Shared decision-making required when choosing first-line regimen for PD-L1-high NSCLC
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CHICAGO — Chemoimmunotherapy and immunotherapy alone conferred comparable benefit as first-line therapy for most patients with advanced non-small cell lung cancer and high PD-L1 expression, results presented at ASCO Annual Meeting showed.
Older patients appeared to derive better OS and PFS outcomes with immunotherapy alone, findings from the exploratory pooled analysis showed.
“These results support shared decision-making that balances potential benefits and risks of adding [chemotherapy to immuno-oncology] regimens based on patient factors that may impact tolerability,” Oladimeji Akinboro, MD, medical oncologist and clinical reviewer with the FDA, and colleagues concluded.
Background and methods
Several first-line treatments are approved in the United States for patients with advanced NSCLC and high PD-L1 expression. These options include immunotherapies with or without chemotherapy.
However, it is unclear whether the addition of chemotherapy to immunotherapy considerably improves efficacy for this population.
Akinboro and colleagues pooled data from 12 randomized controlled trials that assessed anti-PD-1/anti-PD-L1 agents with or without chemotherapy as first-line treatment for patients with advanced NSCLC and high PD-L1 expression, defined as scores of 50% or higher.
Investigators evaluated OS, PFS and overall response rates among patients who received chemotherapy-immunotherapy and immunotherapy alone.
The analysis included 3,189 patients (69% male; 80% white).
Nearly half of study participants were aged older than 65 years (65 to 74 years, 38%; aged 75 years or older, 11%). Two-thirds (66%) of patients had ECOG performance status of 1 or higher, and 89% were current or former smokers.
Overall results
The pooled OS analysis included 1,753 patients (chemoimmunotherapy, 26%; immunotherapy alone, 74%).
Results from the overall cohort showed median OS of 25 months among patients treated with chemotherapy-immunotherapy and 20.9 months among those treated with immunotherapy alone (HR = 0.82; 95% CI, 0.62-1.08).
Researchers reported longer median PFS (9.6 months vs. 7.1 months; HR = 0.69; 95% CI, 0.55-0.87) and a higher ORR (61% vs. 43%; OR = 1.2; 95% CI, 1.1-1.3) in the chemotherapy-immunotherapy group.
Effect of age
Patients aged younger than 65 years derived a statistically significant OS benefit with the addition of chemotherapy to immunotherapy (median, 25 months vs. 23.3 months; HR = 0.67; 95% CI, 0.46-0.99).
Differences in median OS between chemotherapy-immunotherapy and immunotherapy alone did not reach statistical significance among patients aged 65 to 74 years (22.2 months vs. 18.6 months; HR = 0.83; 95% CI, 0.54-1.28) or those aged 75 years or older (not estimable vs. 18.9 months; HR = 1.68; 95% CI, 0.69-4.06).
The chemotherapy-immunotherapy combination conferred a statistically significant improvement in median PFS among patients aged younger than 65 years (9.4 months vs. 7.7 months; HR = 0.54; 95% CI, 0.39-0.75), but not among those aged 65 to 74 years (9.7 months vs. 6.8 months; HR = 0.8; 95% CI, 0.56-1.13) or those aged 75 years or older (11.8 months vs. 7.2 months; HR = 1.22; 95% CI, 0.58-2.57).
The difference in ORR between the chemotherapy-immunotherapy and immunotherapy alone groups appeared greater among those aged younger than 65 years (62% vs. 43%; OR = 2.2; 95% CI, 1.3-3.7) and those aged 65 to 74 years (62% vs. 43%; OR = 1.9; 95% CI, 1.1-3.4) than those aged 75 years or older (52% vs. 45%; OR = 1.2; 95% CI, 0.4-3.8).
Additional subgroup analyses
Analyses based on ECOG performance status showed similar median OS between patients treated with chemoimmunotherapy or immunotherapy alone (ECOG 0, not estimable vs. 31.8 months; HR = 0.7; 95% CI, 0.4-1.21); ECOG 1, 17.7 months vs. 18 months; 95% CI, 0.87; 95% CI, 0.64-1.19).
