Prognostic Impact of KRAS Mutation Subtypes in 677 Patients with Metastatic Lung Adenocarcinomas

BackgroundWe previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer.MethodsWe reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset.ResultsAmong 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11–2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41).ConclusionsAmong individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype

Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases

Abstract Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867

Postdiagnosis BMI Change Is Associated with Non-Small Cell Lung Cancer Survival

Background: Body mass index (BMI) change after a lung cancer diagnosis has been associated with non-small cell lung cancer (NSCLC) survival. This study aimed to quantify the association based on a large-scale observational study. Methods: Included in the study were 7,547 patients with NSCLC with prospectively collected BMI data from Massachusetts General Hospital and Brigham and Women's Hospital/Dana-Farber Cancer Institute. Cox proportional hazards regression with time-dependent covariates was used to estimate effect of time-varying postdiagnosis BMI change rate (% per month) on overall survival (OS), stratified by clinical subgroups. Spline analysis was conducted to quantify the nonlinear association. A Mendelian Randomization (MR) analysis with a total of 3,495 patients further validated the association. Results: There was a J-shape association between postdiagnosis BMI change and OS among patients with NSCLC. Specifically, a moderate BMI decrease [0.5-2.0; HR = 2.45; 95% confidence interval (CI), 2.25-2.67] and large BMI decrease (≥2.0; HR = 4.65; 95% CI, 4.15-5.20) were strongly associated with worse OS, whereas moderate weight gain (0.5-2.0) reduced the risk for mortality (HR = 0.78; 95% CI, 0.68-0.89) and large weight gain (≥2.0) slightly increased the risk of mortality without reaching statistical significance (HR = 1.10; 95% CI, 0.86-1.42).MR analyses supported the potential causal roles of postdiagnosis BMI change in survival. Conclusions: This study indicates that BMI change after diagnosis was associated with mortality risk