Lung Cancer

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

The Direct KRAS^G12C Inhibitor Adagrasib in Advanced KRAS^G12C-Mutant NSCLC: Results From a Registrational Phase 2 Study

KRAS mutations are detected in about one quarter of all lung adenocarcinomas and are the most common oncogene driver in non–small-cell lung cancer (NSCLC). KRAS^G12C amino acid substitutions are the most common KRAS mutations in NSCLC, comprising just about half of all KRAS mutations in this tumor type. Despite being the most common and first detected oncogene driver in lung cancer, until recently there were no targeted therapies in KRAS mutant NSCLC. The development of direct KRAS^G12C inhibitors represents an important step forward in targeting KRAS mutations. These inhibitors bind inactive guanosine diphosphate (GDP)–bound RAS and trap it in its inactive state.

Dr Jänne and colleagues recently published a phase 2 registrational trial of the direct KRAS^G12C inhibitor adagrasib. In this study of 112 patients with measurable disease at baseline treated with adagrasib, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% CI 6.2-13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI 4.7-8.4). The median overall survival (OS) was 12.6 months (95% CI 9.2-19.2). Among 33 patients with previously treated, stable central nervous system (CNS) metastases, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0-51.8). Treatment-related adverse events occurred in 97.4% of the patients: grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events). The most frequent toxicities were fatigue and gastrointestinal-related issues (nausea, vomiting, diarrhea, aspartate transaminase/alanine transaminase elevation). Adagrasib was discontinued in 6.9% of patients.

These results further demonstrate that the KRAS^G12C mutation is an actionable target in NSCLC. Sotorasib, another direct KRAS^G12C inhibitor, is currently US Food and Drug Administration approved after initial systemic treatment. The clinical activity of sotorasib and adagrasib are comparable; for sotorasib the rates are an overall response rate (ORR) of 37.1% (95% CI 28.6-46.2), median PFS of 6.8 months (95% CI 5.1-8.2), and median OS of 12.5 months (95% CI 10.0 to nonestimable). Adagrasib also has published evidence of CNS activity that tracks with its systemic activity. Overall, these direct KRAS^G12C inhibitors represent a major advance in the treatment of KRAS^G12C-mutant NSCLC.

EGFR-Mutated NSCLC: Aumolertinib vs Gefitinib Extends PFS

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved clinical outcomes in EGFR-mutant NSCLC.The current standard of care for first-line treatment of advanced NSCLC with the most frequent EGFR activating mutations (EGFR E19del and L858R)is the third-generation EGFR TKI osimertinib. In the FLAURA trial, patients randomly assigned tofirst-lineosimertinib had a substantial PFS benefit (median PFS 18.9 vs 10.2 months) and OS benefit (median OS 38.6 vs 31.8 months)when receivingosimertinib compared with gefitinib or erlotinib.

In the AENEAS trial, published in the Journal of Clinical Oncologyby Dr Lu and colleagues, 420 patients from China with advanced NSCLC harboring EGFR E19del or L858R activating mutations and naive to systemic treatment were enrolled. Patients were randomly assigned to the next-generation EGFR TKI aumolertinib or the first-generation EGFR TKI gefitinib with the primary endpoint of PFS by investigator assessment.Of note, patients with asymptomatic, untreated brain metastases were allowed into the trial. Upon disease progression, patients in the gefitinib group who acquired an EGFR T790M mutation were eligible to crossover to aumolertinib.

The study met its primary endpoint: Patients treated with aumolertinib compared with those treated with gefitinib had a significantly longer median PFS (19.3 vs 9.9 months; hazard ratio [HR] 0.46; P< .0001). This PFS advantage of aumolertinib over gefitinib was also present in the subgroup of patients with CNS metastases (15.3 vs 8.2 months; HR 0.38; P< .0001). The objective response rate was similar inthe aumolertinib and gefitinib groups (objective response rate 73.8% and 72.1%, respectively). The median duration of response was 18.1 months (95% CI 15.2 to not reached) with aumolertinib vs 8.3 months (95% CI 6.9-11.1) with gefitinib. Treatment-emergent adverse events of grade 3 or more were similar in the aumolertinib and gefitinib groups (36.4% vs 35.8%, respectively). There was less rash and diarrhea as well as transaminitis in the aumolertinib arm compared with the gefitinib arm. However, 35.5% of patients developed an elevation in creatinine phosphokinase (CPK), including 7% with grade 3 CPK elevation. However, no rhabdomyolysis was observed.

Overall, the AENEAS study showed comparable median PFS for first-line aumolertinib comparedwith what was observed with osimertinib in the FLAURA study. We still await the OSdata on aumolertinib compared with gefitinib. In the FLAURA study, investigators could choose between erlotinib or gefitinib in the control arm, whereas in AENEAS only gefitinib was allowed, which may have less CNS activity than erlotinib. Moreover, the FLAURA trial was conducted worldwide, whereas the AENEAS trial only enrolled patients in China. This study provides further support for the use of third-generation EGFR TKI over first-generation EGFR TKI as first-line treatment in advanced/metastatic NSCLC harboring EGFR E19del or L858R mutations.

Advanced ALK+ NSCLC With Brain Metastases: Lorlatinib Boosts PFS, Reduces CNS Progression

The CROWN trial was a pivotal randomized phase 3 trial that demonstrated an impressive improvement in PFS in patients treated with the third-generationALK inhibitor lorlatinib compared with the first-generation ALK inhibitor crizotinib as initial treatment for advanced ALK-postive (ALK+) NSCLC (HR for disease progression or death0.28; 95% CI0.19-0.41; P≤ .001). A major driver of this PFS benefit in ALK+ NSCLC in the CROWN study is the superior CNS penetration of lorlatinib compared with crizotinib. Obtaining CNS control in ALK+ lung cancers is important because up to 40% of patients with ALK+ NSCLC have brain metastases at initial evaluation, and CNS progression is often observed in patients with ALK+ lung cancer whether it be intracranial metastases or leptomeningeal carcinomatosis. A potential challenge in treating patients with lorlatinib is a unique side effect profile including neurocognitive side effects from lorlatinib. In a recently published study in the Journal of Clinical Oncology, Dr Solomon and colleagues conducted a post hoc exploratory analysis of intracranial efficacy and safety of lorlatinib in ALK+ NSCLC from a phase 3 trial. PFS by blinded independent central review was improved with lorlatinib vs crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% vs 22% and 78% vs 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression compared with crizotinib in patients with (7.4% vs 72%) and without (1% vs 18%) brain metastases at baseline. Complete CNS responses with lorlatinib were seen in 23/38(61%) patients with any brain metastases at baseline compared with 6/40 (15%) with crizotinib. In total, 35% of patients had CNS adverse events with lorlatinib: grade 1 (21%), grade 2 (10%), and grade 3 (3%)in severity. These included cognitive (21%), mood (16%), speech (5%), and psychotic effects (3%), some of which overlapped. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification. Dose reductions of lorlatinib did not appear to affect PFS on the basis of a landmark analysis. Overall, this study demonstrates the exceptional CNS activity of lorlatinib in ALK+ NSCLC and that the neurocognitive side effects can often be managed. There are several next-generation ALK inhibitors now approved in the first-line setting —alectinib, lorlatinib, and brigatinib — notably all with enhanced CNS penetration and improved PFS compared with crizotinib. This posthoc study further supports the impressive CNS activity of lorlatinib in ALK+ NSCLC and supports the use of lorlatinib as a first-line treatment option in these patients, particularly those with ALK+ NSCLC diagnosed with baseline CNS disease.

