Proto-oncogene KRAS, GTPase (KRAS) is one of the most intensively studied oncogenes in cancer research. Although several mouse models allow for regulated expression of mutant KRAS, selective isolation and analysis of transforming or tumor cells that produce the KRAS oncogene remains a challenge. In our study, we present a knock-in model of oncogenic variant KRASG12D that enables the “activation” of KRASG12D expression together with production of red fluorescent protein tdTomato. Both proteins are expressed from the endogenous Kras locus after recombination of a transcriptional stop box in the genomic DNA by the enzyme flippase (Flp). We have demonstrated the functionality of the allele termed RedRas (abbreviated KrasRR) under in vitro conditions with mouse embryonic fibroblasts and organoids and in vivo in the lung and colon epithelium. After recombination with adenoviral vectors carrying the Flp gene, the KrasRR allele itself triggers formation of lung adenomas. In the colon epithelium, it causes the progression of adenomas that are triggered by the loss of tumor suppressor adenomatous polyposis coli (APC). Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that KRASG12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the KRASG12D function is effectively suppressed by specific inhibitor MRTX1133.

18 Mar 2025·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS ^G12D inhibitor in KRAS LUAD

Article

Author: Patrucco, Enrico ; Calzada, Nuria ; Olarte-San Juan, Andrea ; Kramer-Drauberg, Maximilian ; Petrini, Ettore ; Arnhof, Heribert ; Kostyrko, Kaja ; Rodríguez-Ramos, Pablo ; Santos, Eugenio ; Ambrogio, Chiara ; Hofmann, Marco H. ; Mair, Barbara ; Borrajo, Javier ; Baltanás, Fernando C. ; Castellano, Esther ; García-Navas, Rósula

We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2 KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRAS mut cell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug. Consistent with prior genetic evidence and the KRAS mut allografts assays in immunocompromised mice, our analyses using an in vivo model of KRAS G12D -driven lung adenocarcinoma (LUAD) in immunocompetent mice showed that single, systemic BI-3406 treatment impaired tumor growth and downmodulated protumorigenic components of the tumor microenvironment comparably to SOS1 genetic ablation or to treatment with the specific KRAS G12D inhibitor MRTX1133. Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.

01 Mar 2025·MOLECULAR THERAPY

Pancreatic cancer-derived extracellular vesicles enhance chemoresistance by delivering KRASG12D protein to cancer-associated fibroblasts

Article

Author: Wang, Yi ; Wang, Jianing ; Zhu, Yupeng ; Huang, Sicong ; Bai, Xueli ; Yang, Jiaqi ; Liu, Xinyuan ; Liang, Tingbo ; Hong, Yifan

KRAS mutations are instrumental in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the efficacy of direct targeting of KRAS mutations to inhibit tumor development remains doubtful. It is therefore necessary to gain a deeper insight into the mechanism in which KRAS mutations influence the effectiveness of clinical treatments. In this study, KRAS^G12D protein was detected in cancer-associated fibroblasts (CAFs) from clinical samples of PDAC. In vitro experiments demonstrated that KRAS^G12D protein in CAFs was not expressed from its own mutant gene but was derived from the ingestion of tumor cell-derived extracellular vesicles (EVs). The presence of KRAS^G12D protein in CAFs resulted in enhanced proliferation and migration. Furthermore, KRAS^G12D-containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo. Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.

News (Medical) associated with MRTX-1133

05 Apr 2024

·www.biospace.com

Novocure Announces 20 Presentations On Tumor Treating Fields, Highlighting Preclinical Effects in Pancreatic Cancer and Immune Effects, at American Association for Cancer Research (AACR) Annual Meeting 2024

