Antonin Levy

Background: Patients with unresectable stage III non-small cell lung cancer (NSCLC) have an unmet need for new therapies that improve survival. This phase III trial investigated the safety and efficacy of concurrent ociperlimab and tislelizumab plus concurrent chemoradiotherapy (cCRT) in treatment-naïve patients with stage III NSCLC. Methods: In this phase III, multicenter, randomized, multiarm, open-label trial, patients with unresectable stage III NSCLC received concurrent ociperlimab plus tislelizumab and cCRT, followed by ociperlimab plus tislelizumab (arm A), tislelizumab and cCRT, followed by tislelizumab (arm B), or cCRT, followed by durvalumab (arm C) ( NCT04866017 ). Objectives were to compare progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response, disease control rate, clinical benefit rate, time to death or distant metastasis (TTDM), and safety and tolerability for arms A versus C, B versus C, and A versus B. Results: 63 patients were randomized to arms A (N=22), B (N=19), and C (N=22) prior to early trial termination. In A, B, and C, respectively, 95.5% (21/22), 84.2% (16/19), and 95.5% (21/22) were current or former smokers, and 68.2% (15/22), 73.7% (14/19), and 68.2% (15/22) had PD-L1 expression in tumor cells of ≥1%. Median PFS (95% CI) was not reached (NR) (6.3–not estimable (NE)) in A, 15.0 months (7.4 to NE) in B, and 10.4 months (5.7 to NE) in C. Median OS and TTDM were NR in any arm. ORR (95% CI) was 68.2% (45.1%–86.1%) in A, 68.4% (43.4%–87.4%) in B, and 59.1% (36.4%–79.3%) in C; all responses were partial responses. Treatment-emergent adverse events (TEAEs) occurred in all patients; in arms A, B, and C, respectively, pneumonitis occurred in 18.2% (4/22), 5.6% (1/18), and 9.1% (2/22) of patients, and interstitial lung disease occurred in 13.6% (3/22), 11.1% (2/18), and 0% of patients, of which the majority of events for each were grade 1/2. Grade ≥3 treatment-related TEAEs occurred in 68.2% (15/22), 66.7% (12/18), and 68.2% (15/22) of patients in arms A, B, and C, respectively. Conclusions: There was a trend toward improved efficacy when adding tislelizumab with or without ociperlimab to cCRT followed by tislelizumab with or without ociperlimab compared with cCRT followed by durvalumab; however, efficacy data were for descriptive purposes only. No unexpected or new safety signals were identified.

RAS mutations are among the most prevalent oncogenic drivers in solid tumors and are consistently associated with suboptimal responses to radiation therapy (RT). Within this family, KRAS is the dominant isoform and a central regulator of tumor stress adaptation. Increasing evidence indicates that oncogenic KRAS orchestrates radioresistance through coordinated tumor-intrinsic and microenvironmental mechanisms. Cell-intrinsically, KRAS enhances DNA damage repair, replication stress tolerance, redox buffering, and ferroptosis defense. The KRAS–NRF2–53BP1 axis exemplifies this program by accelerating non-homologous end joining and enabling rapid repair of radiation-induced DNA double-strand breaks. Concurrently, KRAS reshapes the tumor microenvironment by promoting myeloid recruitment, metabolic rewiring, impaired antigen presentation, and immune checkpoint upregulation, thereby constraining the immunogenic effects of RT. The rapid evolution of RAS-directed therapeutics, including allele-specific, ON-state, dual-state, and pan-RAS inhibitors, as well as emerging degraders and molecular reprogramming strategies, has transformed a historically “undruggable” target into a clinically actionable vulnerability. Preclinical evidence indicates that KRAS inhibition can restore radiosensitivity and partially recondition antitumor immunity. However, adaptive resistance frequently converges on MAPK pathway reactivation and persistent immune suppression. Integrating next-generation RAS inhibitors with RT and immune-directed therapies may therefore represent a critical strategy for achieving durable tumor control in KRAS-mutant cancers.

Summary: Low-dose intestinal irradiation challenges the long-standing view of the gut as a radiation-sensitive organ to avoid. Clinical and mechanistic data suggest that targeted exposure of the small intestine within a 1- to 3-Gy window can remodel the microbiome and enhance systemic antitumor immunity. See related article by Huang et al., p. XX .

The standard of care for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by consolidation immunotherapy. We analysed clinical, biological, and dosimetric data to identify survival predictors and inform personalized treatment strategies. We retrospectively reviewed LA-NSCLC patients treated between December 2015 and January 2023. Data were extracted from electronic medical records. Progression-free survival (PFS) and overall survival (OS) were calculated from diagnosis. Kaplan-Meier estimates and Cox proportional hazards models were used for survival analysis. We included 92 patients (median follow-up: 28.9 months); 66% were male, 60% former smokers, and the median age was 64. Stage IIIB (50%) and adenocarcinoma (60%) were most common. PD-L1 positivity was observed in 75%, and 27% had oncogenic drivers (KRAS: 24%, EGFR: 3%). Most (86%) received concurrent CRT, typically cisplatin-based (60%). Median durvalumab duration was 9.5 months. Median PFS and OS were 31.9 and 51.2 months, respectively. Overall, 47% of patients experienced recurrence, including 15% locoregional recurrence and 85% metastatic recurrence (60% oligometastatic and 25% polymetastatic). PFS was longer in patients aged 1.80 G/L (45.4 vs 27.7 months; P = .047), or PTV P = .01). On multivariate analysis, only radiotherapy planning target volume (PTV) P = .04). No factor was associated with OS in multivariable analysis. Smaller PTV was independently associated with longer PFS, supporting its value in personalized care for LA-NSCLC. PTV emerged as an independent prognostic factor for PFS, suggesting its utility in risk stratification and individualized treatment planning.

Médecine/sciences (M/S), revue internationale dans le domaine de la recherche biologique, médicale et en santé