The Direct KRAS^G12C Inhibitor Adagrasib in Advanced KRAS^G12C-Mutant NSCLC: Results From a Registrational Phase 2 Study

KRAS mutations are detected in about one quarter of all lung adenocarcinomas and are the most common oncogene driver in non–small-cell lung cancer (NSCLC). KRAS^G12C amino acid substitutions are the most common KRAS mutations in NSCLC, comprising just about half of all KRAS mutations in this tumor type. Despite being the most common and first detected oncogene driver in lung cancer, until recently there were no targeted therapies in KRAS mutant NSCLC. The development of direct KRAS^G12C inhibitors represents an important step forward in targeting KRAS mutations. These inhibitors bind inactive guanosine diphosphate (GDP)–bound RAS and trap it in its inactive state.

Dr Jänne and colleagues recently published a phase 2 registrational trial of the direct KRAS^G12C inhibitor adagrasib. In this study of 112 patients with measurable disease at baseline treated with adagrasib, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% CI 6.2-13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI 4.7-8.4). The median overall survival (OS) was 12.6 months (95% CI 9.2-19.2). Among 33 patients with previously treated, stable central nervous system (CNS) metastases, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0-51.8). Treatment-related adverse events occurred in 97.4% of the patients: grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events). The most frequent toxicities were fatigue and gastrointestinal-related issues (nausea, vomiting, diarrhea, aspartate transaminase/alanine transaminase elevation). Adagrasib was discontinued in 6.9% of patients.

These results further demonstrate that the KRAS^G12C mutation is an actionable target in NSCLC. Sotorasib, another direct KRAS^G12C inhibitor, is currently US Food and Drug Administration approved after initial systemic treatment. The clinical activity of sotorasib and adagrasib are comparable; for sotorasib the rates are an overall response rate (ORR) of 37.1% (95% CI 28.6-46.2), median PFS of 6.8 months (95% CI 5.1-8.2), and median OS of 12.5 months (95% CI 10.0 to nonestimable). Adagrasib also has published evidence of CNS activity that tracks with its systemic activity. Overall, these direct KRAS^G12C inhibitors represent a major advance in the treatment of KRAS^G12C-mutant NSCLC.

EGFR-Mutated NSCLC: Aumolertinib vs Gefitinib Extends PFS

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved clinical outcomes in EGFR-mutant NSCLC.The current standard of care for first-line treatment of advanced NSCLC with the most frequent EGFR activating mutations (EGFR E19del and L858R)is the third-generation EGFR TKI osimertinib. In the FLAURA trial, patients randomly assigned tofirst-lineosimertinib had a substantial PFS benefit (median PFS 18.9 vs 10.2 months) and OS benefit (median OS 38.6 vs 31.8 months)when receivingosimertinib compared with gefitinib or erlotinib.

In the AENEAS trial, published in the Journal of Clinical Oncologyby Dr Lu and colleagues, 420 patients from China with advanced NSCLC harboring EGFR E19del or L858R activating mutations and naive to systemic treatment were enrolled. Patients were randomly assigned to the next-generation EGFR TKI aumolertinib or the first-generation EGFR TKI gefitinib with the primary endpoint of PFS by investigator assessment.Of note, patients with asymptomatic, untreated brain metastases were allowed into the trial. Upon disease progression, patients in the gefitinib group who acquired an EGFR T790M mutation were eligible to crossover to aumolertinib.

The study met its primary endpoint: Patients treated with aumolertinib compared with those treated with gefitinib had a significantly longer median PFS (19.3 vs 9.9 months; hazard ratio [HR] 0.46; P< .0001). This PFS advantage of aumolertinib over gefitinib was also present in the subgroup of patients with CNS metastases (15.3 vs 8.2 months; HR 0.38; P< .0001). The objective response rate was similar inthe aumolertinib and gefitinib groups (objective response rate 73.8% and 72.1%, respectively). The median duration of response was 18.1 months (95% CI 15.2 to not reached) with aumolertinib vs 8.3 months (95% CI 6.9-11.1) with gefitinib. Treatment-emergent adverse events of grade 3 or more were similar in the aumolertinib and gefitinib groups (36.4% vs 35.8%, respectively). There was less rash and diarrhea as well as transaminitis in the aumolertinib arm compared with the gefitinib arm. However, 35.5% of patients developed an elevation in creatinine phosphokinase (CPK), including 7% with grade 3 CPK elevation. However, no rhabdomyolysis was observed.

Overall, the AENEAS study showed comparable median PFS for first-line aumolertinib comparedwith what was observed with osimertinib in the FLAURA study. We still await the OSdata on aumolertinib compared with gefitinib. In the FLAURA study, investigators could choose between erlotinib or gefitinib in the control arm, whereas in AENEAS only gefitinib was allowed, which may have less CNS activity than erlotinib. Moreover, the FLAURA trial was conducted worldwide, whereas the AENEAS trial only enrolled patients in China. This study provides further support for the use of third-generation EGFR TKI over first-generation EGFR TKI as first-line treatment in advanced/metastatic NSCLC harboring EGFR E19del or L858R mutations.

Advanced ALK+ NSCLC With Brain Metastases: Lorlatinib Boosts PFS, Reduces CNS Progression

