative care with a patient with cancer is early in the diagnosis and treatment process. Palliative care is not the same as hospice care; it isn’t just about end-of-life. Palliative care focuses on improving a patient’s quality of life throughout cancer treatment. Palliative care specialists can address a wide range of symptoms a patient might experience from cancer or its treatment, including pain, fatigue, nausea, and anxiety.

Early discussions allow for a more comprehensive care plan. Open communication about all treatment options, including palliative care, empowers patients to make informed decisions about their care goals and preferences.

Specific situations where discussing palliative care might be appropriate are:

• Soon after a cancer diagnosis.
• If the patient experiences significant side effects from cancer treatment.
• When considering different treatment options, palliative care can complement those treatments.
• In advanced stages of cancer, to focus on comfort and quality of life.

Clinical trials. Participation in a clinical trial to explore new or investigational treatments should always be considered.

In theory, clinical trials should be an option at any time in the patient’s course. But the organized clinical trial experience may not be available or appropriate. Then, the individual becomes a de facto “clinical trial with an n of 1.” Read this brief open-access blog post at Cancer Commons to learn more about that circumstance.

Innovative testing. The best choice of chemotherapeutic or targeted therapies is often unclear. The clinician is likely to follow published guidelines, often from the National Comprehensive Cancer Network.

These are evidence based and driven by consensus of experts. But guideline-recommended therapy is not always effective, and weeks or months can pass before this ineffectiveness becomes apparent. Thus, many researchers and companies are seeking methods of testing each patient’s specific cancer to determine in advance, or very quickly, whether a particular drug is likely to be effective.

Read more about these leading innovations:

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

Alibrex: A New Blood Test to Reveal Whether a Cancer Treatment is Working

PARIS Test Uses Lab-Grown Mini-Tumors to Find a Patient’s Best Treatment

Using Live Cells from Patients to Find the Right Cancer Drug

Other innovative therapies under investigation could even be agnostic to cancer type:

Treating Pancreatic Cancer: Could Metabolism — Not Genomics — Be the Key?

High-Energy Blue Light Powers a Promising New Treatment to Destroy Cancer Cells

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

Cancer is a tough nut to crack. Many people and organizations are trying very hard. So much is being learned. Some approaches will be effective. We can all hope.

Dr. Lundberg, editor in chief, Cancer Commons, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Each year in the United States, approximately 1.7 million Americans are diagnosed with a potentially lethal malignancy. Typical therapies of choice include surgery, radiation, and occasionally, toxic chemotherapy (chemo) — approaches that eliminate the cancer in about 1,000,000 of these cases. The remaining 700,000 or so often proceed to chemotherapy either immediately or upon cancer recurrence, spread, or newly recognized metastases. “Cures” after that point are rare.

I’m speaking in generalities, understanding that each cancer and each patient is unique.
 

Chemotherapy

Chemotherapy alone can cure a small number of cancer types. When added to radiation or surgery, chemotherapy can help to cure a wider range of cancer types. As an add-on, chemotherapy can extend the length and quality of life for many patients with cancer. Since chemotherapy is by definition “toxic,” it can also shorten the duration or harm the quality of life and provide false hope. The Table summarizes what chemotherapy can and cannot achieve in selected cancer types.

• Lack of response (the tumor failed to shrink).
• Progression (the cancer may have grown or spread further).
• Adverse side effects were too severe to continue.

The drugs used in second-line chemo will typically be different from those used in first line, sometimes because cancer cells can develop resistance to chemotherapy drugs over time. Moreover, the goal of second-line chemo may differ from that of first-line therapy. Rather than chiefly aiming for a cure, second-line treatment might focus on slowing cancer growth, managing symptoms, or improving quality of life. Unfortunately, not every type of cancer has a readily available second-line option.

Third-line treatment. Third-line options come into play when both the initial course of chemo (first line) and the subsequent treatment (second line) have failed to achieve remission or control the cancer’s spread. Owing to the progressive nature of advanced cancers, patients might not be eligible or healthy enough for third-line therapy. Depending on cancer type, the patient’s general health, and response to previous treatments, third-line options could include:

• New or different chemotherapy drugs compared with prior lines.
• Surgery to debulk the tumor.
• Radiation for symptom control.
• Targeted therapy: drugs designed to target specific vulnerabilities in cancer cells.
• Immunotherapy: agents that help the body’s immune system fight cancer cells.
• Clinical trials testing new or investigational treatments, which may be applicable at any time, depending on the questions being addressed.

