KRAS mutation

P1, N=171, Recruiting, Boehringer Ingelheim | N=94 --> 171 | Trial primary completion date: Jun 2028 --> Feb 2029

Impaired ER-phagy triggers protein aggregation, inflammation, and acinar-to-ductal metaplasia, promoting tumorigenesis. These findings highlight selective autophagy's role in cancer, with possible therapeutic implications.

These findings highlight the need to molecularly characterize these lesions as there is no specific histologic finding to identify cases that harbour different pathogenic alterations in specific genes.

Gastric tumors can bypass niche dependence by acquiring KRAS-MAPK-SMAD2/3-driven epithelial WNT secretion. Targeting this axis-through MAPK inhibition, SMAD2/3 blockade, or suppression of WNT secretion-may represent a therapeutic vulnerability in gastric cancer and other KRAS-high malignancies.

P1/2, N=175, Terminated, Synthorx, Inc, a Sanofi company | N=250 --> 175 | Active, not recruiting --> Terminated; The study was terminated as per Sponsor decision. The decision was not related to any safety concerns.

Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.

We outline mechanisms of action, clinical efficacy, and limitations of FDA-approved tyrosine kinase inhibitors (TKIs) and emerging agents, with emphasis on resistance pathways, both on-target and bypass-mediated, observed during treatment with drugs such as osimertinib, crizotinib, sotorasib, and entrectinib. The role of next-generation sequencing (NGS), liquid biopsy, and comprehensive biomarker profiling in guiding personalized therapy selection is also discussed, along with strategies for sequential therapy and rational combination approaches.

There was no difference between KRASm G12C and KRASwt patients in terms of ORR (48% vs. 49%; p = 0.961) and DCR (86% vs. 84%; p = 0.903), nor when comparing KRASm to KRASwt in terms of OS (p = 0.64), PFS (p = 0.28), TTLR (p = 0.26), and TTDR (p = 0.3), with no impact after adjustment for durvalumab. KRAS G12C mutation compared to KRAS wild-type did not affect response to chemoradiotherapy, and KRAS mutations compared to KRAS wild-type were not associated with worse survival in unresectable stage II or III NSCLC treated with chemoradiotherapy.

Our case and related literature review suggest that the multiplex genetic mutation-detection assay should be considered for patients with LCNEC. Furthermore, it also suggests that biomarkers which enable us to distinguish patients who are likely to harbor driver gene alterations are required in near future.

Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options.

Specific emphasis is also placed on intracranial activity and the use of sotorasib in special subgroups, including frail patients and those with comorbidities, providing a practical framework for daily clinical practice. The objective is to offer evidence-based guidance to facilitate treatment personalization and improve clinical outcomes in this complex patient population.

Patients with advanced AC formed the "Descriptive cohort," while those treated with cisplatin-gemcitabine (CisGem) comprised the "CisGem-treated cohort." Among 534 trial participants, 28 (5.24%) had AC, and 17 received CisGem. Molecular profiling has revealed potentially actionable alterations, including HER2 amplification and KRAS mutations, supporting precision oncology approaches. This study provides the most comprehensive reference dataset to date for advanced AC treated with CisGem and emphasizes the importance of international collaboration and molecularly guided research to improve outcomes in this rare malignancy.