Stunning Data of RMC6236 Combined with PD1 Immunotherapy in CT26-KRAS-G12C-KI Model

Recently, the Kyinno Biotechnology research team conducted an important study in the CT26-KRAS-G12C-KI syngeneic mouse model to evaluate the anti-tumor efficacy of RMC6236 combined with PD1 immunotherapy. The results showed that, compared with monotherapy, the combination therapy significantly enhanced the efficacy of RMC6236, providing a new direction and hope for the treatment of KRAS-mutant tumors.

RMC6236 is an oral, direct RAS(ON) protein multi-selective inhibitor

KRAS gene mutations are highly notorious in the field of oncology. According to statistics, approximately 30% of all tumors are driven by RAS mutations, of which KRAS mutations account for up to 85%, earning KRAS the title of “king of targets.” However, the KRAS protein has a smooth, globular structure lacking drug-binding sites, exhibiting “undruggable” characteristics, making drug development extremely challenging. It was not until 2021 and 2022 that the FDA approved the first covalent KRAS G12C inhibitors, Sotorasib (AMG510) and Adagrasib (MRTX849), which completely shattered the “undruggable” label of KRAS.

Oncogenic KRAS signaling (DOI: 10.1038/s41417-021-00383-9)

Daraxonrasib (development code: RMC-6236) is a multi-selective RAS(ON) inhibitor developed by Revolution Medicines. It targets mutant and wild-type RAS proteins in the GTP-bound (active) state, thereby blocking cancer cells from transmitting growth signals. It is capable of acting on multiple common RAS mutations, such as G12X, G13X, and Q61X, which are key drivers in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer, and other prevalent cancers. Therefore, Daraxonrasib is expected to become a new weapon against various RAS-mutant cancers.

RMC-6236 molecular structure and mechanism of action (DOI: 10.1021/acs.jmedchem.4c02314)

In June 2025, the U.S. Food and Drug Administration (FDA) granted Daraxonrasib breakthrough therapy designation for the treatment of previously treated patients with KRAS G12-mutant metastatic PDAC. The latest data also show that RMC-6236 monotherapy (300 mg qd) demonstrates remarkable efficacy in first-line treatment of metastatic PDAC. As of July 28, 2025, among 38 patients with sufficiently long follow-up, the ORR was 47% (including 1 CR), and the DCR was 89%. However, the median follow-up time was only 9.3 months, with most patients still undergoing treatment, requiring further follow-up to confirm OS and PFS benefits. Studies of RMC-6236 combined with standard first-line AG therapy also show relevant conclusions. With RMC-6236 (200 mg qd) combined with AG, median follow-up was 6.9 months. Among 31 evaluable patients, ORR was 55% and DCR was 90%. The safety profile of the combination was consistent with monotherapy, with no new adverse events reported, and most patients tolerated the treatment well.

CT26-KRAS-G12C-KI Model: A High-Quality Research Platform

Kyinno Biotechnology has developed CT26-KRAS-G12C/G12A/V/R/S cell lines and established in vivo models to support cancer therapy research. Notably, CT26 cells are derived from BALB/c mice, and implanting KRAS-mutant CT26 cells into syngeneic immunocompetent mice rarely triggers immune rejection. This allows stable tumor formation in mice and enables the construction of tumor models that more closely mimic physiological conditions. These models can be used to study tumor initiation and progression in the context of an intact immune system and evaluate the real-world efficacy of different therapies, providing critical support for cancer research.

The CT26-KRAS-G12C-KI model launched by Kyinno Biotechnology is a gene knock-in model, more accurately simulating the tumor microenvironment and immune characteristics of human cancers, providing a powerful tool for evaluating KRAS-targeted drugs.

Applications of this model:

Evaluation of KRAS G12C inhibitor monotherapy efficacy
Study of combination therapy strategies (e.g., immunotherapy, chemotherapy)
Mechanistic studies of drug resistance
Biomarker exploration

Stunning Data: RMC6236 Combined with PD1 Shows Significant Synergy

In this study, we evaluated the anti-tumor effects of RMC-6236 combined with PD1 immunotherapy in the CT26-KRAS-G12C-KI model.

The results showed:

RMC6236 monotherapy significantly inhibited tumor growth
PD1 monotherapy showed limited efficacy
RMC6236 combined with PD1 demonstrated marked synergistic effects, with tumor suppression significantly superior to monotherapy
Tumor regression was more pronounced in the combination group (6/10 achieved complete remission mCR), and survival was significantly prolonged

RMC6236 combined with PD1 immunotherapy in CT26-KRAS-G12C-KI

Pan-KRAS Inhibitors: Future Development Direction

RMC-6236 is an innovative tri-complex inhibitor targeting multiple RAS mutations and wild-type RAS. It binds to intracellular chaperone Cyclophilin A to form an inhibitory binary complex, which then interacts with active GTP-bound RAS to form a ternary complex, inhibiting RAS signaling by disrupting interactions with effectors.

Compared to approved KRAS G12C inhibitors, pan-KRAS inhibitors have clear advantages:

Broader patient population, especially those who cannot benefit from approved KRAS inhibitors
Better efficacy against multiple KRAS mutants
Potential to overcome acquired resistance

Additional Recommended KRAS In Situ Mutant Models

In addition to the CT26-KRAS-G12C-KI model, Kyinno Biotechnology also provides various BaF3-KRAS mutant models and KRAS in situ mutant models, covering KRAS G12D, G12V, G12R, and secondary mutations to meet different research needs. Selected in vitro validation data of KRAS in situ mutant models are as follows:

These models are rigorously validated, stably express KRAS mutations, and are suitable for efficacy studies, mechanistic research, and combination therapy strategy evaluation.

Conclusion and Outlook

This study using the CT26-KRAS-G12C-KI model confirmed the synergistic anti-tumor effect of RMC6236 combined with PD1 immunotherapy, providing strong preclinical data support for clinical treatment of KRAS-mutant tumors. With the continuous expansion and refinement of various KRAS mutant models, Kyinno Biotechnology will continue to provide high-quality experimental models and technical services for researchers and pharmaceutical developers, jointly advancing the field of KRAS-mutant tumor therapy.

Scholars and industry partners are welcome to inquire and discuss potential collaborations!