Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases.

We determined the impact of genetic alterations in EGFR, ALK, or KRAS on survival after radiotherapy for brain metastases in non-small cell lung cancer (NSCLC). Of 172 genotyped NSCLC patients treated with radiotherapy for brain metastases in 2005-2012, 54 had cancers with EGFR mutations, 12 had ALK rearrangements, 38 had KRAS mutations, and 68 were wild-type (WT). Overall survival (OS) was determined. Median follow-up was 8.6 months. Median OS was 13.6 months for patients with EGFR mutations and 26.3 months for patients with ALK rearrangements, in contrast to 5.7 months for KRAS-mutant patients and 5.5 months for WT patients (P = .001). On multivariate analysis, adjusting for receipt of targeted therapy after cranial radiotherapy, ALK rearrangements were associated with improved OS (HR, 0.31; 95% CI, 0.13-0.74; P = .008). EGFR mutations were not significantly associated with improved OS on multivariate analysis (HR, 0.71; 95% CI, 0.37-1.38; P = .3). KRAS mutations were also not associated with improved OS (HR, 0.93; 95% CI, 0.59-1.47; P = .8). Receipt of targeted therapy after cranial radiotherapy was independently associated with improved OS (HR, 0.30; 95% CI, 0.17-0.54; P < .001). Receipt of chemotherapy after cranial radiotherapy, number of brain metastases, extracranial metastases, age, and performance status were also associated with OS. NSCLC patients with genetic alterations in ALK have improved survival outcomes after radiotherapy for brain metastases compared with EGFR, KRAS, or WT. Subsequent receipt of targeted therapy was associated with additional improvement in OS.

Mak KS ，Gainor JF ，Niemierko A ，Oh KS ，Willers H ，Choi NC ，Loeffler JS ，Sequist LV ，Shaw AT ，Shih HA ... -  《-》

Response rate of patients with baseline brain metastases from recently diagnosed non-small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status.

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. 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). 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. 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. 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.

Arrieta O ，Ramírez-Tirado LA ，Caballé-Perez E ，Mejia-Perez A ，Zatarain-Barrón ZL ，Cardona AF ，Lozano-Ruíz F ，Segura-González M ，Cruz-Rico G ，Maldonado F ，Rosell R ... -  《-》

Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?

Wang TJ ，Saad S ，Qureshi YH ，Jani A ，Nanda T ，Yaeh AM ，Rozenblat T ，Sisti MB ，Bruce JN ，McKhann GM ，Lesser J ，Halmos B ，Stoopler MB ，Lassman AB ，Cheng SK ，Isaacson SR ... -  《-》

Clinical outcome with platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type non-small-cell lung cancer segregated according to KRAS mutation status.

We hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non-small-cell lung cancer (NSCLC). Consecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT. Two hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P = .04), disease control rate (P = .05), and progression-free survival (PFS) (P = .05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n = 64) (P = .02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n = 12) performed worse than those with a mutation at codon 12 (n = 62) in terms of both PFS and OS (P = .09 for both). KRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation.

Metro G ，Chiari R ，Bennati C ，Cenci M ，Ricciuti B ，Puma F ，Flacco A ，Rebonato A ，Giannarelli D ，Ludovini V ，Bellezza G ，Ferolla P ，Minotti V ，Crinò L ... -  《-》

Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement.

The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P = .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P = .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.

Kim HR ，Shim HS ，Chung JH ，Lee YJ ，Hong YK ，Rha SY ，Kim SH ，Ha SJ ，Kim SK ，Chung KY ，Soo R ，Kim JH ，Cho BC ... -  《-》