Research Summary
Concurrent chemoradiotherapy (cCRT) followed by adjuvant durvalumab is the standard first-line treatment for patients with unresectable Stage III non-small cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) expression of one percent or higher. Although KRAS mutations are common in NSCLC, their prognostic impact is not fully understood. Research is limited on KRAS mutations in the context of Stage III NSCLC treated with cCRT, but the existing data indicate that these mutations have a negative impact on treatment response and survival. In this multicenter retrospective cohort study, Eklund et al1 compared survival outcomes between patients with KRAS-mutated and KRAS-wildtype Stage III NSCLC treated with cCRT before and after the introduction of durvalumab. Their findings are summarized below.
Eligible patients had undergone molecular assessment and received cCRT with curative intent for Stage III NSCLC between 2016 and 2021. Patients who underwent surgery or sequential CRT were excluded from analysis.
Among 145 patients included in the study, 99 (68.3%) had KRAS-wildtype disease, and 46 (31.7%) had KRAS-mutated disease. Median age was 69 years in both cohorts. Slightly more patients were female in the KRAS-mutated cohort (54.3%) compared to the KRAS-wildtype cohort (51.5%). In the KRAS-wildtype cohort, 87.9 percent of patients were current or former smokers, compared to 97.8 percent of the KRAS-mutated cohort. The majority of patients with KRAS-mutated disease (89.1%) had adenocarcinoma histology. Among those with KRAS-wildtype disease, 51.5 percent had adenocarcinoma and 40.4 percent had squamous cell carcinoma. Thirty-five patients (35.2%) with KRAS-wildtype NSCLC harbored a different mutation, most commonly epidermal growth factor receptor (EGFR; 12.1%). The most common KRAS submutation was G12C (52.2%).
There was a median follow-up of 48 months. Median progression-free survival (PFS) was nine months in the KRAS-mutated cohort and 16 months in the KRAS-wildtype cohort; this difference was significant (p=0.038). Patients with KRAS mutation had a median overall survival (OS) of 25 months, which was significantly lower than that of patients without KRAS mutation (median OS: 46 months, p=0.047). KRAS mutation was identified as an independent prognostic factor for reduced PFS (hazard ratio [HR]: 1.628, p=0.020) and OS (HR: 1.703, p=0.024), according to multivariate Cox regression analysis. KRAS mutational status also had a negative impact on survival outcomes after cCRT. Median PFS and OS following cCRT were eight and 24 months, respectively, among patients with KRAS-mutated disease. In comparison, patients with KRAS-wildtype disease had significantly longer median PFS (13 months, p= 0.037) and OS (35 months, p=0.036).
In the overall patient population, those who received consolidation durvalumab (n=48) experienced significantly improved survival outcomes over those who did not receive durvalumab (n=97). Durvalumab-treated patients had a median PFS of 19 months, compared to 10 months for those without durvalumab treatment (p<0.001). Median OS was not reached in durvalumab-treated patients versus 30 months for those without durvalumab treatment (p=0.037).
In the KRAS-wildtype cohort, 62 patients received cCRT alone and 37 received cCRT followed by durvalumab. In the KRAS-mutated cohort, 35 and 11 patients received cCRT alone and cCRT followed by durvalumab, respectively. Among durvalumab-treated patients, mean OS was 40 months for both KRAS-mutated and KRAS-wildtype cohorts (p=0.788; median OS not reached). Additionally, PFS was not significantly different based on KRAS mutational status among patients who received durvalumab, with a median PFS of 19 months in the KRAS-mutated cohort and 23 months in the KRAS-wildtype cohort (p=0.855). Survival outcomes with and without adjuvant durvalumab treatment among the KRAS-mutated and KRAS-wildtype cohorts were evaluated as well. PFS was significantly improved with adjuvant durvalumab, compared to cCRT alone, in patients with KRAS-mutated NSCLC (median PFS: 19 vs. 8 months, p=0.011) and in those with KRAS-wildtype disease (median PFS: 24 vs. 13 months, p=0.033). In the KRAS-wildtype cohort, durvalumab treatment trended toward an improvement in OS compared to cCRT alone (median OS: not reached vs. 35 months, p=0.345). In the KRAS-mutated cohort, adjuvant durvalumab trended toward substantially improved OS compared to cCRT alone (median OS: not reached vs. 24 months, p=0.063).
Limitations include the retrospective nature of the study, which might have led to biased PFS outcomes due to variability in follow-up, and small sample size. Additionally, the impact of comutations, such as KEAP1 or STK11, are unknown. Larger prospective cohort studies should be conducted to confirm these results.
Findings from this study showed that although KRAS-mutated Stage III NSCLC was associated with worse survival compared to KRAS-wildtype disease, the addition of adjuvant durvalumab following cCRT mitigated the negative impact of KRAS mutations. Therefore, cCRT followed by durvalumab appears to be a valuable treatment option for patients with KRAS-mutated NSCLC, and molecular profiling can be utilized to help inform decision-making regarding adjuvant therapy.
Reference
- Eklund EA, Orgard M, Wallin D, et al. Equalizing prognostic disparities in KRAS-mutated Stage III NSCLC patients: addition of durvalumab to combined chemoradiotherapy improves survival. Lung Cancer. 2025;204:108573. Epub ahead of print.