ROOT, Switzerland--(BUSINESS WIRE)-- Novocure (NASDAQ: NVCR) today announced 20 presentations on Tumor Treating Fields (TTFields) therapy will be delivered at the American Association for Cancer Research (AACR) Annual Meeting 2024, to be held April 5 to 10 in San Diego. The presentations, describing preclinical investigations, include new insights on how TTFields therapy can potentially enhance the immune system’s ability to combat cancer cells and on TTFields therapy’s effects and mechanisms in pancreatic cancer. “The research we and our collaborators are presenting at the AACR Annual Meeting underscores the potential of Tumor Treating Fields therapy in treating various solid tumor types,” said Moshe Giladi, Ph.D., Novocure’s Chief Science Officer. “We continually explore the science of TTFields therapy to improve our product and make a difference in the lives of patients with cancer, and we are eager to discuss some of our latest insights with leading cancer investigators.” Highlights include: A preclinical study in a murine model of pancreatic cancer showing that TTFields applied concurrently with standard chemotherapy led to significantly enhanced therapeutic effects. When used alongside gemcitabine and nab-paclitaxel (Gem/NabP), TTFields significantly reduced tumor growth compared to the control group, and a complete regression of tumors was observed in a number of animals. This is a treatment regimen similar to the PANOVA-3 clinical trial examining the efficacy of TTFields in patients with locally advanced pancreatic cancer. A preclinical study demonstrating a novel immunomodulatory role for TTFields by promoting in vitro pro-inflammatory polarization of macrophages. Macrophages exposed to TTFields showed an increase in markers and chemicals that indicate a shift towards a pro-inflammatory, tumor-fighting mode. The study suggests TTFields can potentially modulate macrophages to better attack cancer cells by pushing them toward a state more hostile to tumors. An in vitro study suggesting concomitant application of TTFields and PARP inhibitors in BRCA wild type pancreatic cancer cells leads to improvement over monotherapy. Applied individually, both PARP inhibitors and TTFields killed cancer cells, stopped them from multiplying, and triggered apoptosis. These effects were amplified when TTFields and PARP inhibitors were applied together. These findings contribute to existing data suggesting that TTFields induce a state of BRCAness in cancer cells. Presentations from Novocure-sponsored and partner programs include: Tumor Treating Fields (TTFields) targeted self assembling nanoparticles for pancreatic cancer treatment: In vitro and in vivo assessment. Presenter: P.P. Desai. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields induce the integrated stress response, alter the transcriptional signatures of cellular metabolism, and modulate immune-related cytokines dependent and independent of p53. Presenter: P.R. Srinivasan. 1:30 p.m. PDT on Sunday, April 7. Tumor Treating Fields (TTFields) disrupt cancer cell invasion by impacting cell-ECM traction forces. Presenter: S.M. Short. 9 a.m. PDT on Monday, April 8. N-cadherin-mediated activation of PI3K/Akt pathway following application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Monday, April 8. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure. Presenter: M. Mazzanti. 9 a.m. PDT on Monday, April 8. Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D & unexpectedly in KRAS G12V as well. Presenter: V. Tajiknia. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) for spinal metastasis: Clinical trial concept for use of conductive implants as waveguides to enhance TTFields strength. Presenter: C.E. Tatsui. 9 a.m. PDT on Monday, April 8. Tumor Treating Fields (TTFields) increase cancer cell membrane permeability and improve sensitivity to doxorubicin in vitro and in vivo. Presenter: T. Voloshin. 9 a.m. PDT on Tuesday, April 9. Development of paclitaxel-loaded nanoparticles with high charge density. Presenter: K.Y. Bang. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields alter PDGFR-β localization in immortalized human pericytes in an in vitro model of the blood-brain barrier. Presenter: C. Hagemann. 1:30 p.m. PDT on Tuesday, April 9. Designing arrays for delivering Tumor Treating Fields (TTFields) to the mouse head. Presenter: I Tzchori. 1:30 p.m. PDT on Tuesday, April 9. Tumor Treating Fields (TTFields) induce an anti-tumor immune response in a pancreatic cancer mouse model. Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Macrophage pro-inflammatory phenotype skewing by the application of Tumor Treating Fields (TTFields). Presenter: T. Voloshin. 9 a.m. PDT on Wednesday, April 10. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma. Presenter: Q. Mei. 9 a.m. PDT on Wednesday, April 10. Treatment of pancreatic cancer cells with Tumor Treating Fields (TTFields) and PARP inhibitors. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical effects of Tumor Treating Fields (TTFields) with PARP inhibitors in ovarian cancer. Presenter: E. Dor-On. 9 a.m. PDT on Wednesday, April 10. Preclinical investigations of concomitant Tumor Treating Fields (TTFields) with cisplatin for treatment of cervical cancer. Presenter: I. Tzschori. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) can induce immunogenic cell death in GBM resulting in enhanced immune modulation. Presenter: R.T. Nitta. 9 a.m. PDT on Wednesday, April 10. Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib. Presenter: M. Ghandali. 9 a.m. PDT on Wednesday, April 10. TTFields and imipridone ONC206 co-treatment inhibits p-AKT and spheroid growth and upregulates caspase-10 in human GBM cell lines. Presenter: V. Tajiknia. 9 a.m. PDT on Wednesday, April 10. ABOUT TUMOR TREATING FIELDS THERAPY Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or PARP inhibition in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com. ABOUT NOVOCURE Novocure is a global oncology company working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of its innovative therapy, Tumor Treating Fields. Novocure’s commercialized products are approved in certain countries for the treatment of adult patients with glioblastoma, malignant pleural mesothelioma and pleural mesothelioma. Novocure has ongoing or completed clinical studies investigating Tumor Treating Fields in brain metastases, gastric cancer, glioblastoma, liver cancer, non-small cell lung cancer, pancreatic cancer and ovarian cancer. Headquartered in Root, Switzerland and with a growing global footprint, Novocure has regional operating centers in Portsmouth, New Hampshire and Tokyo, as well as a research center in Haifa, Israel. For additional information about the company, please visit Novocure.com and follow @Novocure on LinkedIn and Twitter. FORWARD-LOOKING STATEMENTS In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Novocure’s current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, clinical study progress, development of potential products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, coverage, collections from third-party payers and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as “could” “anticipate,” “estimate,” “expect,” “project,” “intend,” “plan,” “believe” or other words and terms of similar meaning. Novocure’s performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, environmental, regulatory and political conditions and other more specific risks and uncertainties facing Novocure such as those set forth in its Annual Report on Form 10-K filed on February 22, 2024, and subsequent filings with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Novocure does not intend to update publicly any forward-looking statement, except as required by law. Any forward-looking statements herein speak only as of the date hereof. The Private Securities Litigation Reform Act of 1995 permits this discussion. View source version on businesswire.com: Contacts INVESTORS & MEDIA: Ingrid Goldberg investorinfo@novocure.com media@novocure.com 610-723-7427 Source: Novocure View this news release online at:

