Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial.

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 (mKRAS) 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 mKRAS 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 mKRAS 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 mKRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-WT and/or KEAP1-WT. In mKRAS patients with co-occurring mSTK11 and/or mKEAP1 (44.9%) or mTP53 (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 mKRAS and KEAP1-WT and STK11-WT population vs mKRAS and mKEAP1 and mSTK11 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 mKRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

• Authors: Howard Jack West, Mark McCleland, Federico Cappuzzo, Martin Reck, Tony Sk Mok, Robert M Jotte, Makoto Nishio, Eugene Kim, Stefanie Morris, Wei Zou, David Shames, Meghna Das Thakur, Geetha Shankar, Mark A Socinski
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 2 (02 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35190375 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Monoclonal, Humanized
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• TP53 protein, human
• Tumor Suppressor Protein p53
• Bevacizumab
• atezolizumab
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases (metabolism)
• Adult
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Bevacizumab (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, mortality, pathology)
• Female
• Humans
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Lung Neoplasms (drug therapy, mortality, pathology)
• Middle Aged
• Mutation
• Prognosis
• Progression-Free Survival
• Retrospective Studies
• Tumor Suppressor Protein p53 (metabolism)