On June 21, 2024 Bristol Myers Squibb reported 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 (Press release, Bristol-Myers Squibb, JUN 21, 2024, View Source [SID1234644479]). 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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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 KRASG12 C-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

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 of KRAZATI 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 with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that are known 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 for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, 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) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if 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, abdominal pain, 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 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.