Immunotherapy

23 Jan 2024

·www.biospace.com

Bristol Myers Squibb Completes Acquisition of Mirati Therapeutics, Strengthening and Diversifying Oncology Portfolio

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb Company (NYSE: BMY) today announced that it has successfully completed its acquisition of Mirati Therapeutics, Inc.® (“Mirati”). 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. “The closing of the Mirati transaction is a significant milestone in our efforts to further diversify our oncology portfolio and strengthen our pipeline in the latter half of the decade and beyond,” said Chris Boerner, Ph.D., Chief Executive Officer, Bristol Myers Squibb. “Mirati’s incredibly talented employees have built a strong portfolio of assets and capabilities that are highly complementary with BMS’. We welcome them and look forward to working together to leverage BMS’ global scale and resources to deliver more treatments for cancer patients, faster.” 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. Advisors Evercore Inc. and Morgan Stanley & Co. LLC are serving as financial advisors to Bristol Myers Squibb, and Kirkland & Ellis LLP is serving as legal counsel. Centerview Partners LLC is serving as financial advisor to Mirati, and Skadden, Arps, Slate, Meagher & Flom LLP is serving as legal counsel. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This communication contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, regarding, among other things, the acquisition of Mirati by Bristol Myers Squibb. These statements may be identified by the fact they use words such as “should,” “could,” “expect,” “anticipate,” “estimate,” “target,” “may,” “project,” “guidance,” “intend,” “plan,” “believe,” “will” and other words and terms of similar meaning and expression in connection with any discussion of future operating or financial performance, although not all forward-looking statements contain such terms. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. These statements are only predictions, and such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Actual results may differ materially from current expectations because of numerous risks and uncertainties including with respect to (i) the risk that the expected benefits or synergies of the acquisition will not be realized, (ii) the risk that legal proceedings may be instituted related to the merger agreement, and (iii) unanticipated difficulties or expenditures relating to the transaction, the response of business partners and competitors to the consummation of the transaction and/or potential difficulties in employee retention as a result of the consummation of the transaction. Forward-looking statements in this communication should be evaluated together with the many uncertainties that affect Bristol Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, and its subsequent Quarterly Reports on Form 10-Q and Current Reports on Form 8-K and in Mirati’s Annual Report on Form 10-K for the year ended December 31, 2022 and its subsequent Quarterly Reports on Form 10-Q , as well as other documents that may be filed by Bristol Myers Squibb from time to time with the SEC. Neither Bristol Myers Squibb nor Mirati undertakes any obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. The forward-looking statements made in this communication relate only to events as of the date on which the statements are made. corporatefinancial-news

