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A Randomized Phase II Study Comparing Nivolumab with Carboplatin-Pemetrexed for EGFR-Mutated NSCLC with Resistance to
Hidetoshi Hayashi1, Shunichi Sugawara2, Yasushi Fukuda3
1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Purpose:
Although the efficacy of programmed cell death-1 (PD-1) blockade is generally poor for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs.
Patients And Methods:
Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin-pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS).
Results:
Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin-pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61-2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53-1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin-pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell-inflamed gene expression profile score (0.11 vs. -0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab.
Conclusions:
Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
Insights
Nivolumab did not improve progression-free survival compared to chemotherapy in non-small cell lung cancer patients previously treated with EGFR inhibitors. However, gene expression profiling indicated potential efficacy in a subset with a favorable tumor immune microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Programmed cell death-1 (PD-1) blockade has limited efficacy in non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations.
- EGFR tyrosine kinase inhibitors (TKIs) may modulate the tumor immune microenvironment, potentially influencing immunotherapy response.
Purpose of the Study:
- To evaluate if nivolumab improves outcomes compared to chemotherapy in EGFR-mutated NSCLC patients resistant to prior EGFR-TKIs.
- To assess the impact of nivolumab on progression-free survival (PFS) in this patient population.
Main Methods:
- A randomized study comparing nivolumab to carboplatin-pemetrexed in EGFR-mutated NSCLC patients with acquired resistance to EGFR-TKIs (excluding T790M mutation).
- Primary endpoint was progression-free survival (PFS).
Main Results:
- Nivolumab showed significantly shorter median PFS (1.7 months) and 1-year PFS probability (9.6%) compared to carboplatin-pemetrexed (5.6 months and 14.0%, respectively).
- Overall survival and response rates did not significantly favor nivolumab. No subgroup, including those with high tumor mutation burden, demonstrated substantially longer PFS with nivolumab.
- Higher T-cell-inflamed gene expression profile scores and related gene expression were observed in tumors benefiting from nivolumab.
Conclusions:
- Nivolumab did not demonstrate superior PFS compared to carboplatin-pemetrexed in EGFR-mutated NSCLC patients post-EGFR-TKI treatment.
- Gene expression profiling identified a subset of patients with a favorable tumor immune microenvironment potentially benefiting from nivolumab.
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