MRTX0902 / BMS - LARVOL DELTA

Targeting MCL1 or SOS1 can overcome lenvatinib resistance in HCC (AACR 2025) - "Vetting these leads using a multidose titration assay showed synergy with LEN across all three LR models for two drugs: MRTX0902 targeting SOS1, an intracellular RTK signaling protein, and S63845 targeting MCL1, an anti-apoptosis protein. We also showed that targeting these components (SOS1 and MCL1) synergizes with LEN and inhibits cancer growth. These findings may become relevant patient treatments to extend patient survival against liver cancer."

Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • ANXA5

Preclinical characterization of SGR-4174, a potent and selective SOS1 inhibitor for the treatment of pan KRAS mutant cancers in combination with KRAS pathway inhibitors (AACR 2025) - "Compared to other published SOS1 inhibitors (BI-3406, MRTX0902), SGR-4174 is more potent, and demonstrated similar anti-tumor activity and target engagement at a lower dose both in monotherapy and combination therapy studies in xenograft tumor models. SGR-4174 was well tolerated as monotherapy and in combination with sotorasib or trametinib.SGR-4174 demonstrated favorable PK properties across preclinical species and toxicity profile was well characterized. Our comprehensive preclinical efficacy and safety data support progressing SGR-4174 to clinical development to treat KRAS mutant cancers."

Combination therapy • Preclinical • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • KRAS

Characterization of the BH1406 non-small cell lung cancer (NSCLC) cell line carrying an activating SOS1 mutation. (PubMed, Transl Lung Cancer Res) - "Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406...Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293...BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • CHEK2 • SOS1 • STAT3

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. (PubMed, Mol Cancer Ther) - "MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS • NF1 • PTEN

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. (PubMed, Mol Cancer Ther) - "MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of twelve KRAS G12C-mutant human non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenograft models. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS • NF1 • PTEN

The SOS1 inhibitor MRTX0902 demonstrates activity across cancer models with mutations in proximal components of the RAS-MAPK pathway (AACR 2024) - "Additionally, combination with the RAF/MEK clamp avutometinib demonstrated greater antitumor activity versus either monotherapy treatment. These data support the clinical utility of MRTX0902 as a single agent or combination partner of avutometinib for the treatment of human cancers harboring oncogenic mutations implicated in dysregulation of RAS-dependent signaling including SOS1, PTPN11, NF1, and BRAF (class III)."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • KRAS • NF1 • PTPN11

Wild type Kirsten rat sarcoma (Kras) activation drives evasion of interferon-mediated immunity in hepatocellular carcinoma (AACR 2024) - "This study showed that wild-type Kras, via the activation of its downstream MEK/ERK signaling, acts as a crucial immune evasive mechanism in HCC and contributes to resistance to anti-PD-1 therapy. It also provided new insights into the therapeutic potential of targeting wild-type Kras to enhance the efficacy of anti-PD-1 therapy, providing a foundation for further exploration and potential clinical applications in HCC."

IO biomarker • Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Sarcoma • Solid Tumor • CD8 • CXCL9 • EGFR • KRAS

The MTA-cooperative PRMT5 inhibitor, MRTX1719, demonstrates increased anti-tumor activity in combination with KRAS mutant-selective inhibitors in MTAP del,KRAS-mutant cancers (AACR 2024) - "Combination of MRTX1719 with adagrasib or the KRAS G12D inhibitor MRTX1133 in CDX models harboring both a KRAS mutation (G12C or G12D) and homozygous MTAP deletion resulted in increased anti-tumor activity compared to either single agent. Finally, an NF1 mutant, MTAP del malignant peripheral nerve sheath tumor (MPNST) PDX model was treated with MRTX1719, the SOS1 inhibitor MRTX0902, or the combination, and a similar increase in anti-tumor activity was observed in the combination treatment compared to either monotherapy alone. These results suggest that the combination of an MTA-cooperative PRMT5 inhibitor with a KRAS mutant selective or KRAS pathway inhibitor may lead to deeper and more durable responses in MTAP del cancer patients with co-alterations in the KRAS pathway."

