A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC
Gillianne Lai, Jia Chi Yeo, Amit Jain, Siqin Zhou, Mengyuan Pang, Jacob J.S. Alvarez, Ngak Leng Sim, Aaron C. Tan, Lisda Suteja, Tze Wei Lim, Yu Amanda Guo, Meixin Shen, Stephanie P.L. Saw, Neha Rohatgi, Joe Yeong, Angela Takano, Kiat Hon Lim, Apoorva Gogna, Chow Wei Too, Kun Da Zhuang, Wan Ling Tan, Ravindran Kanesvaran, Quan Sing Ng, Mei Kim Ang, Tanujaa Rajasekaran, Lanying Wang, Chee‐Keong Toh, Wan‐Teck Lim, Wai Leong Tam, Sze Huey Tan, Anders J. Skanderup, Eng-Huat Tan, Daniel S.W. Tan
Abstract
Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.