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Bristol Myers Squibb Announces U.S. FDA Accelerated Approval of KRAZATI® (adagrasib) in Combination with Cetuximab for Adult Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer (CRC)


Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for KRAZATI® (adagrasib) in combination with cetuximab as a targeted treatment option for adult patients with KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR) results. Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial. 

"CRC with a KRASG12C mutation occurs in approximately 3-4% of CRC patients and has historically been challenging to treat,"2 said Rona Yaeger, MD, Gastrointestinal Oncologist & Early Drug Development Specialist, Memorial Sloan Kettering Cancer Center. "The FDA approval of KRAZATI combined with cetuximab now provides a new treatment option to these patients when their tumors do not respond well to prior therapies."

The approval is based on results from cohorts of the Phase 1/2 KRYSTAL-1 open-label study which evaluated KRAZATI (600 mg tablets administered orally twice daily) in combination with cetuximab in 94 patients with heavily pretreated CRC harboring a KRASG12C mutation. The study met its primary endpoint, with a confirmed ORR of 34% (n=94, 95% CI: 25-45) for KRAZATI with cetuximab, all of which were partial responses. The median DOR, one of the secondary endpoints, was 5.8 months (95% CI: 4.2-7.6).1 Current late-line standard of care options result in limited response rates (ORR 1-6%) after progression on chemotherapy ± VEGF/VEGFR inhibitors.3,4

KRAZATI is associated with the following Warnings & Precautions: Gastrointestinal adverse reactions including diarrhea, nausea, and vomiting, QTc interval prolongation, hepatotoxicity, and interstitial lung disease (ILD)/pneumonitis.1 Please see Important Safety Information below.

"Today's approval of KRAZATI in CRC is the second in the U.S. for this therapy and the first for BMS' recently expanded oncology portfolio. This is an important milestone for BMS and the patients we serve as we deliver on our commitment to provide innovative medicines for cancer," said Wendy Short Bartie, senior vice president, U.S. Oncology and Hematology at Bristol Myers Squibb. "We are proud to make KRAZATI - the first KRASG12C inhibitor to be FDA approved beyond non-small cell lung cancer - available to CRC patients, and look forward to further evaluating KRAZATI through our ongoing development program."

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab for patients with KRASG12C-mutated advanced CRC whose cancer has progressed following prior treatment with certain chemotherapy and an anti-VEGF therapy.

KRAZATI is an irreversible inhibitor of KRASG12C with a long half-life (23 hours), dose-dependent pharmacokinetics (PK), and central nervous system (CNS) penetration, which, in combination with cetuximab may enhance inhibition of KRAS-dependent signaling or overcome adaptive feedback.

The company partnered with QIAGEN to develop a tissue-based companion diagnostic (CDx) for KRAZATI that is now available.

KRAZATI is a registered trademark of Mirati Therapeutics, Inc., a Bristol Myers Squibb company.

About KRYSTAL-1

KRYSTAL-1 is an open-label, multicenter, multiple expansion cohort Phase 1/2 trial to determine the safety and efficacy of KRAZATI in patients with advanced colorectal cancer (CRC) that harbor a KRASG12C mutation. The primary endpoint for the Phase 2 cohort of the KRYSTAL-1 study was objective response rate (ORR). Secondary endpoints included duration of response (DOR).

The KRYSTAL-1 study was funded by Mirati Therapeutics, Inc., a Bristol Myers Squibb company.

Select Safety Profile from KRYSTAL-1

The safety profile for KRAZATI plus cetuximab was evaluated in patients with KRASG12C-mutated, locally advanced or metastatic CRC, and is consistent with previous reports and known safety profile of each drug individually. Serious adverse reactions occurred in 30% of 94 patients who received KRAZATI in combination with cetuximab. The most common adverse reactions (?20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.1

About Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body's digestive, or gastrointestinal, system.5 CRC is the third most commonly diagnosed cancer in the world.6 In 2024, it is estimated that there will be approximately 106,590 new cases of the disease in the U.S.; it is the second leading cause of cancer-related deaths in the U.S. among men and women combined.7

KRAS is the most frequently mutated oncogene in human cancer and is one that drives oncogenesis in up to 50% of patients with CRC.2 The KRASG12C mutation occurs in approximately 3-4% of CRC cases.2

About KRAZATI® (adagrasib)

KRAZATI (adagrasib) is a highly selective and potent oral small-molecule inhibitor of KRASG12C that 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.8 KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of non-small cell lung cancer (NSCLC; adenocarcinoma) and 3% of several other cancers.9,10

In 2022, KRAZATI was granted accelerated approval for treatment of adult patients with KRASG12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial.

KRAZATI continues to be evaluated as a monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC and CRC.

Please see U.S. Full Prescribing Information for KRAZATI.

INDICATIONS

KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

KRAZATI, as a single agent, is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

QTc Interval Prolongation

Hepatotoxicity

Interstitial Lung Disease/Pneumonitis

ADVERSE REACTIONS

DRUG INTERACTIONS

Please see Drug Interactions Section of the Full Prescribing Information for additional information.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential

Lactation

Please see U.S. Full Prescribing Information for KRAZATI.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision ? transforming patients' lives through science. The goal of the company's cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient's life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

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, please visit BMS.com or follow us on LinkedIn, X (formerly Twitter), YouTube, Facebook, and Instagram.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, whether KRAZATI (adagrasib) in combination with cetuximab for the additional indication described in this release will be commercially successful, that any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of KRAZATI in combination with cetuximab for such additional indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb's business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

1 KRAZATI. Prescribing Information. Princeton, NJ. Mirati Therapeutics, Inc., a Bristol Myers Squibb company; 2024.
2 Yaeger, R., Weiss, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. New England Journal of Medicine. 2023;388(1), 44?54. https://doi.org/10.1056/nejmoa2212419
3 Prager, G., et al. Trifluridine?Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. New England Journal of Medicine. 2023 May 4;388(18). https://www.nejm.org/doi/full/10.1056/NEJMoa2214963
4 Grothey, A., et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. https://pubmed.ncbi.nlm.nih.gov/23177514/
5 What is colorectal cancer? American Cancer Society. (n.d.) https://www.cancer.org/cancer/colon-rectal-cancer/about/what-is-colorectal-cancer.html
6 Globocan 2020, World https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf
7 Colorectal cancer statistics: How common is colorectal cancer? American Cancer Society. (n.d.). https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
8 Hallin J, Engstrom LD, Hargis L, et al. The KRAS Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020;10(1):54-71
9 Campbell et al, Nature Genetics 2016 "Distinct patterns of somatic genome alterations in lung adenocarcinomas
10 Nassar, A., et al. Distribution of KRASG12C Somatic Mutations across Race, Sex, and Cancer Type. New England Journal of Medicine, 384:185-187. https://doi.org/10.1056/nejmc2030638

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