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DRUG:

RMC-6236

i
Other names: RMC-6236, RMC6236, RMC 6236
Company:
Revolution Medicines
Drug class:
RAS inhibitor
15h
RMC-6236-001: Study of RMC-6236 in Patients With Advanced Solid Tumors Harboring Specific Mutations in RAS (clinicaltrials.gov)
P1, N=614, Recruiting, Revolution Medicines, Inc. | Trial completion date: Dec 2025 --> Jun 2026
Trial completion date
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • RAS mutation • KRAS G12
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RMC-6236
1m
New P3 trial • Metastases
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RAS (Rat Sarcoma Virus)
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RAS mutation
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gemcitabine • 5-fluorouracil • albumin-bound paclitaxel • oxaliplatin • leucovorin calcium • RMC-6236
4ms
Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors (clinicaltrials.gov)
P1, N=444, Recruiting, Revolution Medicines, Inc. | N=290 --> 444 | Trial completion date: Jul 2026 --> Apr 2027 | Trial primary completion date: Aug 2025 --> Apr 2026
Enrollment change • Trial completion date • Trial primary completion date • Metastases
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KRAS (KRAS proto-oncogene GTPase)
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RMC-6236 • RMC-9805
4ms
RRAS and RRAS2 Mutations Are Oncogenic Drivers in Lung Cancer and are Sensitive to the Pan-RAS Inhibitor RMC-6236 (IASLC-WCLC 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.
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NRG1 (Neuregulin 1) • SPRY2 (Sprouty RTK Signaling Antagonist 2)
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KRAS mutation • NRAS mutation • RAS mutation • HRAS mutation • NRG1 fusion • NRG1 mutation • NRG1 fusion
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MSK-IMPACT
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Mektovi (binimetinib) • pictilisib (GDC-0941) • ulixertinib (BVD-523) • SCH772984 • RMC-6236
5ms
New P1/2 trial
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Avastin (bevacizumab) • Erbitux (cetuximab) • gemcitabine • 5-fluorouracil • albumin-bound paclitaxel • oxaliplatin • irinotecan • leucovorin calcium • RMC-6236
6ms
State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies. (PubMed, Curr Opin Oncol)
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.
Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
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MRTX1133 • RMC-6236
7ms
Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. (PubMed, Cancer Discov)
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.
Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • RAS wild-type • KRAS G12
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RMC-6236
7ms
Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. (PubMed, Nature)
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).
Journal
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog)
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KRAS mutation • NRAS mutation • KRAS wild-type • RAS wild-type • HRAS mutation • NRAS wild-type • HRAS G12C • HRAS wild-type
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RMC-6236 • RMC-7977
10ms
Study of RAS(ON) Inhibitor Combinations in Patients With Advanced RAS-mutated NSCLC (clinicaltrials.gov)
P1/2, N=352, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting
Enrollment open • Metastases
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Keytruda (pembrolizumab) • cisplatin • carboplatin • pemetrexed • RMC-6236 • RMC-6291
11ms
Study of RMC-6291 in Combination With RMC-6236 in Participants With Advanced KRAS G12C Mutant Solid Tumors (clinicaltrials.gov)
P1, N=210, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting
Enrollment open
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KRAS (KRAS proto-oncogene GTPase)
|
RMC-6236 • RMC-6291
11ms
New P1/2 trial
|
Keytruda (pembrolizumab) • cisplatin • carboplatin • pemetrexed • RMC-6236 • RMC-6291
1year
New P1 trial • Combination therapy • Metastases
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KRAS (KRAS proto-oncogene GTPase)
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RMC-6236 • RMC-6291
1year
RASMULTI(ON) Inhibitor RMC-7977 Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 Inhibitors in AML Models (ASH 2023)
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.
IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CASP3 (Caspase 3) • CASP7 (Caspase 7)
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KRAS mutation • NRAS mutation • FLT3-ITD mutation • FLT3 mutation • KIT mutation • KRAS G13D • RAS mutation • NRAS Q61K • NRAS Q61 • KIT N822K • NRAS G12 • NRAS G13 • NRAS Q61L • NRAS G13D • NRAS G12C
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Venclexta (venetoclax) • Xospata (gilteritinib) • RMC-6236 • RMC-7977
1year
Enrollment change • Metastases
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • RAS mutation • KRAS G12
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RMC-6236
1year
Drugging RAS: Moving Beyond KRASG12C. (PubMed, Cancer Discov)
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.
Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS G12C • KRAS G12D • KRAS G12
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RMC-6236 • HRS-4642
over1year
Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) (ESMO 2023)
Conclusions RMC-6236 exhibits promising anti-tumor activity in patients with KRASG12X PDAC and NSCLC at doses that are well tolerated. Dose escalation is ongoing and data from additional patients will be available at the time of the meeting.
Clinical
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12A • KRAS G12
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RMC-6236
over1year
Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma (AACR 2023)
Through this approach, we will assess the regulatory adaptations that occur as tumors initially respond and as they escape. Together, these studies provide complementary evidence from in vivo murine and ex vivo human models for promising anti-tumor activity in response to GTP-RAS inhibition, supporting the inclusion of PDAC patients in ongoing and future clinical trials of RMC-6236.
Preclinical
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KRAS (KRAS proto-oncogene GTPase) • MAPK1 (Mitogen-activated protein kinase 1)
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KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • RAS mutation • KRAS G12 • KRAS expression
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RMC-6236
over2years
Evaluation of RMC-6236 in Subjects With Advanced Solid Tumors Harboring Specific Mutations in KRAS (clinicaltrials.gov)
P1, N=141, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting
Enrollment open
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12R • KRAS G12A • KRAS G12 • KRAS G12S
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RMC-6236
over2years
New P1 trial
|
KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12R • KRAS G12A • KRAS G12 • KRAS G12S
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RMC-6236
over2years
Direct targeting of KRASG12X mutant cancers with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RASMULTI(ON) inhibitor (AACR 2022)
Intermittent scheduling of RMC-6236 was active and permitted a higher dose intensity than daily dosing.RMC-6236 promoted anti-tumor immunity in vivo and was additive with anti-PD1 antibodies, driving durable complete responses and immunologic memory in a KRAS mutant CRC model. Furthermore, RMC-6236 treatment reversed oncogenic RAS-driven immune evasion mechanisms in a checkpoint blockade refractory KRAS mutant model, significantly transforming the tumor microenvironment in favor of anti-tumor immunity.These preclinical results support the inclusion of NSCLC, PDAC, and CRC patients in our planned clinical trial of RMC-6236 in patients with KRASG12X advanced solid tumors.
PD(L)-1 Biomarker • IO biomarker
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS G12R • KRAS G12
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RMC-6236