AcquisitionPhase 1ASCO

10 Jan 2024

·www.prnewswire.com

European Commission Approves KRAZATI (adagrasib) as a Targeted Treatment Option for Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation

SAN DIEGO and ZUG, Switzerland, Jan. 10, 2024 /PRNewswire/ -- Mirati Therapeutics, Inc.® (NASDAQ: MRTX), a commercial stage biotechnology company, today announced that the European Commission (EC) granted conditional marketing authorization for KRAZATI® (adagrasib) as a targeted treatment option for adult patients with KRASG12C -mutated advanced non-small cell lung cancer (NSCLC) and disease progression after at least one prior systemic therapy. KRAZATI has demonstrated a positive benefit-risk profile based on the Phase 2 registration-enabling cohort of the KRYSTAL-1 study, evaluating KRAZATI 600 mg administered orally twice daily in 116 patients with KRASG12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor. The primary efficacy endpoints were confirmed ORR and DOR as evaluated by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST v1.1). "KRAZATI offers an efficacious and tolerable therapeutic option for patients living with advanced KRASG12C -mutated NSCLC and this approval expands the potential treatment options available," Martin Reck, MD, PhD, Lung Clinic Grosshansdorf, Germany. "With it's differentiated profile, KRAZATI offers an impactful treatment option for patients living with lung cancer. This approval will assist physicians in tailoring treatment approaches for patients." Conditional marketing authorization for KRAZATI is valid in all 27 EU member states plus Iceland, Norway and Liechtenstein. This authorization follows the positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in November 2023. "This is a meaningful day for patients living with this difficult-to-treat cancer in the European Union as we can now offer a differentiated and potentially best-in-class therapeutic option to this underserved population," Charles Baum, M.D., PhD, founder, president and chief executive officer, Mirati Therapeutics, Inc., "Mirati is resolute in our commitment to improve upon treatment options for these patients and looks forward to continued partnership with EU members states to create broad access for all qualified patients." Mirati thanks the patients, physicians, investigators and site coordinators who participated in the clinical trials that led to this important approval. Important Safety Information The Summary of Product Characteristics (SmPC) for KRAZATI (adagrasib) will be available from the European Medicines Agency at the Union Register of medicinal products. About KRAZATI (adagrasib) Mirati has risen to meet one of the most challenging mutations in cancer research by developing KRAZATI, a highly selective and potent oral small-molecule inhibitor of KRASG12C. Intentionally designed to meet the challenge of KRASG12C, adagrasib is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24−48 hours.1 Adagrasib has shown clinically to be a CNS penetrant, which may be important given that CNS metastases frequently occur in NSCLC and lead to poor prognosis.2-34 The FDA provided KRAZATI Accelerated Approval (Subpart H), allowing for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science. About the KRYSTAL-1 Study KRYSTAL-1 is an open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumors harboring the KRASG12C mutation. About KRASG12C in NSCLC Lung cancer is one of the most common cancers worldwide, accounting for 2.21 million new cases and 1.8 million deaths worldwide in 2020.5 Lung cancer consists of NSCLC in approximately 85% of cases and small cell lung cancer (SCLC) in approximately 15% of cases.6 KRASG12C is the most common KRAS mutation in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker mutation of poor prognosis.1,3 About Mirati Therapeutics, Inc. Mirati Therapeutics, Inc. is a commercial stage biotechnology company whose mission is to discover, design and deliver breakthrough therapies to transform the lives of patients with cancer and their loved ones. The company is relentlessly focused on bringing forward therapies that address areas of high unmet need, including lung cancer, and advancing a pipeline of novel therapeutics targeting the genetic and immunological drivers of cancer. Unified for patients, Mirati's vision is to unlock the science behind the promise of a life beyond cancer. For more information about Mirati, visit us at Mirati.com or follow us on Twitter, LinkedIn and Facebook. Forward Looking Statements This press release includes forward-looking statements regarding Mirati's business, financial guidance and the therapeutic and commercial potential of KRAZATI® (adagrasib), MRTX1719 (MTA-cooperative PRMT5 inhibitor), MRTX0902 (SOS1 inhibitor), and MRTX1133 (selective KRASG12D inhibitor), Mirati's technologies and Mirati's other products in development. Any statement describing Mirati's goals, expectations, intentions or beliefs, financial or other projections, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including those related to the impact COVID-19 could have on our business, and including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Mirati's forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Mirati's forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Mirati. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Mirati's programs are described in additional detail in Mirati's annual report on Form 10-K, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission and available at the SEC's Internet site (). These forward-looking statements are made as of the date of this press release, and Mirati assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Mirati Contacts Investor Relations: [email protected] Media Relations: [email protected] References 1 Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020;10(1):54-71. 2 Sabari JK, Velcheti V, Shimizu K, et al. Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2022;28(15):3318-3328. 3 Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol. 2017;19(11):1511-1521. 4 Ali A, Goffin JR, Arnold A, Ellis PM. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol. 2013;20(4):e300-6. 5 Lung cancer statistics. WCRF International. . Published April 14, 2022. 6 Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. SOURCE Mirati Therapeutics, Inc.

