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)
Approval based on results from the Phase 1/2 KRYSTAL-1 study where KRAZATI in combination with cetuximab showed an objective response rate of 34% in pretreated patients with locally advanced or metastatic CRC harboring a KRASG12C mutation1
Second FDA approval for KRAZATI - reinforcing its potential across tumor types
“CRC with a KRASG12Cmutation occurs in approximately 3-4% of CRC patients and has historically been challenging to treat,”2 said
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
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
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 KRASG12Cmutation. 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
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
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 KRASG12Cmutation 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.8KRASG12C 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
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
- KRAZATI can cause severe gastrointestinal adverse reactions.
- Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated.Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity.
QTc Interval Prolongation
- KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death.
- Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use ofKRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation.
- Monitor ECGs and electrolytes, particularly potassium and magnesium, prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients withcongestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that areknown to prolong the QT interval. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity.
Hepatotoxicity
- KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
- Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce thedose, withhold, or permanently discontinue KRAZATI based on severity.
Interstitial Lung Disease/Pneumonitis
- KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal.
- Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever) duringtreatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATIif no other potential causes of ILD/pneumonitis are identified.
ADVERSE REACTIONS
- Serious adverse reactions occurred in 57% of 116 patients who received adagrasib in NSCLC patients. The most common adverse reactions in NSCLC patients (≥20%) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain,hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominalpain, and QTc interval prolongation.
- Serious adverse reactions occurred in 30% of 94 patients who received adagrasib in combination with cetuximab. The most common adverse reactions in CRC patients (≥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.
DRUG INTERACTIONS
- Strong CYP3A4 Inducers: Avoid concomitant use.
- Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state (after ~8 days).
- Sensitive CYP3A4 Substrates: Avoid concomitant use with sensitive CYP3A4 substrates.
- Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates: Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions.
- Drugs That Prolong QT Interval: Avoid concomitant use with KRAZATI.
Please see Drug Interactions Section of the Full Prescribing Information for additional information.
USE IN SPECIFIC POPULATIONS
Females and Males of Reproductive Potential
- Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential.
Lactation
- Advise not to breastfeed.
Please see
Cancer can have a relentless grasp on many parts of a patient’s life, and
About
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
1 KRAZATI. Prescribing Information.
2 Yaeger, R., Weiss, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C.
3 Prager, G., et al. Trifluridine–Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer.
4 Grothey, A., et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
5 What is colorectal cancer?
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?
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.
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