The goals of third-line therapy may shift from aiming for a cure to managing symptoms, improving quality of life, and potentially slowing cancer growth. The decision to pursue third-line therapy involves careful consideration by the doctor and patient, weighing the potential benefits and risks of treatment considering the individual’s overall health and specific situation.

It’s important to have realistic expectations about the potential outcomes of third-line therapy. Although remission may be unlikely, third-line therapy can still play a role in managing the disease.

Navigating advanced cancer treatment is very complex. The patient and physician must together consider detailed explanations and clarifications to set expectations and make informed decisions about care.
 

Interventions to Consider Earlier

In traditional clinical oncology practice, other interventions are possible, but these may not be offered until treatment has reached the third line:

• Molecular testing.
• Palliation.
• Clinical trials.
• Innovative testing to guide targeted therapy by ascertaining which agents are most likely (or not likely at all) to be effective.

I would argue that the patient’s interests are better served by considering and offering these other interventions much earlier, even before starting first-line chemotherapy.

Molecular testing. The best time for molecular testing of a new malignant tumor is typically at the time of diagnosis. Here’s why:

• Molecular testing helps identify specific genetic mutations in the cancer cells. This information can be crucial for selecting targeted therapies that are most effective against those specific mutations. Early detection allows for the most treatment options. For example, for non–small cell lung cancer, early is best because treatment and outcomes may well be changed by test results.
• Knowing the tumor’s molecular makeup can help determine whether a patient qualifies for clinical trials of new drugs designed for specific mutations.
• Some molecular markers can offer information about the tumor’s aggressiveness and potential for metastasis so that prognosis can be informed.

Molecular testing can be a valuable tool throughout a cancer patient’s journey. With genetically diverse tumors, the initial biopsy might not capture the full picture. Molecular testing of circulating tumor DNA can be used to monitor a patient’s response to treatment and detect potential mutations that might arise during treatment resistance. Retesting after metastasis can provide additional information that can aid in treatment decisions.

Palliative care. The ideal time to discuss palliative care with a patient with cancer is early in the diagnosis and treatment process. Palliative care is not the same as hospice care; it isn’t just about end-of-life. Palliative care focuses on improving a patient’s quality of life throughout cancer treatment. Palliative care specialists can address a wide range of symptoms a patient might experience from cancer or its treatment, including pain, fatigue, nausea, and anxiety.

Early discussions allow for a more comprehensive care plan. Open communication about all treatment options, including palliative care, empowers patients to make informed decisions about their care goals and preferences.

Specific situations where discussing palliative care might be appropriate are:

• Soon after a cancer diagnosis.
• If the patient experiences significant side effects from cancer treatment.
• When considering different treatment options, palliative care can complement those treatments.
• In advanced stages of cancer, to focus on comfort and quality of life.

Clinical trials. Participation in a clinical trial to explore new or investigational treatments should always be considered.

In theory, clinical trials should be an option at any time in the patient’s course. But the organized clinical trial experience may not be available or appropriate. Then, the individual becomes a de facto “clinical trial with an n of 1.” Read this brief open-access blog post at Cancer Commons to learn more about that circumstance.

Innovative testing. The best choice of chemotherapeutic or targeted therapies is often unclear. The clinician is likely to follow published guidelines, often from the National Comprehensive Cancer Network.

These are evidence based and driven by consensus of experts. But guideline-recommended therapy is not always effective, and weeks or months can pass before this ineffectiveness becomes apparent. Thus, many researchers and companies are seeking methods of testing each patient’s specific cancer to determine in advance, or very quickly, whether a particular drug is likely to be effective.

Read more about these leading innovations:

SAGE Oncotest: Entering the Next Generation of Tailored Cancer Treatment

Alibrex: A New Blood Test to Reveal Whether a Cancer Treatment is Working

PARIS Test Uses Lab-Grown Mini-Tumors to Find a Patient’s Best Treatment

Using Live Cells from Patients to Find the Right Cancer Drug

Other innovative therapies under investigation could even be agnostic to cancer type:

Treating Pancreatic Cancer: Could Metabolism — Not Genomics — Be the Key?

High-Energy Blue Light Powers a Promising New Treatment to Destroy Cancer Cells

All-Clear Follow-Up: Hydrogen Peroxide Appears to Treat Oral and Skin Lesions

Cancer is a tough nut to crack. Many people and organizations are trying very hard. So much is being learned. Some approaches will be effective. We can all hope.

Dr. Lundberg, editor in chief, Cancer Commons, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.