RAS wild-type

P2, N=38, Active, not recruiting, Australasian Gastro-Intestinal Trials Group | Recruiting --> Active, not recruiting | N=90 --> 38 | Trial primary completion date: Apr 2026 --> Jan 2026

Inhibiting PI3K enhanced sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including in cells with clinically identified PIK3CA mutations. These findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven wild-type RAS activation drives resistance to KRAS inhibition, and illuminate avenues for augmenting KRAS-targeted therapies in PDAC.

BBO-8520 exerted more potent and sustained inhibition of KRAS G12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRAS G12C (OFF)-only inhibitor...Moreover, in some contexts, disruption of RAS-PI3Kα further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3Kα-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3Kα-AKT to improve the response to KRAS inhibitors.

Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

P1, N=54, Recruiting, West China Hospital | Not yet recruiting --> Recruiting

P1, N=96, Not yet recruiting, Philogen S.p.A.

P1, N=54, Not yet recruiting, West China Hospital

Long considered undruggable due to its molecular structure, the advent of sotorasib and adagrasib has ushered in multiple novel therapeutics targeting the RAS pathway, including mutation-selective, pan-KRAS, and pan-RAS inhibitors. Here, we detail the different areas of investigation targeting KRAS and other precision-based therapies in PDAC, as well as the potential emerging roles of local interventions (radiation, surgery) for select patients with oligometastatic disease. Composite predictive biomarkers using genomic, proteomic, and radiographic factors are needed to refine and individualize treatment selection and ultimately improve patient outcomes.

This study assessed clinical features and survival outcomes according to KRAS mutation in a real-life population of nsq-NSCLC patients treated with first-line platinum-pemetrexed-pembrolizumab.MethodsThis is a retrospective-prospective study including patients with nsq-NSCLC who received first-line platinum-pemetrexed-pembrolizumab from 4 September 2018 in 33 Italian Centers.ResultsAmong the 765 patients included in this analysis, 121 (15.8%) had KRAS p.G12C mutation, 201 (26.3%) KRAS non-p.G12C mutation and 443 (57.9%) KRAS WT. No difference in OS was found between KRAS p.G12C and KRAS non-p.G12C (15.9 vs 17.0 months, HR 0.93, 95% CI: 0.66-1.31, p=0.676).Median progression-free survival was significantly shorter in KRAS-mutated compared to KRAS WT patients (8.8 vs 10.8 months; adjusted HR 1.29, 95% CI 1.04-1.59, p=0.018), with no differences between KRAS p.G12C and KRAS non-p.G12C (8.8 vs 8.8 months, HR 0.95, 95% CI: 0.70-1.30, p=0.756).ConclusionsKRAS mutation showed a potential negative predictive role in advanced nsq-NSCLC treated with first-line chemo-immunotherapy. The impact of co-mutations and post-progression outcomes warrants further investigation.

Comprehensive molecular testing in SGC may allow access to MMT, with a subset of patients experiencing clinical benefit from this strategy.

P1/2, N=11, Active, not recruiting, AIO-Studien-gGmbH | Completed --> Active, not recruiting

P2, N=80, Recruiting, Suzhou Teligene Ltd. | Not yet recruiting --> Recruiting