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Krystal-1 Efficacy For Patients Taking KRAZATI+ cetuximab Heading

Heavily pretreated patients may experience a response1

34% Overall Response Rate KRAZATI® (adagrasib) + cetuximab for CRC

Median DOR: 5.8 months (95% CI: 4.2–7.6)

  • 31% had a response duration of ≥6 months†
Category 2A NCCN Recommended banner

CRC
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for colon and rectal cancers recommend adagrasib (KRAZATI) + cetuximab as a systemic therapy option for patients with KRAS G12C-mutated advanced CRC.2,3

*Tumor response was assessed by BICR. Data cutoff: June 30, 2023.4
†Observed proportion of patients with duration of response beyond landmark time.1

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KRAZATI delivered a response in KRYSTAL-1 for KRAS G12C-mutated advanced CRC.

In non-comparative cohorts of the phase 1 and phase 2 KRYSTAL-1 trial, patients who received Krazati + cetuximab (pooled analysis phase 1/2; N=94) achieved 34% ORR, and patients who received Krazati monotherapy (phase 1; N=42) achieved 21% ORR.

Indication

KRAZATI® (adagrasib) in combination with cetuximab is indicated for the treatment of adult patients with KRAS G12C-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 ORR and DOR. Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial.

In a phase 1 cohort of KRYSTAL-1, KRAZATI plus cetuximab yielded a numerically higher ORR compared to a separate phase I cohort of patients with KRAS G12C–mutated mCRC receiving KRAZATI monotherapy (34% ORR for KRAZATI + cetuximab vs 21% for KRAZATI monotherapy, N=42; 95% CI: 10.3-36.8).

BICR=blinded independent central review; CI=confidence interval; CRC=colorectal cancer; CR=complete response; DOR=duration of response; NCCN=National Comprehensive Cancer Network; ORR=objective response rate; PR=partial response.

Review the safety and tolerability of KRAZATI + cetuximab  →

References:

  1. KRAZATI®. Prescribing information. Princeton, NJ. Mirati Therapeutics, Inc., a Bristol Myers Squibb company; 2024.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.5.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 29, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.4.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 29, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  4. Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov. 2024;14(6):982-993. doi:10.1158/2159-8290.CD-24-0217.

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 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 Full Prescribing Information.

 

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© 2024 Mirati Therapeutics, Inc., a Bristol Myers Squibb company. KRAZATI® and the related logo are registered trademarks of Mirati Therapeutics, Inc.

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