Real-world retrospective study of KRAS mutations in advanced non-small cell lung cancer in the era of immunotherapy.

BACKGROUND: KRAS mutation-positive (KRAS-positive), advanced nonsmall-cell lung cancer (NSCLC) is characterized by a poor prognosis. KRAS mutations are extremely heterogeneous from a biologic point of view, and real-world data by mutation subtype in the era of immunotherapy are still incomplete. METHODS: The objective of this study was to retrospectively analyze all consecutive patients with advanced/metastatic, KRAS-positive NSCLC who were diagnosed at a single academic institution since the advent of immunotherapy. The authors report on the natural history of the disease as well as the efficacy of first-line treatments in the entire cohort and by KRAS mutation subtypes as well as the presence/absence of co-mutations. RESULTS: From March 2016 to December 2021, the authors identified 199 consecutive patients who had KRAS-positive, advanced or metastatic NSCLC. The median overall survival (OS) was 10.7 months (95% confidence interval [CI], 8.5-12.9 months), and there were no differences by mutation subtype. Among 134 patients who received first-line treatment, the median OS was 12.2 months (95% CI, 8.3-16.1 months), and the median progression-free survival was 5.6 months (95% CI, 4.5-6.6 months). At multivariate analysis, only an Eastern Cooperative Oncology Group performance status of 2 was associated with significantly shorter progression-free survival and OS. CONCLUSIONS: KRAS-positive, advanced NSCLC is characterized by a poor prognosis despite the introduction of immunotherapy. Survival was not associated with KRAS mutation subtype. PLAIN LANGUAGE SUMMARY: This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes. The authors found that advanced/metastatic, KRAS-positive nonsmall cell lung cancer is characterized by a poor prognosis and that first-line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression-free survival was observed in patients who had p.G12D and p.G12A mutations. These results underline the need for novel treatment options in this population, such as next-generation KRAS inhibitors, which are in clinical and preclinical development.

Adjuvant chemotherapy in resected colon cancer: When, how and how long?

The benefit of adjuvant chemotherapy has been clearly established in the adjuvant setting for node-positive colon cancer. A number of trials in the adjuvant setting have analyzed the efficacy of multiple-agent combinations, including irinotecan, oxaliplatin, bevacizumab and cetuximab. Only oxaliplatin added to fluorouracil/capecitabine has been shown to be superior beyond a fluropyrimidine alone in the adjuvant setting. As such, standard treatment options include fluorouracil (FU) or capecitabine with or without oxaliplatin. However, oxaliplatin is associated with cumulative dose-dependent neurotoxicity, characterized by distal or perioral paresthesias or dysesthesias; for this reason, in this review we discuss the results of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial. The IDEA trail is the largest prospective clinical trial ever conducted in colorectal cancer, wherein patients were treated with either 3 months or 6 months of adjuvant chemotherapy. In the era of cancer gene expression-based subtyping, the Colorectal Cancer Subtyping Consortium has proposed a four-subgroup molecular classification system for colorectal cancer, consisting of CMS1 (immune), CMS2 (canonical), CMS3 (metabolic) and CMS4 (mesenchymal). In this review, we present and analyze the available data on efficacy and toxicity of the combination regimen approved for treatment of resected colon cancer, and discuss the questions of when, how and how long we need to treat such patients.