The difference in median PFS between the chemoimmunotherapy and immunotherapy groups reached statistical significance among patients regardless of ECOG performance status (ECOG 0, 13.7 months vs. 8.5 months; HR = 0.61; 95% CI, 0.4-0.92; ECOG 1, 8.2 months vs. 6.3 months; HR = 0.75; 95% CI, 0.57-0.98).
Chemoimmunotherapy also appeared associated with higher ORRs regardless of ECOG status (0, 66% vs. 47%; OR = 2.6; 95% CI, 1.5-4.7; 1, 58% vs. 41%; OR = 1.7; 95% CI, 1.1-2.6).
Analyses based on smoking status showed at least comparable efficacy with chemoimmunotherapy vs. immunotherapy alone with regard to median OS (never-smokers, not estimable vs. 14.4 months; HR = 0.39; 95% CI, 0.15-0.98; ever-smokers, 23 months vs. 22.1 months; 95% CI, 0.92; 95% CI, 0.69-1.22), PFS (never-smokers, 10.2 months vs. 3.7 months; HR = 0.46; 95% CI, 0.23-0.92; ever-smokers, 9.3 months vs. 8.2 months; HR = 0.75; 95% CI, 0.59-0.95) and ORR (never-smokers, 69% vs. 28%; OR = 4.6; 95% CI, 1.5-14.5; ever-smokers, 60% vs. 45%; OR = 1.7; 95% CI, 1.2-2.5).
Limitations
Akinboro acknowledged several study limitations.
“This was a retrospective and exploratory pooled analysis. It was a cross-trial comparison, as none of these trials directly compared [chemotherapy-immunotherapy and immunotherapy alone],” he said. “As such, the results are only hypothesis generating.”
Researchers did not examine factors that may potentially explain the lack of concordance between OS results and the PFS and ORR outcomes.
“Subsequent receipt of platinum-based chemotherapy by patients with in the [immunotherapy only] arm potentially could have attenuated the OS difference between arms,” Akinboro said. “We also acknowledge the clinical trial populations in our analysis may be different from real-world patients with regard to attributes such as age, performance status and race.”
Perspective
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The FDA pooled analysis presented in this abstract indicates that, for patients with NSCLC and PD-L1 expression of 50% or higher, the combination of a checkpoint inhibitor plus chemotherapy results in slightly higher median PFS and OS. We knew that responses can be higher with the combination of chemotherapy and a checkpoint inhibitor based on prior studies. This is an important clinical question for us. We can use single-agent checkpoint inhibitors in this subgroup of patients based on the results of published clinical trials. Combination with chemotherapy is also a possibility and supported by another set of trials, but we do not have data from head-to-head comparisons of these treatment options. This retrospective analysis seems to suggest that at least some patients might draw more PFS and OS benefit using a combination approach. This must be balanced against potential toxicities of the combination vs. a single-agent checkpoint inhibitor.
Perspective
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Sally C. Lau, MD, MPH
PD-1 inhibition alone or in combination with chemotherapy both are accepted standards for first-line treatment of NSCLC with PD-L1 scores of 50% or higher, but the necessity of chemotherapy is controversial. Peters and colleagues presented observational data at ESMO Congress in 2021 based on 520 patients identified from the Flatiron Health database. Results demonstrated that omitting chemotherapy did not affect OS, except among nonsmokers.
This abstract by Akinboro and colleagues examines the same question using a pooled analysis of 12 studies. For the first time, prospective data are presented on this issue.
The OS analysis showed comparability between PD-1 inhibitor monotherapy and an immunotherapy-chemotherapy combination. Not unexpectedly, PFS and ORR appear modestly improved with the combination. These results largely complement those from the observational study.
The ongoing phase 3 INSIGNA trial will address this question in a randomized study. Until then, clinicians will need to make decisions based on available observational and pooled data. Given that benefits are modest — and only in PFS and ORR — chemotherapy likely can be spared for many patients with NSCLC with PD-L1 scores of 50% or higher. However, certain subgroups, such as nonsmokers, had a clear benefit from the addition of chemotherapy in the observational study. Results showed no difference among patients with brain or liver metastases, but the study had limited power given the sample size.
Although Akinboro and colleagues only reported on major treatment outcomes, which are reassuring, the sample size with this pooled analysis is optimal for exploratory work to identify unique subgroups and generate hypotheses for future precision oncology studies.
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Akinboro O, et al. Abstract 9000. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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