Combination therapy • Brain Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Neurofibrosarcoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • KRAS • MTAP • NF1

Bristol Myers Squibb Completes Acquisition of Mirati Therapeutics, Strengthening and Diversifying Oncology Portfolio (Businesswire) - "Bristol Myers Squibb...today announced that it has successfully completed its acquisition of Mirati Therapeutics, Inc...With the completion of the acquisition, Mirati shares have ceased trading on the NASDAQ Global Select Market and Mirati is now a wholly owned subsidiary of Bristol Myers Squibb...Through this transaction, BMS has added commercialized lung cancer medicine KRAZATI (adagrasib) to its oncology portfolio as well as several promising clinical assets, including a potential first-in-class MTA-cooperative PRMT5 inhibitor in Phase 1 development, and a leading KRAS and KRAS enabling program with two candidates in Phase 1 development....The transaction is expected to be treated as a business combination and to be dilutive to Bristol Myers Squibb’s non-GAAP earnings per share by approximately $0.35 per share in 2024."

M&A • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Bristol Myers Squibb Strengthens and Diversifies Oncology Portfolio With Acquisition of Mirati Therapeutics (Businesswire) - "Bristol Myers Squibb (NYSE: BMY) and Mirati Therapeutics...announced that they have entered into a definitive merger agreement under which Bristol Myers Squibb has agreed to acquire Mirati for $58.00 per share in cash, for a total equity value of $4.8 billion....The transaction was unanimously approved by both the Bristol Myers Squibb and the Mirati Boards of Directors....Through this acquisition, Bristol Myers Squibb will add KRAZATI, an important lung cancer medicine, to its commercial portfolio....Mirati’s Promising Pipeline Includes a Potent Selective PRMT5/MTA Inhibitor, MRTX1719, a Potential First-in-Class and Best-in-Class Asset; and Early Clinical Pipeline Features a KRAS and KRAS Enabling Program, including MRTX1133, and a SOS1 Inhibitor, MRTX0902....The transaction is anticipated to close by the first half of 2024, subject to fulfillment of customary closing conditions, including approval of Mirati’s stockholders and receipt of required regulatory approvals."

M&A • Non Small Cell Lung Cancer

Mirati Therapeutics Reports Second Quarter 2023 Financial Results and Recent Corporate Updates (PRNewswire) - "MRTX1133 (Potent and selective KRASG12D inhibitor): The Company continues to enroll patients in the Phase 1/2 clinical study with plans to share initial clinical data in the first half of 2024; MRTX0902 (Potent SOS1 inhibitor): In July, the Company initiated a cohort within the Phase 1/2 trial evaluating the combination of MRTX0902 plus adagrasib with plans to share initial clinical data in 2024."

