Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in <i>KRAS-</i>mutated non-small cell lung cancer with <i>STK11</i>, <i>KEAP1,</i> or <i>TP53</i> comutations: subgroup results from the phase III IMpower150 trial
Howard West, Mark L. McCleland, Federico Cappuzzo, Martin Reck, Tony Mok, Robert M. Jotte, Makoto Nishio, Eugene Kim, Stefanie Morris, Wei Zou, David S. Shames, Meghna Das Thakur, Geetha Shankar, Mark A. Socinski
Abstract
Background The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (m KRAS ) and co-occurring STK11 , KEAP1, or TP53 mutations. Methods Mutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774). Results Within the m KRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)—greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in m KRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS -WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11 , KEAP1, and TP53 ; these subgroups conferred different prognostic outcomes. Within the m KRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11 -WT and/or KEAP 1-WT. In m KRAS patients with co-occurring m STK11 and/or m KEAP1 (44.9%) or m TP53 (49.3%), survival was longer with ABCP than with ACP or BCP. Conclusions These analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the m KRAS and KEAP1 -WT and STK11 -WT population vs m KRAS and m KEAP1 and m STK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with m KRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.