Small cell lung cancer responds to immunogenic chemotherapy followed by PD-1 blockade.
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ABSTRACT:
SUBMITTER: Kroemer G
PROVIDER: S-EPMC8565809 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Small cell lung cancer responds to immunogenic chemotherapy followed by PD-1 blockade.
Oncoimmunology 20211102 1
Sequential combination of immunogenic cell death (ICD)-induced interventions with subsequent immunotherapy has shown efficacy in preclinical models and clinical evaluation. Recently, a clinical trial enrolling small cell lung cancer patients treated with amrubicin together with PD-1 blockade confirmed the notion that ICD sensitizes tumors to immune checkpoint inhibitors. ...[more]
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Project description:BackgroundPD-1 blockade plus chemotherapy has become the first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without oncogenic drivers. Oncogenic-driven advanced NSCLC showed limited response to PD-1 blockade monotherapy or chemotherapy alone. Whether NSCLC patients with oncogenic drivers could benefit from PD-1 blockade plus chemotherapy remains undetermined.MethodsThree hundred twelve NSCLC patients with at least one oncogenic driver alteration received PD-1 plus chemotherapy or each monotherapy were retrospectively identified. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared to evaluate the therapeutic outcomes differences among patients with different oncogenic drivers.ResultsOne hundred sixty-two patients received PD-1 blockade plus chemotherapy, 57 received PD-1 blockade monotherapy and 93 received chemotherapy alone were included. Oncogenic driver mutations including KRAS (31.4%), EGFR (28.8%), HER2 (14.7%), BRAF (10.6%), RET (7.4%), and other mutations (7.1%) were identified. Patients with oncogenic drivers who received PD-1 blockade plus chemotherapy had significantly better outcomes compared to those received PD-1 blockade or chemotherapy alone (ORR: 51% vs. 18% vs. 25%, P < 0.001; median PFS: 10.0 [95% CI: 8.9-12.6] vs. 3.7 [95% CI: 2.9-5.1] vs. 5.3 [95% CI: 4.5-6.2] months, P < 0.001; median OS: 26.0 [95% CI: 23.0-30.0] vs. 14.3 [95% CI: 9.6-19.8] vs. 16.1 [95% CI: 11.6-21.9] months, P < 0.001). The superior efficacy was consistently found in separate analyses for patients received first-line and second/third line treatments. Among individual gene alterations, patients with KRAS, EGFR, or BRAF mutations treated with PD-1 blockade plus chemotherapy achieved markedly improved PFS and OS than those received PD-1 blockade or chemotherapy alone. Multivariate Cox regression analysis revealed that PD-1 blockade plus chemotherapy was independently associated with better PFS and OS.ConclusionPD-1 blockade plus chemotherapy demonstrated superior efficacy than PD-1 blockade monotherapy or chemotherapy alone in patients with oncogenic-driven advanced NSCLC, particularly in KRAS, EGFR and BRAF subgroups. These findings suggest that PD-1 blockade plus chemotherapy may be considered as an optional treatment option for patients without available targeted therapies.
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Project description:BackgroundDirect KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations.Patients and methodsThrough next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups.ResultsOne hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053).ConclusionsWe define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies.
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