P1/2 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Inhibition of SOS1 by MRTX0902 augments the anti-tumor response of the targeted EGFR inhibitor osimertinib in NSCLC (AACR 2023) - "While single agent MRTX0902 treatment effectively inhibited EGFR mutant cell survival, combination treatment of MRTX0902 with osimertinib resulted in (1) deeper and sustained inhibition of MAPK and PI3K/AKT pathway signaling, (2) enhanced inhibition of 3D cell viability and increased apoptosis, and (3) increased anti-tumor efficacy compared to osimertinib monotherapy in EGFR mutant CDX models in vivo. These studies uncover the potential clinical application of combined vertical inhibition of RTK/MAPK pathway signaling by osimertinib and MRTX0902 and ultimately aide in the understanding of EGFR and RAS biology in targeted cancer therapy."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Mirati To Present Research at the AACR Annual Congress for Two Potentially First-in-Class Clinical Stage Programs (PRNewswire) - "Mirati Therapeutics...announced a presentation demonstrating in preclinical models the ability of MRTX0902, a selective and potent SOS1 inhibitor, to enhance anti-tumor activity and overcome acquired resistance in combination with either adagrasib, a potent and selective KRASG12C inhibitor, or an epidermal growth factor receptor (EGFR) inhibitor (e.g. osimertinib). Findings will be presented on April 17 at the American Association for Cancer Research (AACR 2023) Annual Congress....In addition, Mirati will share poster presentations featuring MRTX1719, the company's novel MTA cooperative PRMT5 inhibitor. These posters highlight the mechanism by which MRTX1719 elicits potent and selective synthetic lethality in MTAP deleted tumors as well as the further enhancement of antitumor activity via rational targeted combination strategies (Posters #2778/1 and 2779/2)."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Mirati Therapeutics Reports Fourth Quarter and Full Year 2022 Financial Results and Recent Corporate Updates (PRNewswire) - "Pipeline Updates: (i) MRTX1719 (MTA cooperative PRMT5 inhibitor): A Phase 1/2 clinical study to evaluate MRTX1719, an MTA cooperative PRMT5 inhibitor, in patients with solid tumors harboring MTAP-gene deletions is ongoing. The study continues to enroll, and the Company expects to share the initial clinical data in the second half of 2023; (ii) MRTX0902 (Potent SOS1 inhibitor): The Company initiated a Phase 1/2 clinical study initially evaluating MRTX0902, a selective KRAS signal modifying SOS1 inhibitor, in an escalating dose cohort as a monotherapy and expects to initiate dose escalation cohorts combining MRTX0902 and adagrasib in the second half of 2023."

P1/2 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

A Phase 1/2 Study of MRTX0902 in Solid Tumors With Mutations in the KRAS MAPK Pathway (clinicaltrials.gov) - P1/2 | N=225 | Recruiting | Sponsor: Mirati Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS • NF1 • PTPN11

A Phase 1/2 Study of MRTX0902 in Solid Tumors With Mutations in the KRAS MAPK Pathway (clinicaltrials.gov) - P1/2 | N=225 | Not yet recruiting | Sponsor: Mirati Therapeutics Inc.

New P1/2 trial • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS • NF1 • PTPN11

"And still not up to date! Where's MRTX0902 (SOS1i), Vs-6766 (AVUTOMETINIB) RAF/MEK clamp, Defactinib FAKi? https://t.co/McU8bNdbvX" (@CrozrX)

Mirati Therapeutics Reports Second Quarter 2022 Financial Results and Recent Corporate Updates (PRNewswire) - "Pipeline Updates: (i) Sitravatinib (Potent TAM receptor inhibitor): Anticipated to achieve the number of events needed to trigger an interim analysis of overall survival in the global, registrational Phase 3 SAPPHIRE study evaluating sitravatinib plus nivolumab (OPDIVO) in second or third line non-squamous NSCLC in the fourth quarter of 2022; (ii) MRTX0902 (Potent SOS1 inhibitor): Submitted an Investigational New Drug (IND) application to the U.S. FDA to evaluate MRTX0902...in patients with KRAS G12C mutations. The Company expects to initiate a Phase 1/2 clinical study by year-end 2022."

IND • New P1/2 trial • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction. (PubMed, J Med Chem) - "In this report, we detail the design and discovery of MRTX0902─a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRAS PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model."

Journal • Oncology • KRAS

Mirati Therapeutics Reports First Quarter 2022 Financial Results and Recent Corporate Updates (PRNewswire) - "Enrolling patients in an ongoing Phase 1 dose escalation cohort of the Company's investigational MTA cooperative PRMT5 inhibitor, MRTX1719, with initial clinical data expected in 2023....MRTX1133 (Potent and selective KRASG12D inhibitor)...The Company plans to file an IND application for this program in the second half of 2022....MRTX0902 (Potent SOS-1 inhibitor)...The Company expects to file an IND application for this program in the second half of 2022."

IND • P1 data • Oncology • Solid Tumor