The CROWN trial was a pivotal randomized phase 3 trial that demonstrated an impressive improvement in PFS in patients treated with the third-generationALK inhibitor lorlatinib compared with the first-generation ALK inhibitor crizotinib as initial treatment for advanced ALK-postive (ALK+) NSCLC (HR for disease progression or death0.28; 95% CI0.19-0.41; P≤ .001). A major driver of this PFS benefit in ALK+ NSCLC in the CROWN study is the superior CNS penetration of lorlatinib compared with crizotinib. Obtaining CNS control in ALK+ lung cancers is important because up to 40% of patients with ALK+ NSCLC have brain metastases at initial evaluation, and CNS progression is often observed in patients with ALK+ lung cancer whether it be intracranial metastases or leptomeningeal carcinomatosis. A potential challenge in treating patients with lorlatinib is a unique side effect profile including neurocognitive side effects from lorlatinib. In a recently published study in the Journal of Clinical Oncology, Dr Solomon and colleagues conducted a post hoc exploratory analysis of intracranial efficacy and safety of lorlatinib in ALK+ NSCLC from a phase 3 trial. PFS by blinded independent central review was improved with lorlatinib vs crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% vs 22% and 78% vs 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression compared with crizotinib in patients with (7.4% vs 72%) and without (1% vs 18%) brain metastases at baseline. Complete CNS responses with lorlatinib were seen in 23/38(61%) patients with any brain metastases at baseline compared with 6/40 (15%) with crizotinib. In total, 35% of patients had CNS adverse events with lorlatinib: grade 1 (21%), grade 2 (10%), and grade 3 (3%)in severity. These included cognitive (21%), mood (16%), speech (5%), and psychotic effects (3%), some of which overlapped. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification. Dose reductions of lorlatinib did not appear to affect PFS on the basis of a landmark analysis. Overall, this study demonstrates the exceptional CNS activity of lorlatinib in ALK+ NSCLC and that the neurocognitive side effects can often be managed. There are several next-generation ALK inhibitors now approved in the first-line setting —alectinib, lorlatinib, and brigatinib — notably all with enhanced CNS penetration and improved PFS compared with crizotinib. This posthoc study further supports the impressive CNS activity of lorlatinib in ALK+ NSCLC and supports the use of lorlatinib as a first-line treatment option in these patients, particularly those with ALK+ NSCLC diagnosed with baseline CNS disease.

The Direct KRAS^G12C Inhibitor Adagrasib in Advanced KRAS^G12C-Mutant NSCLC: Results From a Registrational Phase 2 Study

KRAS mutations are detected in about one quarter of all lung adenocarcinomas and are the most common oncogene driver in non–small-cell lung cancer (NSCLC). KRAS^G12C amino acid substitutions are the most common KRAS mutations in NSCLC, comprising just about half of all KRAS mutations in this tumor type. Despite being the most common and first detected oncogene driver in lung cancer, until recently there were no targeted therapies in KRAS mutant NSCLC. The development of direct KRAS^G12C inhibitors represents an important step forward in targeting KRAS mutations. These inhibitors bind inactive guanosine diphosphate (GDP)–bound RAS and trap it in its inactive state.

Dr Jänne and colleagues recently published a phase 2 registrational trial of the direct KRAS^G12C inhibitor adagrasib. In this study of 112 patients with measurable disease at baseline treated with adagrasib, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% CI 6.2-13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI 4.7-8.4). The median overall survival (OS) was 12.6 months (95% CI 9.2-19.2). Among 33 patients with previously treated, stable central nervous system (CNS) metastases, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0-51.8). Treatment-related adverse events occurred in 97.4% of the patients: grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events). The most frequent toxicities were fatigue and gastrointestinal-related issues (nausea, vomiting, diarrhea, aspartate transaminase/alanine transaminase elevation). Adagrasib was discontinued in 6.9% of patients.

These results further demonstrate that the KRAS^G12C mutation is an actionable target in NSCLC. Sotorasib, another direct KRAS^G12C inhibitor, is currently US Food and Drug Administration approved after initial systemic treatment. The clinical activity of sotorasib and adagrasib are comparable; for sotorasib the rates are an overall response rate (ORR) of 37.1% (95% CI 28.6-46.2), median PFS of 6.8 months (95% CI 5.1-8.2), and median OS of 12.5 months (95% CI 10.0 to nonestimable). Adagrasib also has published evidence of CNS activity that tracks with its systemic activity. Overall, these direct KRAS^G12C inhibitors represent a major advance in the treatment of KRAS^G12C-mutant NSCLC.

EGFR-Mutated NSCLC: Aumolertinib vs Gefitinib Extends PFS

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved clinical outcomes in EGFR-mutant NSCLC.The current standard of care for first-line treatment of advanced NSCLC with the most frequent EGFR activating mutations (EGFR E19del and L858R)is the third-generation EGFR TKI osimertinib. In the FLAURA trial, patients randomly assigned tofirst-lineosimertinib had a substantial PFS benefit (median PFS 18.9 vs 10.2 months) and OS benefit (median OS 38.6 vs 31.8 months)when receivingosimertinib compared with gefitinib or erlotinib.

In the AENEAS trial, published in the Journal of Clinical Oncologyby Dr Lu and colleagues, 420 patients from China with advanced NSCLC harboring EGFR E19del or L858R activating mutations and naive to systemic treatment were enrolled. Patients were randomly assigned to the next-generation EGFR TKI aumolertinib or the first-generation EGFR TKI gefitinib with the primary endpoint of PFS by investigator assessment.Of note, patients with asymptomatic, untreated brain metastases were allowed into the trial. Upon disease progression, patients in the gefitinib group who acquired an EGFR T790M mutation were eligible to crossover to aumolertinib.

The study met its primary endpoint: Patients treated with aumolertinib compared with those treated with gefitinib had a significantly longer median PFS (19.3 vs 9.9 months; hazard ratio [HR] 0.46; P< .0001). This PFS advantage of aumolertinib over gefitinib was also present in the subgroup of patients with CNS metastases (15.3 vs 8.2 months; HR 0.38; P< .0001). The objective response rate was similar inthe aumolertinib and gefitinib groups (objective response rate 73.8% and 72.1%, respectively). The median duration of response was 18.1 months (95% CI 15.2 to not reached) with aumolertinib vs 8.3 months (95% CI 6.9-11.1) with gefitinib. Treatment-emergent adverse events of grade 3 or more were similar in the aumolertinib and gefitinib groups (36.4% vs 35.8%, respectively). There was less rash and diarrhea as well as transaminitis in the aumolertinib arm compared with the gefitinib arm. However, 35.5% of patients developed an elevation in creatinine phosphokinase (CPK), including 7% with grade 3 CPK elevation. However, no rhabdomyolysis was observed.

Overall, the AENEAS study showed comparable median PFS for first-line aumolertinib comparedwith what was observed with osimertinib in the FLAURA study. We still await the OSdata on aumolertinib compared with gefitinib. In the FLAURA study, investigators could choose between erlotinib or gefitinib in the control arm, whereas in AENEAS only gefitinib was allowed, which may have less CNS activity than erlotinib. Moreover, the FLAURA trial was conducted worldwide, whereas the AENEAS trial only enrolled patients in China. This study provides further support for the use of third-generation EGFR TKI over first-generation EGFR TKI as first-line treatment in advanced/metastatic NSCLC harboring EGFR E19del or L858R mutations.

