SAFETY HIGHLIGHTS
Adverse reactions (ARs) with KRAZATI + cetuximab1
ARs (≥20%) in Patients With KRAS G12C-Mutated CRC Who Received KRAZATI in Combination With Cetuximab in KRYSTAL-11
Serious adverse reactions were reported in 30% taking KRAZATI + cetuximab.
- The most common serious ARs (≥2%) were pneumonia (4.3%), pleural effusion, pyrexia, acute kidney injury, dehydration, and small intestinal obstruction (2.1% each)
- A fatal AR of pneumonia occurred in 1 patient who received KRAZATI in combination with cetuximab
15% of patients experienced infusion-related reactions in KRYSTAL-1 (N=94).
No new safety signals observed with KRAZATI use in KRYSTAL-1
Safety was evaluated in patients with KRAS G12C-mutated locally advanced or metastatic CRC. Patients initiated treatment with KRAZATI 600 mg BID in combination with cetuximab weekly (n=17) or every 2 weeks (n=77).
*Graded per CTCAE version 5.0.1
†Grouped term; includes multiple related terms.1
62% DOSE INTERRUPTIONS DUE TO AN AR
ARs requiring dosage interruption in ≥2.0% of patients who received KRAZATI included diarrhea, nausea, vomiting, abdominal pain, dizziness, headache, pneumonia, alanine aminotransferase increased, aspartate aminotransferase increased, dyspnea, fatigue, pleural effusion, rash, anemia, electrocardiogram QT prolongation, blood bilirubin increased, blood creatinine increased, decreased appetite, dehydration, hemorrhage, hypomagnesemia, lipase increased, muscular weakness, musculoskeletal pain, and pyrexia.
35% DOSE REDUCTIONS DUE TO AN AR
ARs requiring dose reductions in ≥2.0% of patients who received KRAZATI included fatigue, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, decreased appetite, electrocardiogram QT prolongation, dizziness, acute kidney injury, diarrhea, dysarthria, and vomiting.
2% DISCONTINUED DUE TO AN AR1
Permanent discontinuation of KRAZATI due to an AR occurred in 2 patients due to abdominal pain and prolonged QT interval (1 patient each).
KRAZATI WARNINGS AND PRECAUTIONS1
GASTROINTESTINAL ADVERSE REACTIONS
- KRAZATI can cause severe gastrointestinal adverse reactions.
- In patients who received KRAZATI in combination with cetuximab, serious gastrointestinal adverse reactions included gastrointestinal bleeding in 8.5% including 1.1% Grade 3 or 4, gastrointestinal obstruction in 5.3% including 5.3% Grade 3 or 4, colitis in 1.1% including 1.1% Grade 3 and ileus in 1.1%. In addition, nausea, diarrhea, or vomiting occurred in 92% of 94 patients, including 6% Grade 3. Nausea, diarrhea, or vomiting led to KRAZATI dose interruption or dose reduction in 23% of patients.
- 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.
- In patients who received KRAZATI in combination with cetuximab, 5% of 93 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 msec and 16% of patients had an increase from baseline of QTc > 60 msec.
- 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.
- In patients who received KRAZATI in combination with cetuximab, 29% had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were Grade 3 and 1.1% were Grade 4. The median time to first onset of increased ALT/AST was 4 weeks (range: 0.1 to 27). Overall hepatotoxicity occurred in 38%, and 10% were Grade 3 or 4. Hepatotoxicity leading to adagrasib dose interruption or reduction occurred in 12% of patients.
- 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.
- In patients who received KRAZATI in combination with cetuximab, Grade 1 ILD/pneumonitis occurred in 1.1% of patients. The time to first onset for ILD/pneumonitis was 38 weeks.
- 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.
For more information about monitoring and management, refer to the KRAZATI Prescribing Information and Therapy Management Guide.
BID=twice-daily; CRC=colorectal cancer; CTCAE=Common Terminology Criteria for Adverse Events; TRAE=treatment-related adverse event.
Reference:
- KRAZATI®. Prescribing information. Princeton, NJ. Mirati Therapeutics, Inc., a Bristol Myers Squibb company; 2024.