Efficacy of first‐line immune checkpoint inhibitors in patients with advanced NSCLC with KRAS, MET, FGFR, RET, BRAF, and HER2 alterations

Abstract

Background: In patients with non-small cell lung cancer (NSCLC) harboring driver alterations, the efficacy of immune checkpoint inhibitors (ICIs) remains uncertain. Our study aimed to examine the first-line ICI efficacy in patients with NSCLC harboring KRAS, MET, FGFR, RET, BRAF, and HER2 alterations in a real-world setting. Methods: This single-center, retrospective cohort study included patients with advanced NSCLC harboring KRAS, MET, FGFR, RET, BRAF, HER2 alterations or driver-negative, and were treated with first-line ICI therapy. Best overall response, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Seventy-eight patients with NSCLC were included (median age, 72 years): 67% were men, 15% were never-smokers, and 83% had adenocarcinoma. The driver alterations involved KRAS (n = 21), MET (n = 6), FGFR (n = 3), RET (n = 2), BRAF (n = 2), HER2 (n = 1), and driver-negative (n = 43). The partial responses for KRAS, MET, FGFR, RET, BRAF, HER2, and driver-negative were 57%, 50%, 100%, 50%, 100%, 0%, and 47%, respectively. The median PFS (months) was 16.2 (95% confidence interval [CI]: 6.3-not reached [NR]) for KRAS, 2.8 (95% CI: 2.7-NR) for MET, 11.7 (95% CI: 5.9-NR) for other alterations (FGFR, RET, BRAF, and HER2), and 10.0 (95% CI: 3.7-14.3) for driver-negative, respectively. The median OS (months) was 31.3 (95% CI: 9.0-NR) for KRAS, not reached for MET, 23.5 (95% CI: 18.3-NR) for other alterations, and 21.1 (95% CI: 15.2-NR) for driver-negative, respectively. Conclusions: The benefit of the first-line ICI was similar in advanced NSCLC regardless of the driver alterations, except for MET alterations.

Equalizing prognostic disparities in stage III KRAS-mutant NSCLC: addition of durvalumab to combined chemoradiotherapy improves survival

“…After the introduction of ICB in the stage IV treatment paradigm new assessment of the impact of KRAS have been performed but do not consistently point in the same direction, and the predictive value of KRAS related to ICB treatment remains debatable. 21 The prognostic value of mutated KRAS in stage III patients treated with concurrent chemoradiotherapy likely indicates an association with an inferior prognosis, as suggested by previous data where mutated KRAS was independently connected to a decrease in overall survival in multivariate analysis. 22, 24 Regarding the significance of KRAS mutations in stage III disease after the introduction of durvalumab, there are a few reported cohorts.…”

“…[16][17][18] In addition, some have reported shorter OS for KRAS MUT compared to wild type (KRAS WT ) patients following first-line platinum-based chemotherapy. [19][20][21] Hence, the significance of KRAS mutation for prognosis and treatment response in NSCLC disease remains a pending topic. 22 First-line treatment for unresectable stage III NSCLC is concurrent chemoradiotherapy (cCRT) provided that patients have a decent performance status, adequate lung function and no discouraging comorbidity.…”

“…18 Although relatively few studies have been conducted regarding the impact of KRAS mutation on prognosis after cCRT in stage III NSCLC, the available data suggests KRAS mutation as a negative predictor for treatment response and OS. 20,21 Furthermore, data on KRAS MUT in the context of ICB treatment in stage III disease is scarce. In summary, given previous findings of heterogeneity of stage III NSCLC, worsened prognosis in the presence of KRAS mutations in this group, and improved prognosis after the introduction of consolidation therapy with durvalumab in the overall group, we wondered whether KRAS mutation subgroups may respond differentially to durvalumab.…”

“…16-18 In addition, some have reported shorter OS for KRAS MUT compared to wild type (KRAS WT ) patients following first-line platinum-based chemotherapy. 19-21 Hence, the significance of KRAS mutation for prognosis and treatment response in NSCLC disease remains a pending topic. 22…”

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

“…Meanwhile, a retrospective analysis noted that patients with non-small cell lung cancer carrying FGFR4 alterations had better objective remission rates (ORR) (50.0% vs. 19.4%; P = 0.057) and longer median PFS to immunotherapy (13.17 vs. 3.17 months; HR 0.37; 95% CI 0.14–1; P = 0.04) [ 194 ]. However, in urothelial carcinoma, some evidence indicate that the remission and survival rates after ICB monotherapy are independent of whether FGFR is mutated or not [ 20 , 66 , 195 – 197 ]. Real-world retrospective studies evaluating the effect of ICB therapy in patients with mutated FGFR3 and WT FGFR3 tumors observed no significant difference in OS or PFS between the two [ 66 ].…”