RAS wild-type

P=N/A, N=152, Active, not recruiting, Gustave Roussy, Cancer Campus, Grand Paris | N=61 --> 152 | Trial completion date: Jan 2028 --> Jan 2029 | Trial primary completion date: Jan 2027 --> Jan 2028

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.

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.

NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers and highlight the importance of RNA testing. NRG1+ PDAC is enriched in younger patients with KRAS wild-type disease and has a unique biology.

Histopathological evaluation may aid risk stratification alongside KRAS status. Prognostic assessment in clinical settings should take both TNM staging and KRAS status into account.

This is the largest national dataset on melanoma NRAS and KIT status published to date. Variations in NRAS/KIT testing by geographic/demographic factors drives initiatives to ensure consistent care. NRAS mutated melanoma had high incidence which emphasises the unmet need to develop therapies and trials for NRAS mutated melanoma. This study increases our understanding of biomarkers NRAS and KIT and provides a foundation for optimising melanoma care, contributing to advancements in precision oncology.

Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval for NGR1 fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches.

Dual HER2-targeted therapy combined with chemotherapy is a promising strategy for HER2-positive mCRC patients with good performance status. This approach warrants validation in large-scale clinical trials to confirm its efficacy.

The research also integrates recent advances in multi-targeted strategies, including combinations of KRAS inhibitors with metabolic or epigenetic modulators or immune checkpoint blockade. These findings provide potential strategies for overcoming resistance in KRAS-mutant CRC, addressing a critical gap in precision oncology.

Our findings directly inform clinical guidelines, address gaps in current therapeutic decision-making. Durvalumab or pembrolizumab combined with GC are optimal first-line regimens for advanced BTC, balancing survival benefits and safety. Sintilimab plus anlotinib combined with GC demonstrates superior PFS but requires further validation. While EGFR inhibitors plus chemotherapy demonstrate potential in KRAS wild-type patients, confirmation in large-scale RCTs is required. PD-L1 expression may represent a promising predictive biomarker for response to PD-1 inhibitor therapy.

The exploratory analysis of FIRE-3 suggests that the efficacy of cetuximab combined with FOLFIRI in RAS wild-type mCRC is related to sex and primary tumor sidedness. The results support the inclusion of patient sex into the design of future trials.

The chemotherapy history included fluoropyrimidine (101 patients, 100%), oxaliplatin (95 patients, 94.1%), irinotecan (82 patients, 81.2%), anti-vascular endothelial growth factor antibody (92 patients, 91.1%) and anti-epidermal growth factor receptor antibody (41 patients, accounting for 87.2% of the RAS wild-type subgroup). The results of the present study suggested that TAS-102 combined with bevacizumab in subsequent treatment may have greater efficacy in rectal cancer than in colon cancer, possibly due to the lower frequency of liver metastases in rectal cancer. However, this finding is exploratory and requires further validation via larger prospective studies.