Background: Previous studies have identified that patients with EGFR mutations tend to have better responses to targeted therapy, as well as chemotherapy; however, the effect of genetic alterations in terms of radiotherapy (RT)‐related outcomes has not been fully assessed. We studied the impact of common non‐small cell lung cancer (NSCLC) genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR) to RT in patients with brain metastases.Methods: From 2009–2015, 153 patients with an available genotyping status were treated with whole‐brain irradiation (WBI) before receiving systemic therapy. Primary outcome was ORR; secondary outcomes included intracranial progression‐free survival (IPFS) and overall survival (OS).Results: Overall, ORR was 47.1%. ORR to RT varied significantly according to molecular status: EGFR (64.5%) ALK (54.5%) KRAS (20%) and WT (35.4%) (P = 0.001). EGFR mutation was the only independently associated factor for response to WBI (RR 3.52 [95% CI 1.6–7.7]; P = 0.002). Median IPFS was 10.8 months [95% CI 8.2–13.5] overall; however, IPFS also varied significantly according to molecular status: EGFR (18.2 months), ALK (18.4 months), KRAS (6.0 months) and WT (8.7 months) (P < 0.0001). OS for EGFR, ALK, KRAS and WT patients was 36.6, 32.2, 15.5 and 22.4 months, respectively (P = 0.014). Intracranial‐ORR (HR 0.4 [95% CI 0.2–0.6], P < 0.001) and mutation status (HR 0.7 [95% CI 0.6–0.9], P < 0.042) were independently associated with a higher OS.Conclusions: RT response varies as per tumor molecular status. The presence of EGFR mutations favors the organ‐specific response to RT, and is associated with longer OS in patients with NSCLC and BM.Key points: This study addressed for the first time the difference in radiotherapy‐related outcomes in patients with different genotypes of non‐small cell lung cancer (NSCLC) before they received systemic therapy. Results show that response to radiotherapy varies as per tumor molecular status, particularly EGFR‐mutated tumors, have a favorable response to radiotherapy, contrary to KRAS‐mutated tumors.

Background: Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations has a distinct biology and heterogeneous clinical behavior. We evaluated the characteristics to progression such as clinical patterns of progression (dramatic, gradual, and local) with the prognosis of NSCLC patients treated with tyrosine kinase inhibitors (TKIs). Methods: We reviewed 123 advanced-NSCLC patients with an EGFR-sensitizing mutation treated with TKIs (gefitinib, erlotinib and afatinib). We assessed patients according to clinical factors and progression pattern to TKIs at three centers. Results: For all patients, 58.5%, 31.7% and 9.8% harbored exon19 deletion, exon21 L858R mutation and other-sensitivity mutations, respectively. Median progression-free survival (PFS) was 8.8 months (95% CI: 7.9–9.7). Sixty percent of patients were asymptomatic. Dramatic-progression was the most frequent pattern (50.4%), followed by gradual-progression (32.5%), and local-progression (17.1%). Median overall survival (OS) was 23.1 months (95% CI: 17.4–28.9). In the univariate analysis, factors associated to a longer OS included pattern [gradual-progression (32.1), dramatic (19.5) and local (18.8 months), P=0.008], and the time to progression to TKI [>12 months (38.5), 6-12 months (19.1), <6 months (9.6), P<0.001]. Multivariate analysis showed that only time to progression to TKI was independently associated to OS and PFS. Conclusions: Factors at TKI progression associated to a longer OS can define a subset of patients who may benefit from continued TKI therapy, as well as from local-ablative therapy in progression sites, especially in patients without T790M or who lack access to third-generation TKI.

PURPOSE: Targeted therapies are indicated for patients with non–small cell lung cancer (NSCLC) and driver tumor mutations. However, real-world studies on the survival benefits of these agents are limited. This study aimed to evaluate the effect of targeted therapies matched to a genomic alteration on the survival of patients with NSCLC. METHODS: This retrospective study included 446 patients with advanced NSCLC who underwent next-generation sequencing between 2016 and 2023 at the Instituto Nacional de Cancerología in Mexico. The primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: For the entire cohort, the PFS and OS were 10.71 months (95% CI, 9.35 to 12.06) and 47.77 months (95% CI, 29.67 to 65.86). PFS was significantly longer in patients with actionable mutations treated with targeted therapies (19.41 months [95% CI, 14.27 to 24.55]; P < .001) than in patients without actionable mutations (6.4 months [95% CI, 4.4 to 8.4]) or not treated with targeted therapies (6.6 months [95% CI, 5.3 to 7.89]). Similarly, OS was significantly longer in patients with actionable mutations treated with targeted therapies (89.69 months [95% CI, 45.54 to 133.84]; P < .001) than in patients without actionable mutations (17.11 months [95% CI, 8.65 to 25.57]) or not treated with targeted therapies (22.3 months [95% CI, 12.48 to 32.1]). Survival gains were driven by significant improvements in PFS and OS in patients with EGFR and ALK mutations. CONCLUSION: This real-world data analysis demonstrated that targeted therapies improve the survival of patients with NSCLC with actionable mutations, which supports a recommendation for widening access to broad-based genomic testing and targeted therapies.