MYC amplification was reported to be a main contributor to the development of resistance. Six trials are currently ongoing, including one randomized trial, and promising results are expected from combination with other agents, such as immune-checkpoint blockers.

P1/2, N=484, Recruiting, Revolution Medicines, Inc. | N=352 --> 484

P1, N=614, Recruiting, Revolution Medicines, Inc. | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Jun 2024 --> May 2026

P1, N=195, Recruiting, Chugai Pharmaceutical | Trial completion date: Mar 2025 --> May 2026

P1, N=25, Recruiting, DeuterOncology | Trial completion date: Apr 2025 --> Dec 2026 | Trial primary completion date: Oct 2024 --> Dec 2025

P1/2, N=49, Recruiting, Neonc Technologies, Inc. | Trial primary completion date: Jun 2024 --> Dec 2024

P1, N=15, Not yet recruiting, Neonc Technologies, Inc. | Trial completion date: Oct 2024 --> Oct 2025 | Initiation date: May 2024 --> Dec 2024 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=153, Recruiting, TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics | Not yet recruiting --> Recruiting

P3, N=460, Recruiting, Revolution Medicines, Inc.

P1, N=153, Not yet recruiting, TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics

P1/2, N=52, Active, not recruiting, Golden Biotechnology Corporation | Trial completion date: Mar 2024 --> Dec 2024

ERK1/2 (ulixertinib and SCH772984), MEK1/2 (binimetinib), and PI3K (pictilisib) inhibitors inhibited growth of RRAS Q87L or RRAS2 Q72L cells more potently than cells expressing wildtype proteins. Oncogenic R RAS/RRAS2 mutations were detected in LUAD at a rate similar to some other well-characterized lung cancer drivers, such as HRAS/NRAS hotspot mutations or NRG1 fusions. Our study supports the inclusion of RRAS /RRAS2 into routine molecular diagnostic protocols for precision oncology and clinical development of pan-RAS inhibitors, such as RMC-6236, for patients with these driver mutations in order to fully realize the potential benefit of RAS-targeted therapies.

P2, N=92, Recruiting, Jiangjin Central Hospital of Chongqing; Jiangjin Central Hospital of Chongqing

Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.

The results revealed that 4-AAQB and erinacine A effectively suppressed breast cancer-induced osteoclastogenesis and migration, and reduced TGF-β and MMP-9 production via Erk or JNK signaling transductions, specifically in breast cancer cells or in breast cancer cells-induced osteoclasts. Based on these findings, either 4-AAQB or erinacine A showed promise in preventing breast cancer metastases in bone.

P1, N=134, Recruiting, RasCal Therapeutics, Inc. | Phase classification: P1a/1b --> P1 | Trial completion date: Mar 2024 --> Sep 2025 | Trial primary completion date: Jan 2024 --> Jul 2025

This review systematically summarizes the recent advances in POH and highlights its therapeutic effects and potential mechanisms as well as the clinical settings, which is helpful to develop POH into functional food and new candidate drug for prevention and management of diseases. Future studies are needed to conduct more biological activity studies of POH and its derivatives, and check their clinical efficacy and potential side effects.

P1/2, N=406, Recruiting, Revolution Medicines, Inc.

Targeting RAS has become an important strategy in treating gastrointestinal cancer. These findings in this review underscore the importance of a multidisciplinary approach, integrating advances in molecular profiling, targeted therapy, immunotherapy, and clinical research to optimize treatment strategies for patients with KRAS-mutant gastrointestinal malignancies.

However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.

P=N/A, N=104, Completed, Centre Hospitalier Universitaire de Nice | Unknown status --> Completed

P1, N=15, Not yet recruiting, Neonc Technologies, Inc.

The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors.

RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RAS(ON) multi-selective)3...Analysis of relapsed tumors identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need.

P1, N=230, Recruiting, Nested Therapeutics, Inc | Not yet recruiting --> Recruiting

P1, N=230, Not yet recruiting, Nested Therapeutics, Inc

P1, N=25, Recruiting, DeuterOncology | N=15 --> 25 | Trial completion date: Nov 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Oct 2024

P1/2, N=52, Active, not recruiting, Golden Biotechnology Corporation | Trial completion date: Dec 2023 --> Mar 2024

We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.

P1/2, N=352, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting

P1, N=210, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting

P1/2, N=352, Not yet recruiting, Revolution Medicines, Inc.

In this phase I/II trial, antroquinonol plus Gem/Nab-P showed good efficacy in survival and less adverse events than a first-line strategy of Gem/Nab-P for mPC patients. Clinical trial information: NCT03310632. >Abbreviations: mPC, metastatic pancreatic cancer; Gem/Nab-P, gemcitabine and nab-paclitaxel.#, data from U.S. FDA-approved Supplemental New Drug Application (NDA 21660/S-037) dated March 21, 2013 for paclitaxel protein-bound particles for injectable suspension (albumin-bound), 100 mg/vial.

Computational analysis of the complex revealed the presence of two large binding pockets that possess physicochemical features typically found in pockets considered druggable. Small-molecule binding to these pockets may stabilize this autoinhibited structure of KRAS if it exists in cells to provide a new strategy to inhibit RAS signaling.

P1, N=210, Not yet recruiting, Revolution Medicines, Inc.

When combined with chloroquine and TMZ, the anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel autophagy inhibitor that could become useful for overcoming chemoresistance in glioblastoma.Abbreviations: ATG: autophagy related; BAFA1: bafilomycin A; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.

RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RASMULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236, currently in clinical evaluation (NCT05379985)...Gilteritinib and the gilteritinib/venetoclax combination selected for survival of cells harboring NRAS mutations, but RMC-7977 inhibited outgrowth of all cell populations...In vivo studies investigating the tolerability and activity of RMC-7977 and RMC-7977 combinations in RAS mutant/FLT3i-resistant patient-derived xenograft models are ongoing and will be presented. Collectively, our data provide preclinical evidence that combination therapies leveraging RASMULTI(ON) inhibition are effective in suppressing RAS-mutant AML clones, a common mechanism of resistance to currently approved targeted therapies in AML and a current area of high unmet clinical need.

P1, N=474, Recruiting, Revolution Medicines, Inc. | N=141 --> 474

Preliminary results from phase I trials respectively evaluating RMC-6236, a pan-RAS inhibitor, and HRS-4642, a KRASG12D inhibitor, indicate that both are safe and show promising signs of antitumor activity. These are just two of the candidate RAS therapies in a burgeoning development space as the field looks ahead to drugs that hit more than just KRASG12C.