AN ESTABLISHED SAFETY PROFILE DEMONSTRATED ACROSS 2 TRIALS AND >400 NSCLC PATIENTS TREATED WITH KRAZATI® (adagrasib)1-3
IN KRYSTAL-1, ARs (≥20) IN PATIENTS WITH KRAS G12C–MUTATED NSCLC WHO RECEIVED KRAZATI1
- In KRYSTAL-1, 116 patients with KRAS G12C–mutated advanced NSCLC received KRAZATI 600 mg orally BID1
- Serious adverse reactions in ≥2% of patients were pneumonia (17%), dyspnea (9%), renal impairment (8%), sepsis (5%), hypoxia (4.3%), pleural effusion (4.3%), respiratory failure (4.3%), anemia (3.4%), cardiac failure (3.4%), hyponatremia (3.4%), hypotension (3.4%), muscular weakness (3.4%), pyrexia (3.4%), dehydration (2.6%), diarrhea (2.6%), mental status changes (2.6%), pulmonary embolism (2.6%), and pulmonary hemorrhage (2.6%). Fatal adverse reactions occurred in 11% of patients who received adagrasib due to pneumonia (3.4%), respiratory failure (1.7%), sudden death (1.7%), cardiac failure (0.9%), cerebrovascular accident (0.9%), mental status change (0.9%), pulmonary embolism (0.9%), and pulmonary hemorrhage (0.9%)1
*Grouped term.1
†Hepatotoxicity includes mixed liver injury, blood alkaline phosphatase increased, alanine aminotransferase increased, aspartate aminotransferase increased, liver function test increased, blood bilirubin increased, and bilirubin conjugated increased.1
‡Renal impairment includes acute kidney injury and increased blood creatinine.1
AR=adverse reaction; BID=twice daily; GI=gastrointestinal; I-O=immunotherapy; KRAS=Kirsten rat sarcoma viral oncogene homologue; NSCLC=non-small cell lung cancer.
LABORATORY ABNORMALITIES1
Select laboratory abnormalities (occurring ≥25%) that worsened from baseline in patients with KRAS G12C–mutated NSCLC who received KRAZATI in KRYSTAL-1
*Denominator used to calculate the rate varied from 106 to 113 based on the number of patients with a baseline value and at least one post-treatment value.1
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
KRYSTAL-1: THE MAJORITY OF LIVER AND GI ARs RESOLVED IN <3* WEEKS WITH A <1%† DISCONTINUATION RATE1,5
Hepatotoxicity1
KRAZATI was discontinued due to hepatotoxicity in 0.5% of patients†
The median time to resolution after an initial occurrence was 1.7 weeks for ALT/AST elevations5‡
GI ARs5
Overall, 92% of patients with GI ARs (diarrhea, nausea, and vomiting) reported the initial event within the first 2 cycles.
The median time to resolution after an initial occurrence was 2.1 weeks for GI ARs5§
Nausea, diarrhea, and vomiting were managed with dose reductions, interruptions, and/or use of supportive concomitant medications.6
There were no clinically significant differences in the PK of adagrasib when used concomitantly with a PPI.1
FOR MORE INFORMATION ABOUT MONITORING AND MANAGEMENT OF ARs, REFER TO THE KRAZATI PRESCRIBING INFORMATION AND THERAPY MANAGEMENT GUIDE.
*Based on the KRYSTAL-1 study population of 116 patients.5
†In the pooled safety population of 366 patients treated with KRAZATI.1
‡The range for the time to resolution after an initial occurrence was 0.3-15.1 weeks.5
§The range for the time to resolution after an initial occurrence was 0.1-50.1 weeks.5
PK=pharmacokinetics; PPI=proton pump inhibitor.
KRAZATI DISCONTINUATION AND DOSAGE MODIFICATION RATES IN KRYSTAL-11
DOSE INTERRUPTIONS DUE TO AN AR
ARs requiring dosage interruption in ≥2% of patients who received KRAZATI included nausea, hepatotoxicity, fatigue, vomiting, pneumonia, renal impairment, diarrhea, QTc interval prolongation, anemia, dyspnea, increased lipase, decreased appetite, dizziness, hyponatremia, muscular weakness, increased amylase, pneumonitis, sepsis, and decreased weight.
DOSE REDUCTIONS DUE TO AN AR
ARs which required dose reductions in ≥2% of patients who received KRAZATI included hepatotoxicity, fatigue, nausea, diarrhea, vomiting, and renal impairment.
