Martin Reck, MD, PhD
This retrospective analysis of the IMpower150 trial (NCT02486718) explored efficacy endpoints within patients with NSCLC, stratified by the tumor KRAS mutational status. Despite limited patient numbers in this exploratory analysis, disease-free survival (DFS) appeared to be consistent and in favor of atezolizumab across subgroups regardless of KRAS status. This research was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023, held 2-6 June in Chicago. Physician’s Weekly discussed these findings with lead study author Martin Reck, MD, PhD.
PW: What was the study question and rationale?
Dr. Reck: Mutations in the KRAS oncogene are a major driver of nonsquamous NSCLC and occur in about 25%–40% of non-Asian patients, with the glycine 12 to cysteine (G12C) activating mutation having the highest prevalence, at about 11%. Once the IMpower010 trial met its primary endpoint of DFS, leading to approval of atezolizumab after adjuvant platinum-based chemotherapy for completely resected PD-L1 TC ≥1% or ≥50% stage II-IIIA NSCLC in the United States, European Union and other parts of the world, we asked whether the presence of mutant KRAS (mKRAS) in the tumor was relevant to response. At ASCO 2023, we reported the post-hoc exploratory DFS outcomes stratified by KRAS mutational status in patients from IMpower010.
What did you find?
To obtain that answer, we retrospectively assessed KRAS mutational status using whole-exome sequencing on resected tumor tissue from 603 patients in total. Our analysis evaluated DFS in subgroups of patients by KRAS mutational status: wild-type KRAS versus any mKRAS type, including G12C. A separate analysis of the KRAS G12C subgroup was not possible due to too few patient numbers.
Of the 603 patients for whom we had whole-exome sequencing data, 536 had stage II-IIIA NSCLC. We found that 22% of those stage II-IIIA patients had mKRAS, while 10% harbored KRAS G12C. Consistent with previous literature, mKRAS was enriched in White, nonsquamous and smoker populations. Compared with best standard of care, atezolizumab showed improved DFS regardless of KRAS status in the stage II-IIIA population, and this was also regardless of PD-L1 status. We have also explored KRAS mutational status in the context of co-mutations, but we did not present that data at ASCO.
What were the limitations?
One major limitation of this retrospective exploratory analysis was numbers of patients were small. The prevalence of mKRAS was found to be slightly lower in this study than previously published, perhaps due to the methodology employed. Therefore, due to the small subgroup size, comparisons were not adequately powered to detect treatment differences, although exploratory endpoints were prespecified.
What are the clinical implications?
While the current findings from this study offer interesting insights into the personalized treatment of patients with KRAS-mutated NSCLC, there are no immediate practice-changing aspects. We are, however, excited to continue to analyze additional data to work towards better patient selection to incrementally improve the care we can offer, as well as working towards a better understanding of the biology behind response.