Advanced ALK+ NSCLC With Brain Metastases: Lorlatinib Boosts PFS, Reduces CNS Progression

The CROWN trial was a pivotal randomized phase 3 trial that demonstrated an impressive improvement in PFS in patients treated with the third-generationALK inhibitor lorlatinib compared with the first-generation ALK inhibitor crizotinib as initial treatment for advanced ALK-postive (ALK+) NSCLC (HR for disease progression or death0.28; 95% CI0.19-0.41; P≤ .001). A major driver of this PFS benefit in ALK+ NSCLC in the CROWN study is the superior CNS penetration of lorlatinib compared with crizotinib. Obtaining CNS control in ALK+ lung cancers is important because up to 40% of patients with ALK+ NSCLC have brain metastases at initial evaluation, and CNS progression is often observed in patients with ALK+ lung cancer whether it be intracranial metastases or leptomeningeal carcinomatosis. A potential challenge in treating patients with lorlatinib is a unique side effect profile including neurocognitive side effects from lorlatinib. In a recently published study in the Journal of Clinical Oncology, Dr Solomon and colleagues conducted a post hoc exploratory analysis of intracranial efficacy and safety of lorlatinib in ALK+ NSCLC from a phase 3 trial. PFS by blinded independent central review was improved with lorlatinib vs crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% vs 22% and 78% vs 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression compared with crizotinib in patients with (7.4% vs 72%) and without (1% vs 18%) brain metastases at baseline. Complete CNS responses with lorlatinib were seen in 23/38(61%) patients with any brain metastases at baseline compared with 6/40 (15%) with crizotinib. In total, 35% of patients had CNS adverse events with lorlatinib: grade 1 (21%), grade 2 (10%), and grade 3 (3%)in severity. These included cognitive (21%), mood (16%), speech (5%), and psychotic effects (3%), some of which overlapped. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification. Dose reductions of lorlatinib did not appear to affect PFS on the basis of a landmark analysis. Overall, this study demonstrates the exceptional CNS activity of lorlatinib in ALK+ NSCLC and that the neurocognitive side effects can often be managed. There are several next-generation ALK inhibitors now approved in the first-line setting —alectinib, lorlatinib, and brigatinib — notably all with enhanced CNS penetration and improved PFS compared with crizotinib. This posthoc study further supports the impressive CNS activity of lorlatinib in ALK+ NSCLC and supports the use of lorlatinib as a first-line treatment option in these patients, particularly those with ALK+ NSCLC diagnosed with baseline CNS disease.

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

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

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

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

A large Danish study has found that cancer increases the risk of new-onset type 2 diabetes, especially certain types of cancer, most notably pancreatic malignancies.

“Our study demonstrates that there is an elevated risk of developing diabetes if a person is affected by lung, pancreatic, breast, brain, urinary tract, or uterine cancers,” said Lykke Sylow, PhD, associate professor in the Molecular Metabolism in Cancer and Ageing Group at the University of Copenhagen, in a statement.

“It is great to see such a large, well-designed study confirm the findings of previous smaller studies and observations,” said Elias S. Siraj, MD, the David L. Bernd Distinguished Chair for EVMS-Sentara Cardiovascular Diabetes Program at Eastern Virginia Medical School in Norfolk, when asked for comment by this news organization. Dr. Siraj also noted that “in clinical care we do observe that many patients develop diabetes after being diagnosed with cancer although one needs a well-designed study to confirm that observation.”
 

Diabetes risk highest with pancreatic cancer

Type 2 diabetes at the time of cancer diagnosis is known to increase cancer-specific and all-cause mortality, but not much is known about whether cancer is a risk factor for type 2 diabetes, the researchers state in their study, published in Diabetes Care.

Dr. Sylow and colleagues from the Steno Diabetes Center Copenhagen, Rigshospitalet, analyzed a database consisting of 112 million blood samples from 1.3 million Danes from 2000 to 2015. They looked at cancer cases with an incidence of more than 1,000 and excluded individuals with diabetes prior to cancer diagnosis. 

They found an increased risk of new-onset type 2 diabetes for all cancers (hazard ratio, 1.09; 95% confidence interval, 1.03-1.14). For pancreatic cancer, the hazard ratio rose to 5.0 (95% CI, 3.62-6.90), for brain and nervous system cancers the hazard ratio was 1.54 (95% CI, 1.22-1.95), and for uterine cancer the hazard ratio was 1.41 (95% CI, 1.10-1.84).

The link with pancreatic cancer was not surprising, said Dr. Sylow.

Dr. Siraj agreed, noting that a few studies have shown a strong association. “It has also been observed for years that many patients with pancreatic cancer may present with new-onset diabetes,” he said. “The mechanism is not clearly understood but could include a direct damage of the beta cells by the pancreatic cancer or could be due to a paraneoplastic secretion of special factors by the cancer that can affect beta-cell function or insulin resistance,” said Dr. Siraj, who is also professor and chief of endocrinology and director of the Strelitz Diabetes Center at Eastern Virginia Medical School.

The higher diabetes risk associated with brain and nervous system cancers has not been previously described and is “an intriguing finding,” he said.

In their statement, the Danish investigators said there is nothing in their research to suggest why some cancers are associated with a higher risk of new-onset type 2 diabetes, but they offered some theories, including that chemotherapeutics and perhaps the cancer, itself, may contribute.

“We know that cancer cells are able to secrete substances that can affect organs and possibility contribute to an increased incidence of diabetes,” said Dr. Sylow in the statement.
 

Increased mortality risk in those with cancer and type 2 diabetes

Dr. Sylow and colleagues also analyzed mortality in a subset of 28,308 patients with cancer who were still alive 2 years after diagnosis. They documented a 21% higher rate of all-cause mortality in these patients compared with those who did not have new-onset type 2 diabetes.

“We do not know enough about the patients who were diagnosed with type 2 diabetes, but we think our findings illustrate a potential new area of intervention in the cancer clinic,” Dr. Sylow said. However, the findings still require replication before drawing any definite conclusions, she added.

Christoffer Johansen, MD, PhD, DMSc, of Rigshospitalet, said in the statement that it might be prudent to screen patients with lung, breast, brain, uterine, and urinary tract cancers for diabetes. “Early intervention could have an impact on certain cancer patients,” said Dr. Johansen.

Dr. Siraj said he would urge oncologists to routinely monitor blood glucose levels during cancer treatment and as part of long-term surveillance, and to consider the potential risk of new-onset diabetes when choosing a cancer therapy. If diabetes is diagnosed, clinicians should be sure that it’s managed by a primary care physician or endocrinologist, “as proper treatment may contribute to better outcomes of the cancer,” said Dr. Siraj.

Endocrinologists should consider the possibility of pancreatic cancer if someone with few risk factors for type 2 diabetes has a new-onset diagnosis, he said. And they should aim for good glycemic control in those with new-onset type 2 diabetes, as it may lead to better cancer outcomes, he said.

Dr. Sylow has reported grant support from the Novo Nordisk Foundation and Independent Research Fund Denmark. Dr. Johansen has reported serving as an educator for Janssen and Pfizer. Coauthors have received grant support from the Danish Cancer Society and served as consultants, on advisory boards, or as educators for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Incyte, GSK, MSD, Mundipharma, Novartis, Novo Nordisk, Pfizer, and Sanofi.

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

A new study finds that mortality is significantly higher among patients with advanced solid tumors who are admitted to the hospital for chemotherapy treatment.