DISCONTINUED DUE TO AN AR
ARs which resulted in permanent discontinuation of KRAZATI occurring in 2 patients each (1.7%) were pneumonia and pneumonitis, and occurring in 1 patient each (0.9%) were cerebrovascular accident, dyspnea, decreased ejection fraction, encephalitis, gastrointestinal obstruction, hemorrhage, hepatotoxicity, hypotension, muscular weakness, pulmonary embolism, pyrexia, respiratory failure, and sepsis.
Serious ARs were reported in 57% of patients receiving KRAZATI. Fatal ARs occurred in 11% of patients.
KRAZATI WARNINGS AND PRECAUTIONS1
GASTROINTESTINAL ADVERSE REACTIONS
KRAZATI can cause severe gastrointestinal adverse reactions.
In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal bleeding in 3.8% including 0.8% Grade 3 or 4, gastrointestinal obstruction in 1.6% including 1.4% Grade 3 or 4, colitis in 0.5% including 0.3% Grade 3, ileus in 0.5%, and stenosis in 0.3%. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% Grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%.
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 of ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death.
In the pooled safety population, 6% of 366 patients with at least 1 post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval.
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 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. 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 the pooled safety population, drug-induced liver injury was reported in 0.3% of patients, including 0.3% Grade 3. A total of 32% of patients who received KRAZATI had increased ALT/AST; 5% were Grade 3 and 0.5% were Grade 4. The median time to first onset of increased ALT/AST was 3 weeks (range: 0.1–48). Overall hepatotoxicity occurred in 37%, and 7% were Grade 3 or 4. Hepatotoxicity leading to 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 the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients; 1.4% were Grade 3 or 4, and one case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients.
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 OF ARs, REFER TO THE KRAZATI PRESCRIBING INFORMATION AND THERAPY MANAGEMENT GUIDE.
References:
- KRAZATI [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2024.
- Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRASG12C mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10503):615-626.
- Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRASG12C mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10503):615-626 [supplementary appendix].
- Gadgeel SM, Jänne PA, Spira AI, et al. KRYSTAL-1: two-year follow-up of adagrasib (MRTX849) monotherapy in patients with advanced/metastatic KRASG12C-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.
- Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387(2):120-131.
- Zhang J, Johnson M, Barve M, et al. Practical guidance for the management of adverse events in patients with KRASG12C-mutated non-small cell lung cancer receiving adagrasib. Oncologist. 2023;28(4):287-296.
THE SAFETY PROFILE OF KRYSTAL-12 IS CONSISTENT WITH KRYSTAL-12
In KRYSTAL-12, TRAEs (≥10%) in patients with KRAS G12C–mutated NSCLC who received KRAZATI vs docetaxel3*
- In KRYSTAL-1, 116 patients with KRAS G12C–mutated advanced NSCLC received KRAZATI 600 mg orally BID1
- Serious adverse reactions in ≥2% of patients were pneumonia (17%), dyspnea (9%), renal impairment (8%), sepsis (5%), hypoxia (4.3%), pleural effusion (4.3%), respiratory failure (4.3%), anemia (3.4%), cardiac failure (3.4%), hyponatremia (3.4%), hypotension (3.4%), muscular weakness (3.4%), pyrexia (3.4%), dehydration (2.6%), diarrhea (2.6%), mental status changes (2.6%), pulmonary embolism (2.6%), and pulmonary hemorrhage (2.6%). Fatal adverse reactions occurred in 11% of patients who received adagrasib due to pneumonia (3.4%), respiratory failure (1.7%), sudden death (1.7%), cardiac failure (0.9%), cerebrovascular accident (0.9%), mental status change (0.9%), pulmonary embolism (0.9%), and pulmonary hemorrhage (0.9%)1
*Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and reported using the Medical Dictionary for Regulatory Activities, version 26.0. Patients were followed for adverse events for at least 28 days after the last study dose.3
†Calculated values.
KRAS=Kirsten rat sarcoma viral oncogene homologue; TRAE=treatment-related adverse event.
LABORATORY ABNORMALITIES3
Select laboratory abnormalities occurring in ≥10% of patients in either treatment arm*
*Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and reported using the Medical Dictionary for Regulatory Activities, version 26.0. Patients were followed for adverse events for at least 28 days after the last study dose.3
†Calculated values.
FOR MORE INFORMATION ABOUT MONITORING AND MANAGEMENT OF ARs, REFER TO THE KRAZATI PRESCRIBING INFORMATION AND THERAPY MANAGEMENT GUIDE.
References:
- KRAZATI [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2024.
- Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRASG12C mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10503):615-626.
- Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRASG12C mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10503):615-626 [supplementary appendix].