Anti-PD-(L)1 for KRAS-mutant advanced non-small-cell lung cancers: a meta-analysis of randomized-controlled trials

The most frequent mutation in advanced non-small-cell lung cancer (NSCLC), Kirsten rat-sarcoma viral oncogene (KRAS) is found in 20-25% of these patients' tumors. While phase III trials on therapies targeting KRAS, especially KRAS^G12C, are ongoing, the clinical efficacy of anti-programmed death protein-1 (PD-1) or its ligand (PD-L1) against KRAS-mutant NSCLCs remains a topic of debate.

This meta-analysis examined randomized-trial data comparing first- or second-line anti-PD-(L)1 with or without chemotherapy vs. chemotherapy alone for advanced KRAS-mutant NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK).

We analyzed 3 first-line trials (IMpower-150, Keynote-189 and Keynote-042) and 3 second-line trials (Oak, Poplar and CheckMate-057) that included 1313 NSCLCs (386 KRAS-mutant and 927 KRAS wild-type tumors). For KRAS-mutant NSCLCs, anti-PD-(L)1 with or without chemotherapy was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p < 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to chemotherapy alone. OS benefited in both first- and second-line trials. OS for patients with KRAS-mutant NSCLCs was significantly longer than that for those with KRAS wild-type tumors (p = 0.001).

Anti-PD-(L)1 with or without chemotherapy seemed to achieve longer OS and PFS than chemotherapy alone for patients with KRAS-mutant and wild-type KRAS advanced NSCLCs, with an even greater OS benefit for the former.