Frontline aumolertinib plus carboplatin/pemetrexed significantly prolonged progression-free survival (PFS) vs aumolertinib alone for EGFR-mutated advanced non-small cell lung cancer (NSCLC) with concomitant tumor suppressor gene (TSG) alterations in the phase 3 ACROSS-2 trial. At 25.3 months median follow-up, investigator-assessed median PFS was 19.8 months with the combination vs 16.5 months with monotherapy (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.34–0.91; P=.021). Benefit was consistent in key subgroups with TP53 co-mutations (18.7 vs 16.3 months; HR 0.55; P=.024) and numerically favored the combination in EGFR 19del (not reached vs 16.3 months; HR 0.46; P=.055) and L858R (18.7 vs 16.5 months; HR 0.63; P=.154). Overall response rates were similar (70.4% vs 67.2%), and disease control was high in both arms (92.6% vs 98.4%).

Safety reflected added chemotherapy: In the combination arm, common any-grade treatment-emergent adverse events (TEAEs) included anemia (61%), decreased white blood cell count (54%), AST/ALT elevations (52%/48%), and decreased neutrophils (44%). Monotherapy had lower overall TEAE rates, with the most often reported being creatine kinase elevation (42%), transaminase elevations (27%/19%), and rash (20%). These data support aumolertinib-chemotherapy as a feasible option to improve PFS in EGFR-mutated NSCLC with co-occurring TSG alterations, while balancing higher myelosuppression and hepatic laboratory abnormalities associated with chemotherapy.

Reference: DiEugenio J. Aumolertinib Plus Chemotherapy Improves PFS in EGFR-Mutated NSCLC. OncLive. Published September 7, 2025. Accessed September 22, 2025. https://www.onclive.com/view/aumolertinib-plus-chemotherapy-improves-pfs-in-egfr-mutated-nsclc

In a prospective multicenter cohort of 162 patients with advanced non-small cell lung cancer (NSCLC) (EGFR/ALK–) treated with first-line immunochemotherapy, traditional biomarkers were inconsistent, with higher tumor mutation burden (TMB) tracked with longer progression-free survival (PFS), and PD-L1 correlated with response but not survival. Genomics highlighted signals such as ARID1A mutations (with high PD-L1) predicting response, KDM6A predicting worse overall survival (OS), and RTK-RAS pathway mutations associating with better PFS. ARID1B co-mutations with DNA damage response genes marked poorer survival. A seven-feature genomic risk score (RS) independently predicted PFS beyond TMB, separating low- vs high-risk groups with clear PFS/OS differences, and was validated internally and in external datasets.

Hematoxylin and eosin-stained tumor slides analyzed by HoVer-Net quantified tumor microenvironment cell types. A higher epithelial-cell proportion was protective for PFS and modestly improved RS performance. Integrating RS with image-derived features produced a multimodal classifier (PMCP) that stratified patients into subgroups with distinct PFS/OS, independent of TMB. Favorable groups showed immune activation while poor-risk groups skewed immunosuppressive, supporting PMCP as a practical framework to refine prognosis and guide first-line immunotherapy combined with chemotherapy (ICT) selection, pending broader validation in ICT-treated cohorts.

Reference: Han Y, Ma J, Liu Z, et al. Integrating genomic and pathological characteristics to enhance prognostic precision in advanced NSCLC. npj Precis Oncol. 2025;9:271. doi: 10.1038/s41698-025-01056-8.

Researchers of a registrational phase 2 cohort of the KRYSTAL-1 study evaluated adagrasib 600 mg twice daily in previously treated KRAS^G12C-mutated non-small cell lung cancer (NSCLC) after platinum chemotherapy and anti–PD-1/PD-L1 therapy. Among 116 treated patients (median follow-up 12.9 months; 98.3% pretreated with both chemotherapy and immunotherapy), 112 had measurable disease and 48 achieved a confirmed objective response (overall response rate, 42.9%). Median duration of response was 8.5 months (95% confidence interval [CI], 6.2–13.8), median progression-free survival was 6.5 months (95% CI, 4.7–8.4), and at a later cutoff (median follow-up 15.6 months), median overall survival was 12.6 months (95% CI, 9.2–19.2). Objective responses were assessed by blinded independent central review as the primary endpoint.

Safety was consistent with prior experience: Treatment-related adverse events occurred in 97.4% of patients (grade 1–2 in 52.6%, grade ≥3 in 44.8%, including two grade 5 events), and led to discontinuation in 6.9%. Overall, adagrasib demonstrated clinical activity and manageable toxicity in this heavily pretreated KRAS^G12C-mutated NSCLC population, without new safety signals. Findings support adagrasib as a post-chemotherapy targeted option.

Reference: Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022;387(2):120-131. doi: 10.1056/NEJMoa2204619.