Clinical ResultDrug ApprovalPhase 2Accelerated Approval

100 Deals associated with MRTX-1133

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	United States	Mirati Therapeutics, Inc.	20 Mar 2023
Colorectal Cancer	Phase 1	United States	Mirati Therapeutics, Inc.	20 Mar 2023
Non-Small Cell Lung Cancer	Phase 1	United States	Mirati Therapeutics, Inc.	20 Mar 2023
Pancreatic adenocarcinoma	Phase 1	United States	Mirati Therapeutics, Inc.	20 Mar 2023
Pancreatic Ductal Adenocarcinoma	Phase 1	United States	Mirati Therapeutics, Inc.	20 Mar 2023
Neoplasms	Phase 1	United States	Mirati Therapeutics, Inc.	19 Jan 2023
Pancreatic Cancer	Preclinical	United States	Mirati Therapeutics, Inc.	01 Aug 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2025	Not Applicable	Appendiceal Neoplasms	-	MRTX1133	xqsthyjbki(qemdhbvanv) = Both inhibitors significantly increased Caspase-3/7, consistent with induction of apoptosis (p-value < 0.01) koosasmxlt (yvgswovcru ) View more	Positive	29 Apr 2025
				RMC-6236
AACR2025	Not Applicable	Pancreatic Cancer	-	MRTX1133	depsecefqa(unfmcyxvvc) = osjgfdjeow puozkuawam (sibwaqjyar )	Positive	29 Apr 2025
				Nab-paclitaxel and gemcitabine (NPT-GEM)	depsecefqa(unfmcyxvvc) = kkclzfklvv puozkuawam (sibwaqjyar )
MRTX1133 (AACR2025)	Not Applicable	EGFR	-	MRTX1133 (Standard EGF concentration (50 ug/mL))	jtpwjsaiyt(vanfulgnfl) = cfydilbhnn zxuuqtgnut (stvpxzxday )	-	28 Apr 2025
				MRTX1133 (Physiological EGF concentration (0.5 ug/mL))	jtpwjsaiyt(vanfulgnfl) = yfqazidxep zxuuqtgnut (stvpxzxday )

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