The findings – released in a poster session at the annual meeting of the American Society of Clinical Oncology – found that patients with solid tumors were more likely to be treated for nonurgent indications, not be referred to palliative care, and die within 60 days, compared with patients with hematologic malignancies.

Decisions about inpatient chemotherapy should not be uniform and instead should be based on a case-by-case basis, said Natalie Berger, MD, a hematologist-oncologist at Mount Sinai Hospital,, New York, and the study’s lead author.

Inpatient chemotherapy can be appropriate in certain situations, such as when chemotherapy must be given in the hospital and when it must be administered quickly after a patient presents with cancer symptoms and needs relief, she said.

However, “sometimes patients are admitted due to infection, side effects of chemotherapy or cancer, or for reasons unrelated to their cancer, and chemotherapy may be administered when it is not appropriate. It is also overutilized at the end of life which can lead to more aggressive end-of-life care rather than focusing on quality of life and supportive care,” Dr. Berger said.

The study is based on a retrospective chart review of 880 patients admitted to Mount Sinai Hospital between January 2016 and December 2017 to receive chemotherapy.

They found that the type of tumor was used to determine the urgency of an in-hospital stay for chemotherapy (odds ratio, 0.42; 95% CI, 0.25-0.72; P = .001). Patients with solid tumors or older patients or patients with a functional impairment score (Karnofsky Performance Scale) of 50% were less likely to respond to chemotherapy. There was also a decrease in quality of life among these patients, but only 46% of patients with solid tumors and 15% of patients with hematologic malignancies met with a palliative care professional.

One-third (34%) of patients with solid tumors didn’t have urgent indications, 43% of patients had no response to inpatient chemotherapy, and 20% died within 60 days, compared with patients with hematologic malignancies (19%, 19%, and 9%, respectively).

“There are many reasons why this [high mortality rate in patients with solid tumors] may be happening. Solid tumor patients are more often admitted at a later stage of their cancer when they are sicker, and they were also less likely to have a response to inpatient chemotherapy. Older patients and patients with a poor performance status were also less likely to respond to chemotherapy. This indicates that these patients were sicker, and chemotherapy use may not have been appropriate and palliative care may be underutilized,” she said.

Dr. Berger and colleagues have created a standardized protocol to assess “the appropriateness” of inpatient chemotherapy, improve quality of life, and reduce chemotherapy and health care utilization at the end of life. The protocol has been implemented as a pilot program at Mount Sinai Hospital, Dr. Berger said.

“Any inpatient chemotherapy case that meets standard accepted criteria for required inpatient administration are auto-approved through the electronic survey. For cases outside of standard criteria, further information must be inputted to determine appropriateness of inpatient treatment and are then scored electronically and reviewed by committee physicians and pharmacists,” she said.

Gabriel A. Brooks, MD, MPH, an oncologist with Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not affiliated with the study, said that inpatient chemotherapy treatment is under scrutiny elsewhere as well.

“There has been recognition that patients who are otherwise sick enough to require hospital admission are often too sick to benefit from chemotherapy,” although there are exceptions. “There is certainly a movement to limit inpatient chemotherapy to situations where it is most likely to be beneficial. Some of this is driven by cost pressures. For instance, Medicare pays for inpatient hospitalizations using the DRG [diagnosis-related group] system. Hospitals cannot charge a la carte for treatments given in the hospital. Instead, they are reimbursed at a fixed rate based on the hospital diagnoses. This will often lead to poor reimbursement of high-cost cancer treatments.”

Dr. Brooks said the study offers insight into who’s getting inpatient chemotherapy. However, “what I can’t tell from this poster is how often the solid tumor patients are getting first-line chemotherapy [as] these patients may be presenting late or may have a potentially treatable cancer with a narrow closing window for treatment versus later-line chemotherapy.”

He also noted that patient and family wishes are missing from the research. “This is critical. Patients and families should be informed that inpatient chemotherapy may not provide the benefit they are hoping for, especially for patients with solid tumors starting later lines of therapy. Patients should be informed that there are alternatives to inpatient chemotherapy, such as hospice referral or waiting for possible outpatient treatment – if their condition improves. But when a patient wants to try inpatient chemotherapy and their doctor wants to offer it, then it is likely a reasonable thing to try.”

Going forward, he said, “qualitative study is needed to better understand when and why inpatient chemotherapy is used. There are likely some clear good uses and some clear bad uses of inpatient chemotherapy. Can outpatient regimens be substituted for the regimens where patients are directly admitted? Or, can outpatient protocols be devised for these regimens? Are there specific situations where inpatient chemotherapy is the right thing (leukemia, esophageal cancer with worsening dysphagia, etc.)?”

No study funding was received.

A new study finds that mortality is significantly higher among patients with advanced solid tumors who are admitted to the hospital for chemotherapy treatment.

The findings – released in a poster session at the annual meeting of the American Society of Clinical Oncology – found that patients with solid tumors were more likely to be treated for nonurgent indications, not be referred to palliative care, and die within 60 days, compared with patients with hematologic malignancies.

Decisions about inpatient chemotherapy should not be uniform and instead should be based on a case-by-case basis, said Natalie Berger, MD, a hematologist-oncologist at Mount Sinai Hospital,, New York, and the study’s lead author.

Inpatient chemotherapy can be appropriate in certain situations, such as when chemotherapy must be given in the hospital and when it must be administered quickly after a patient presents with cancer symptoms and needs relief, she said.

However, “sometimes patients are admitted due to infection, side effects of chemotherapy or cancer, or for reasons unrelated to their cancer, and chemotherapy may be administered when it is not appropriate. It is also overutilized at the end of life which can lead to more aggressive end-of-life care rather than focusing on quality of life and supportive care,” Dr. Berger said.

The study is based on a retrospective chart review of 880 patients admitted to Mount Sinai Hospital between January 2016 and December 2017 to receive chemotherapy.

They found that the type of tumor was used to determine the urgency of an in-hospital stay for chemotherapy (odds ratio, 0.42; 95% CI, 0.25-0.72; P = .001). Patients with solid tumors or older patients or patients with a functional impairment score (Karnofsky Performance Scale) of 50% were less likely to respond to chemotherapy. There was also a decrease in quality of life among these patients, but only 46% of patients with solid tumors and 15% of patients with hematologic malignancies met with a palliative care professional.

One-third (34%) of patients with solid tumors didn’t have urgent indications, 43% of patients had no response to inpatient chemotherapy, and 20% died within 60 days, compared with patients with hematologic malignancies (19%, 19%, and 9%, respectively).

“There are many reasons why this [high mortality rate in patients with solid tumors] may be happening. Solid tumor patients are more often admitted at a later stage of their cancer when they are sicker, and they were also less likely to have a response to inpatient chemotherapy. Older patients and patients with a poor performance status were also less likely to respond to chemotherapy. This indicates that these patients were sicker, and chemotherapy use may not have been appropriate and palliative care may be underutilized,” she said.

