Abstract
BackgroundClinically-available biomarkers to identify the fraction of patients with small cell lung cancer (SCLC) who respond to immune-checkpoint inhibitors (ICIs) are lacking. High nonsynonymous tumor mutational burden (TMB), as assessed by whole exome sequencing, correlates with improved clinical outcomes for patients with SCLC treated with ICIs. Whether TMB as assessed by targeted next generation sequencing (NGS) is associated with improved efficacy of ICIs in patients with SCLC is currently unknown. Here we determined whether TMB by targeted NGS is associated with efficacy of ICIs in patients with SCLC.MethodsWe collected clinicopathologic data from patients with relapsed or refractory SCLC which underwent targeted NGS with TMB assessment by the Dana-Farber Cancer Institute OncoPanel platform. The relationship between TMB and clinical outcomes after treatment with ICIs was investigated.ResultsAmong the 52 patients treated with ICIs, we found no significant difference in the objective response rate (ORR) between patients with a TMB above the 50th percentile (“TMB high”) and those with a TMB at or below the 50th percentile (“TMB low”). The median progression-free survival (mPFS) and median overall survival (mOS) were significantly longer in patients with a high TMB compared to those with a low TMB (mPFS: 3.3 versus 1.2 months, HR: 0.37 [95% CI: 0.20–0.69], P < 0.01; mOS: 10.4 versus 2.5 months, HR: 0.38 [95% CI: 0.19–0.77], P < 0.01). The one-year PFS and OS rates improved with increasing mutational load when TMB was divided into tertiles.ConclusionsThese findings show that targeted NGS, a readily available clinical diagnostic test, can be used to identify patients with SCLC who are most likely to benefit from treatment with immune checkpoint inhibitors.
Highlights
The majority of patients diagnosed with extensive-stage small cell lung cancer (ES-SCLC) respond to first-line chemotherapy, relapse invariably occurs and only 5% of patients are alive two years after initial diagnosis [1,2,3]
The phase I/III IMpower 133 trial demonstrated an overall survival benefit when the Programmed death (PD)-L1 inhibitor atezolizumab was added to platinum/etoposide chemotherapy for the initial treatment of Extensive stage (ES)-SCLC [8], why only a subset of patients benefitted from this combination therapy is not currently known
In the present study we investigate the feasibility of using targeted next generation sequencing (NGS) to quantify tumor mutational burden (TMB) in SCLC and determine if patients with SCLC and a high TMB are more likely to benefit from treatment with immune checkpoint inhibitors than in patients with SCLC and a low TMB
Summary
The majority of patients diagnosed with extensive-stage small cell lung cancer (ES-SCLC) respond to first-line chemotherapy, relapse invariably occurs and only 5% of patients are alive two years after initial diagnosis [1,2,3]. In the CheckMate 032 phase I/ II trial [5], the objective response rate (ORR) to nivolumab monotherapy and nivolumab plus ipilimumab was 11 and 23%, and the two-year overall survival rates were 14 and 26%, respectively [6] Based on these results, single-agent nivolumab was granted accelerated FDA approval for patients with SCLC with disease progression following platinum-based chemotherapy and one other line of therapy. The phase I/III IMpower 133 trial demonstrated an overall survival benefit when the PD-L1 inhibitor atezolizumab was added to platinum/etoposide chemotherapy for the initial treatment of ES-SCLC [8], why only a subset of patients benefitted from this combination therapy is not currently known.
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