Concurrent KRAS Mutations Render Single-Agent EGFR Inhibitors Futile in Advanced NSCLC
Recommended Citation
Aza I, Nagasaka M, Azmi A, Al Baghdadi T, Dib E, Abu Rous F, Qin A, Shah R, Vojjala N, Goyal K, Li G, Quintanilha J, Altenburg J, Graf R. Concurrent KRAS Mutations Render Single-Agent EGFR Inhibitors Futile in Advanced NSCLC. J Thorac Oncol 2025; 20(10):S485.
Document Type
Conference Proceeding
Publication Date
10-1-2025
Publication Title
J Thorac Oncol
Keywords
afatinib, amivantamab, epidermal growth factor receptor, lazertinib, osimertinib, prochlorperazine, bone metastasis, cohort analysis, conference abstract, controlled study, diagnosis, drug therapy, exon, female, high throughput sequencing, histology, human, major clinical study, male, neoplastic cell transformation, non small cell lung cancer, prescription, prevalence, retrospective study, social status
Abstract
Introduction: Anti-EGFR tyrosine kinase inhibitors (TKI) are transformational drugs for patients with advanced NSCLC and EGFR alterations. Osimertinib, a third generation TKI, is considered first line for metastatic EGFRmut(+) NSCLC, among other TKIs. While rare, some tu- mors with EGFR alterations have concomitant KRAS mutations, and may have an activated oncogenic pathway not inhibited by current TKIs. We hypothesized that patients with EGFR-mutant NSCLC receiving current generation anti-EGFR targeted therapy will have reduced clinical benefit when there are co-occurring KRAS alterations. Methods: Following a prespecified analysis plan, this study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine NSCLC clinicogenomic database (FH-FMI CGDB), with data originating from approxi- mately 280 US cancer clinics (w 800 sites of care). The prevalence cohort included patients with NSCLC treated in the advanced setting with first-line and had both EGFR and KRAS status assessed via tissue NGS obtained prior to treatment initiation. The outcome cohort included patients in the prevalence cohort treated with single-agent anti-EGFR TKIs and were EGFRmut(+). Differences in outcomes between groups were assessed via Kaplan-Meier plots and multivariable Cox PH models additionally adjusting for clinical factors: age, sex, ECOG performance score, pre-therapy [IA1] opioid prescription, presence of brain or bone metastases, socioeconomic status, histology, stage at diagnosis, and specific TKI. We additionally explored similar outcome associations on standard chemotherapy regimens. Results: Prevalence cohort: among 10,740 1s t line treatment decisions, 1359 (12.6%) were EGFRmut(+), and among these, 36 (2.5%) had EGFR and KRAS co-mutations. Outcome cohort: of 859 patients with EGFR-alterations meeting selec- tion criteria, 11 (1.2%) had co-alteration of EGFR and KRAS, with the rest being KRAS wild-type. Among the 11 co-altered, 2 had EGFR exon 19 deletion, 2 had L858R, 6 had other EGFR alterations, and 1 had multiple EGFR alterations. Among co-altered, 4 received afatinib, 1 received getfitinib, and 6 received osimertinib. Compared to those with wild-type KRAS, co-altered patients had shorter median PFS (4.2 vs. 12.4 months, adjusted HR: 2.41, 95%CI: 1.24 - 4.65, p = 0.009) and directionally consistent OS (17.7 vs. 26.2 months, adjusted HR: 1.5, 95% CI: 0.71 - 3.17, p = 0.284). Evaluating patients who received chemo- therapy and not anti-EGFR TKIs, we additionally saw less favorable PFS (HR: 2.66, 95%CI: 1.47 - 4.81, p = 0.001) and directionally consistent OS (HR: 1.24, 95%CI: 0.57 - 2.66, p = 0.59). Additional associations of specific concurrent KRAS alterations and prior treatment exposure will be presented at conference. Conclusions: While rare, co-alteration of EGFR and KRAS appears to be a poor prognostic marker and compro- mises anti-EGFR treatment efficacy with numerically lower PFS (statistically significant) and OS for current generation TKIs. The results are consistent with our biologically informed hypothesis. We also saw similar associations with standard chemotherapy, underscoring the challenge of treating this subgroup Recently, the FLAURA2 (chemotherapy, Osimertinib) and MARIPOSA: Amivantamab/Lazertinib trials showed improved PFS as compared to osimertinib but with increased toxicity. In the setting of approved treatment-intensification strategies, co-alteration of KRAS should be further evaluated as a biomarker of aggressive disease that may warrant more aggressive frontline treat- ment.
Volume
20
Issue
10
First Page
S485