Dr. Berger and colleagues have created a standardized protocol to assess “the appropriateness” of inpatient chemotherapy, improve quality of life, and reduce chemotherapy and health care utilization at the end of life. The protocol has been implemented as a pilot program at Mount Sinai Hospital, Dr. Berger said.

“Any inpatient chemotherapy case that meets standard accepted criteria for required inpatient administration are auto-approved through the electronic survey. For cases outside of standard criteria, further information must be inputted to determine appropriateness of inpatient treatment and are then scored electronically and reviewed by committee physicians and pharmacists,” she said.

Gabriel A. Brooks, MD, MPH, an oncologist with Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not affiliated with the study, said that inpatient chemotherapy treatment is under scrutiny elsewhere as well.

“There has been recognition that patients who are otherwise sick enough to require hospital admission are often too sick to benefit from chemotherapy,” although there are exceptions. “There is certainly a movement to limit inpatient chemotherapy to situations where it is most likely to be beneficial. Some of this is driven by cost pressures. For instance, Medicare pays for inpatient hospitalizations using the DRG [diagnosis-related group] system. Hospitals cannot charge a la carte for treatments given in the hospital. Instead, they are reimbursed at a fixed rate based on the hospital diagnoses. This will often lead to poor reimbursement of high-cost cancer treatments.”

Dr. Brooks said the study offers insight into who’s getting inpatient chemotherapy. However, “what I can’t tell from this poster is how often the solid tumor patients are getting first-line chemotherapy [as] these patients may be presenting late or may have a potentially treatable cancer with a narrow closing window for treatment versus later-line chemotherapy.”

He also noted that patient and family wishes are missing from the research. “This is critical. Patients and families should be informed that inpatient chemotherapy may not provide the benefit they are hoping for, especially for patients with solid tumors starting later lines of therapy. Patients should be informed that there are alternatives to inpatient chemotherapy, such as hospice referral or waiting for possible outpatient treatment – if their condition improves. But when a patient wants to try inpatient chemotherapy and their doctor wants to offer it, then it is likely a reasonable thing to try.”

Going forward, he said, “qualitative study is needed to better understand when and why inpatient chemotherapy is used. There are likely some clear good uses and some clear bad uses of inpatient chemotherapy. Can outpatient regimens be substituted for the regimens where patients are directly admitted? Or, can outpatient protocols be devised for these regimens? Are there specific situations where inpatient chemotherapy is the right thing (leukemia, esophageal cancer with worsening dysphagia, etc.)?”

No study funding was received.

A new study finds that mortality is significantly higher among patients with advanced solid tumors who are admitted to the hospital for chemotherapy treatment.

The findings – released in a poster session at the annual meeting of the American Society of Clinical Oncology – found that patients with solid tumors were more likely to be treated for nonurgent indications, not be referred to palliative care, and die within 60 days, compared with patients with hematologic malignancies.

Decisions about inpatient chemotherapy should not be uniform and instead should be based on a case-by-case basis, said Natalie Berger, MD, a hematologist-oncologist at Mount Sinai Hospital,, New York, and the study’s lead author.

Inpatient chemotherapy can be appropriate in certain situations, such as when chemotherapy must be given in the hospital and when it must be administered quickly after a patient presents with cancer symptoms and needs relief, she said.

However, “sometimes patients are admitted due to infection, side effects of chemotherapy or cancer, or for reasons unrelated to their cancer, and chemotherapy may be administered when it is not appropriate. It is also overutilized at the end of life which can lead to more aggressive end-of-life care rather than focusing on quality of life and supportive care,” Dr. Berger said.

The study is based on a retrospective chart review of 880 patients admitted to Mount Sinai Hospital between January 2016 and December 2017 to receive chemotherapy.

They found that the type of tumor was used to determine the urgency of an in-hospital stay for chemotherapy (odds ratio, 0.42; 95% CI, 0.25-0.72; P = .001). Patients with solid tumors or older patients or patients with a functional impairment score (Karnofsky Performance Scale) of 50% were less likely to respond to chemotherapy. There was also a decrease in quality of life among these patients, but only 46% of patients with solid tumors and 15% of patients with hematologic malignancies met with a palliative care professional.

One-third (34%) of patients with solid tumors didn’t have urgent indications, 43% of patients had no response to inpatient chemotherapy, and 20% died within 60 days, compared with patients with hematologic malignancies (19%, 19%, and 9%, respectively).

“There are many reasons why this [high mortality rate in patients with solid tumors] may be happening. Solid tumor patients are more often admitted at a later stage of their cancer when they are sicker, and they were also less likely to have a response to inpatient chemotherapy. Older patients and patients with a poor performance status were also less likely to respond to chemotherapy. This indicates that these patients were sicker, and chemotherapy use may not have been appropriate and palliative care may be underutilized,” she said.

Dr. Berger and colleagues have created a standardized protocol to assess “the appropriateness” of inpatient chemotherapy, improve quality of life, and reduce chemotherapy and health care utilization at the end of life. The protocol has been implemented as a pilot program at Mount Sinai Hospital, Dr. Berger said.

“Any inpatient chemotherapy case that meets standard accepted criteria for required inpatient administration are auto-approved through the electronic survey. For cases outside of standard criteria, further information must be inputted to determine appropriateness of inpatient treatment and are then scored electronically and reviewed by committee physicians and pharmacists,” she said.

Gabriel A. Brooks, MD, MPH, an oncologist with Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not affiliated with the study, said that inpatient chemotherapy treatment is under scrutiny elsewhere as well.

“There has been recognition that patients who are otherwise sick enough to require hospital admission are often too sick to benefit from chemotherapy,” although there are exceptions. “There is certainly a movement to limit inpatient chemotherapy to situations where it is most likely to be beneficial. Some of this is driven by cost pressures. For instance, Medicare pays for inpatient hospitalizations using the DRG [diagnosis-related group] system. Hospitals cannot charge a la carte for treatments given in the hospital. Instead, they are reimbursed at a fixed rate based on the hospital diagnoses. This will often lead to poor reimbursement of high-cost cancer treatments.”

Dr. Brooks said the study offers insight into who’s getting inpatient chemotherapy. However, “what I can’t tell from this poster is how often the solid tumor patients are getting first-line chemotherapy [as] these patients may be presenting late or may have a potentially treatable cancer with a narrow closing window for treatment versus later-line chemotherapy.”

He also noted that patient and family wishes are missing from the research. “This is critical. Patients and families should be informed that inpatient chemotherapy may not provide the benefit they are hoping for, especially for patients with solid tumors starting later lines of therapy. Patients should be informed that there are alternatives to inpatient chemotherapy, such as hospice referral or waiting for possible outpatient treatment – if their condition improves. But when a patient wants to try inpatient chemotherapy and their doctor wants to offer it, then it is likely a reasonable thing to try.”

Going forward, he said, “qualitative study is needed to better understand when and why inpatient chemotherapy is used. There are likely some clear good uses and some clear bad uses of inpatient chemotherapy. Can outpatient regimens be substituted for the regimens where patients are directly admitted? Or, can outpatient protocols be devised for these regimens? Are there specific situations where inpatient chemotherapy is the right thing (leukemia, esophageal cancer with worsening dysphagia, etc.)?”

