KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non–small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development. Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type. Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%). KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

Historically, geriatric patients have been underrepresented in clinical trials. Between 2005 and 2015, patients aged 80 years or older comprised only 4% of cancer clinical trial participants, largely owing to restrictive eligibility criteria, exclusionary comorbidities, prior cancers, and worse performance status.^1-3 Because of this poor representation, geriatric patients and their oncologists must extrapolate from clinical trial data of younger patients to make treatment decisions.

Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

PURPOSE: Major adverse cardiac events (MACEs) because of immune checkpoint inhibitors (ICIs) are infrequent immune-related adverse events (irAEs) that comprise a spectrum of cardiac toxicities with variable manifestations. ICI-related MACEs can lead to significant morbidity and mortality, hence the need to better define presentations of MACEs and their association with noncardiac irAEs in ICI-treated patients. METHODS: We conducted a retrospective pooled analysis of MACE captured in the serious adverse events reporting database of the National Cancer Institute–Cancer Therapy Evaluation Program for National Cancer Institute–sponsored investigational clinical trials between June 2015 and December 2019. Patients were eligible if they had been treated with anti–programmed cell death protein-1 (anti–PD-1)/programmed cell death-ligand 1 (anti–PD-L1) alone or with additional anticancer therapies. RESULTS: A total of 6,925 participants received anti–PD-(L)1-based therapies; 48% (n = 3,354) were treated with single-agent anti–PD-(L)1 therapy. Of 6,925 patients, 0.6% (n = 40) qualified as ICI-related MACE, with 77.5% (n = 31 of 40) being ≥ grade 3. Myocarditis accounted for 45% (n = 18 of 40) of total ICI-MACEs. Concurrent multisystem involvement with other noncardiac irAEs was seen in 65% (n = 26 of 40). Most patients with myocarditis (83%, n = 15 of 18) had one or more noncardiac irAEs associated. Incidence of MACE was higher with anti–PD-(L)1 + targeted therapies compared with anti–PD-(L)1 + anti–cytotoxic T-cell lymphocyte-4 combinations (2.1% v 0.9%, P = .08). There was a higher incidence of myocarditis with anti–PD-(L)1-based combination therapies versus single-agent anti–PD-(L)1 therapies (0.36%, n = 13 of 3,571 v 0.15%, n = 5 of 3,354, P = .08). Deaths related to myocarditis were identified in 22.5% (n = 4 of 18). All four patients who died had concurrent myositis. CONCLUSION: Increasing patient and prescriber awareness in understanding patterns of ICI-MACE and associated noncardiac irAEs should be emphasized. Better characterization of the risk of MACE with the concurrent use of non–ICI-based anticancer therapies with anti–PD-(L)1 treatments is needed.