No study funding was received.

CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Many of us attended virtually, or in person, and were wowed by some of the abstracts and their implications for our patients – some practice changing. Here, I highlight some presentations that stood out to me.

A first-line treatment for metastatic colorectal cancer

The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.

The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients. 
 

A possible new standard of care in breast cancer

Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy. 

Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.

The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.

Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%. 

Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.

The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
 

Improving outcomes in multiple myeloma

In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.

The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.

The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.

This study was simultaneously published in the New England Journal of Medicine.
 

Adagrasib promising for pretreated patients with NSCLC with KRAS mutation

In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.

The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
 

Neoadjuvant chemotherapy with immunotherapy for NSCLC

It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.

In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.

In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.

CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Many of us attended virtually, or in person, and were wowed by some of the abstracts and their implications for our patients – some practice changing. Here, I highlight some presentations that stood out to me.

A first-line treatment for metastatic colorectal cancer

The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.

The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients. 
 

A possible new standard of care in breast cancer

Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy. 

Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.

The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.

Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%. 

Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.

The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
 

Improving outcomes in multiple myeloma

In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.

The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.

The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.

This study was simultaneously published in the New England Journal of Medicine.
 

Adagrasib promising for pretreated patients with NSCLC with KRAS mutation

In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.

The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
 

Neoadjuvant chemotherapy with immunotherapy for NSCLC

It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.

In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.

In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.

CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Many of us attended virtually, or in person, and were wowed by some of the abstracts and their implications for our patients – some practice changing. Here, I highlight some presentations that stood out to me.

A first-line treatment for metastatic colorectal cancer

The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.

The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients. 
 

A possible new standard of care in breast cancer

Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy. 

Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.

The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.

Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%. 

Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.

The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
 

Improving outcomes in multiple myeloma

In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.

The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.

The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.

This study was simultaneously published in the New England Journal of Medicine.
 

Adagrasib promising for pretreated patients with NSCLC with KRAS mutation

In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.

The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
 

Neoadjuvant chemotherapy with immunotherapy for NSCLC

It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.

In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.

In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.

We’ve still got some work to do before we can say with authority whether concurrent neoadjuvant chemotherapy and immunotherapy is better than concurrent adjuvant chemotherapy with immunotherapy for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.

Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.

In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.

In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.

The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
 

What else did we learn about neoadjuvant treatment at the meeting?

Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).

Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).

We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.

Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.

Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).

KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
 

What to do when a patient presents with resectable disease?

Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.

Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.

Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.

So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.

Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).

Hopefully, ASCO 2023 will provide more answers.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

We’ve still got some work to do before we can say with authority whether concurrent neoadjuvant chemotherapy and immunotherapy is better than concurrent adjuvant chemotherapy with immunotherapy for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.

Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.

In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.

In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.

The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
 

What else did we learn about neoadjuvant treatment at the meeting?

Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).

Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).

We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.

Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.

Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).

KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
 

What to do when a patient presents with resectable disease?

Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.

Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.

Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.

So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.

Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).

Hopefully, ASCO 2023 will provide more answers.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

We’ve still got some work to do before we can say with authority whether concurrent neoadjuvant chemotherapy and immunotherapy is better than concurrent adjuvant chemotherapy with immunotherapy for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.

Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.

In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.

In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.

The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
 

What else did we learn about neoadjuvant treatment at the meeting?

Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).

Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).

We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.

Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.

Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).

KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
 

What to do when a patient presents with resectable disease?

Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.

Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.

Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.

So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.

Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).

Hopefully, ASCO 2023 will provide more answers.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

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

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

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

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

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These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

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

Key clinical point: Adagrasib shows favorable clinical efficacy without any new safety signals in patients with previously treated KRAS^G12C-mutated nonsmall cell lung cancer (NSCLC).

Major finding: Among patients with measurable disease at baseline, 42.9% had a confirmed objective response. The median progression-free survival was 6.5 (95% CI 4.7-8.4) months. At a median follow-up of 15.6 months, the median overall survival was 12.6 (95% CI 9.2-19.2) months. The treatment-related adverse events of grade 1/2 and 3 occurred in 52.6% and 44.8% of patients, respectively.

Study details: This registrational phase 2 cohort study investigated adagrasib in 116 patients with KRAS^G12C-mutated NSCLC previously treated with platinum-based chemotherapy with or without anti-programmed death 1 or programmed death ligand 1 therapy.

Disclosures: The study was funded by Mirati Therapeutics. The authors reported ties with one or more pharmaceutical companies, including employment or stock options in Mirati Therapeutics.

Source: Jänne PA et al. Adagrasib in non–small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med. 2022 (Jun 3). Doi: 10.1056/NEJMoa2204619

Key clinical point: Adagrasib shows favorable clinical efficacy without any new safety signals in patients with previously treated KRAS^G12C-mutated nonsmall cell lung cancer (NSCLC).

Major finding: Among patients with measurable disease at baseline, 42.9% had a confirmed objective response. The median progression-free survival was 6.5 (95% CI 4.7-8.4) months. At a median follow-up of 15.6 months, the median overall survival was 12.6 (95% CI 9.2-19.2) months. The treatment-related adverse events of grade 1/2 and 3 occurred in 52.6% and 44.8% of patients, respectively.

Study details: This registrational phase 2 cohort study investigated adagrasib in 116 patients with KRAS^G12C-mutated NSCLC previously treated with platinum-based chemotherapy with or without anti-programmed death 1 or programmed death ligand 1 therapy.

Disclosures: The study was funded by Mirati Therapeutics. The authors reported ties with one or more pharmaceutical companies, including employment or stock options in Mirati Therapeutics.

Source: Jänne PA et al. Adagrasib in non–small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med. 2022 (Jun 3). Doi: 10.1056/NEJMoa2204619

Key clinical point: Adagrasib shows favorable clinical efficacy without any new safety signals in patients with previously treated KRAS^G12C-mutated nonsmall cell lung cancer (NSCLC).

Major finding: Among patients with measurable disease at baseline, 42.9% had a confirmed objective response. The median progression-free survival was 6.5 (95% CI 4.7-8.4) months. At a median follow-up of 15.6 months, the median overall survival was 12.6 (95% CI 9.2-19.2) months. The treatment-related adverse events of grade 1/2 and 3 occurred in 52.6% and 44.8% of patients, respectively.

Study details: This registrational phase 2 cohort study investigated adagrasib in 116 patients with KRAS^G12C-mutated NSCLC previously treated with platinum-based chemotherapy with or without anti-programmed death 1 or programmed death ligand 1 therapy.

Disclosures: The study was funded by Mirati Therapeutics. The authors reported ties with one or more pharmaceutical companies, including employment or stock options in Mirati Therapeutics.

Source: Jänne PA et al. Adagrasib in non–small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med. 2022 (Jun 3). Doi: 10.1056/NEJMoa2204619

Key clinical point: Cemiplimab appears to have the most favorable benefit-risk ratio among the analyzed immune checkpoint inhibitors (ICI) for the treatment of patients with nonsmall cell lung cancer (NSCLC).

Major finding: Cemiplimab was associated with the lowest hazard ratio (HR) for overall survival (OS) relative to chemotherapy (HR 0.68; 95% CI 0. 57-0.81), translating to the highest surface under the cumulative ranking curve (SUCRA) value of 49.5%. Additionally, cemiplimab was associated with the lowest incidence of treatment-related adverse events (TRAE) relative to chemotherapy (odds ratio 0.17; 95% credible interval 0.06-0.45).

Study details: The data come from a network meta-analysis of 13 randomized controlled trials (n = 7795). The SUCRA values of all ICI (cemiplimab, avelumab, atezolizumab, nivolumab, and pembrolizumab) were determined for OS and TRAE.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Jiang M et al. Comparative efficacy and safety of anti-PD-1/PD-L1 for the treatment of non-small cell lung cancer: A network meta-analysis of 13 randomized controlled studies. Front Oncol. 2022;12:827050 (May 10). Doi: 10.3389/fonc.2022.827050

Key clinical point: Cemiplimab appears to have the most favorable benefit-risk ratio among the analyzed immune checkpoint inhibitors (ICI) for the treatment of patients with nonsmall cell lung cancer (NSCLC).

Major finding: Cemiplimab was associated with the lowest hazard ratio (HR) for overall survival (OS) relative to chemotherapy (HR 0.68; 95% CI 0. 57-0.81), translating to the highest surface under the cumulative ranking curve (SUCRA) value of 49.5%. Additionally, cemiplimab was associated with the lowest incidence of treatment-related adverse events (TRAE) relative to chemotherapy (odds ratio 0.17; 95% credible interval 0.06-0.45).

Study details: The data come from a network meta-analysis of 13 randomized controlled trials (n = 7795). The SUCRA values of all ICI (cemiplimab, avelumab, atezolizumab, nivolumab, and pembrolizumab) were determined for OS and TRAE.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Jiang M et al. Comparative efficacy and safety of anti-PD-1/PD-L1 for the treatment of non-small cell lung cancer: A network meta-analysis of 13 randomized controlled studies. Front Oncol. 2022;12:827050 (May 10). Doi: 10.3389/fonc.2022.827050

Key clinical point: Cemiplimab appears to have the most favorable benefit-risk ratio among the analyzed immune checkpoint inhibitors (ICI) for the treatment of patients with nonsmall cell lung cancer (NSCLC).

Major finding: Cemiplimab was associated with the lowest hazard ratio (HR) for overall survival (OS) relative to chemotherapy (HR 0.68; 95% CI 0. 57-0.81), translating to the highest surface under the cumulative ranking curve (SUCRA) value of 49.5%. Additionally, cemiplimab was associated with the lowest incidence of treatment-related adverse events (TRAE) relative to chemotherapy (odds ratio 0.17; 95% credible interval 0.06-0.45).

Study details: The data come from a network meta-analysis of 13 randomized controlled trials (n = 7795). The SUCRA values of all ICI (cemiplimab, avelumab, atezolizumab, nivolumab, and pembrolizumab) were determined for OS and TRAE.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Jiang M et al. Comparative efficacy and safety of anti-PD-1/PD-L1 for the treatment of non-small cell lung cancer: A network meta-analysis of 13 randomized controlled studies. Front Oncol. 2022;12:827050 (May 10). Doi: 10.3389/fonc.2022.827050

Key clinical point: Adagrasib shows favorable clinical efficacy without any new safety signals in patients with previously treated KRAS^G12C-mutated nonsmall cell lung cancer (NSCLC).

Major finding: Among patients with measurable disease at baseline, 42.9% had a confirmed objective response. The median progression-free survival was 6.5 (95% CI 4.7-8.4) months. At a median follow-up of 15.6 months, the median overall survival was 12.6 (95% CI 9.2-19.2) months. The treatment-related adverse events of grade 1/2 and 3 occurred in 52.6% and 44.8% of patients, respectively.

Study details: This registrational phase 2 cohort study investigated adagrasib in 116 patients with KRAS^G12C-mutated NSCLC previously treated with platinum-based chemotherapy with or without anti-programmed death 1 or programmed death ligand 1 therapy.

Disclosures: The study was funded by Mirati Therapeutics. The authors reported ties with one or more pharmaceutical companies, including employment or stock options in Mirati Therapeutics.

Source: Jänne PA et al. Adagrasib in non–small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med. 2022 (Jun 3). Doi: 10.1056/NEJMoa2204619

Key clinical point: Adagrasib shows favorable clinical efficacy without any new safety signals in patients with previously treated KRAS^G12C-mutated nonsmall cell lung cancer (NSCLC).

Major finding: Among patients with measurable disease at baseline, 42.9% had a confirmed objective response. The median progression-free survival was 6.5 (95% CI 4.7-8.4) months. At a median follow-up of 15.6 months, the median overall survival was 12.6 (95% CI 9.2-19.2) months. The treatment-related adverse events of grade 1/2 and 3 occurred in 52.6% and 44.8% of patients, respectively.

Study details: This registrational phase 2 cohort study investigated adagrasib in 116 patients with KRAS^G12C-mutated NSCLC previously treated with platinum-based chemotherapy with or without anti-programmed death 1 or programmed death ligand 1 therapy.

Disclosures: The study was funded by Mirati Therapeutics. The authors reported ties with one or more pharmaceutical companies, including employment or stock options in Mirati Therapeutics.

Source: Jänne PA et al. Adagrasib in non–small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med. 2022 (Jun 3). Doi: 10.1056/NEJMoa2204619

Key clinical point: Adagrasib shows favorable clinical efficacy without any new safety signals in patients with previously treated KRAS^G12C-mutated nonsmall cell lung cancer (NSCLC).

Major finding: Among patients with measurable disease at baseline, 42.9% had a confirmed objective response. The median progression-free survival was 6.5 (95% CI 4.7-8.4) months. At a median follow-up of 15.6 months, the median overall survival was 12.6 (95% CI 9.2-19.2) months. The treatment-related adverse events of grade 1/2 and 3 occurred in 52.6% and 44.8% of patients, respectively.

Study details: This registrational phase 2 cohort study investigated adagrasib in 116 patients with KRAS^G12C-mutated NSCLC previously treated with platinum-based chemotherapy with or without anti-programmed death 1 or programmed death ligand 1 therapy.

Disclosures: The study was funded by Mirati Therapeutics. The authors reported ties with one or more pharmaceutical companies, including employment or stock options in Mirati Therapeutics.

Source: Jänne PA et al. Adagrasib in non–small-cell lung cancer harboring a KRAS^G12C mutation. N Engl J Med. 2022 (Jun 3). Doi: 10.1056/NEJMoa2204619