On March 28, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the pivotal Phase 3 KRYSTAL-12 study, evaluating KRAZATI (adagrasib) as a monotherapy in patients with pretreated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation, met the primary endpoint of progression-free survival (PFS) and the key secondary endpoint of overall response rate (ORR) as assessed by Blinded Independent Central Review (BICR) at final analysis for these endpoints (Press release, Bristol-Myers Squibb, MAR 28, 2024, View Source [SID1234641556]). The study remains ongoing to assess the additional key secondary endpoint of overall survival. Results of the confirmatory trial showed that KRAZATI demonstrated a statistically significant and clinically meaningful benefit in PFS and ORR compared to standard-of-care chemotherapy as a second-line or later treatment for these patients. KRAZATI had no new safety signals and the safety data was consistent with the known safety profile.

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"Today’s news is an important reinforcement of the power of a targeted therapy for patients with locally advanced or metastatic KRASG12C-mutated lung cancer. FDA approval of KRAZATI in the U.S. has allowed us to provide a new treatment option for these patients, and topline results of the KRYSTAL-12 confirmatory study will build greater trust in the medical and patient community," said Abderrahim Oukessou, M.D., vice president, global program lead, KRAZATI, Bristol Myers Squibb. "We are encouraged by the results from KRYSTAL-12 and look forward to helping more patients with KRASG12C-mutated lung cancer."

The company will complete a full evaluation of the available data and looks forward to sharing the results with the scientific community at an upcoming medical conference as well as discussing the results with health authorities.

The U.S. FDA granted accelerated approval for KRAZATI as a targeted treatment for patients with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy in December 2022. In 2023, Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization for KRAZATI as a targeted treatment option for adult patients with KRASG12C-mutated advanced NSCLC and disease progression after at least one prior systemic therapy followed by the European Commission (EC) in 2024.

In addition to KRASG12C-mutated NSCLC, KRAZATI and KRAZATI-based combinations have shown encouraging meaningful benefit in Phase 2 clinical trials across several tumors, including advanced colorectal cancer, pancreatic cancer and other solid tumors. In February, the U.S. FDA accepted for priority review the supplemental new drug application (sNDA) for KRAZATI in combination with cetuximab for the treatment of patients with previously treated KRASG12C-mutated locally advanced or metastatic colorectal cancer (CRC). The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

Bristol Myers Squibb thanks the patients and investigators involved in the KRYSTAL-12 clinical trial.

ABOUT KRAZATI (adagrasib)

KRAZATI (adagrasib) is 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 KRAS protein regenerates every 24-48 hours. KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of non-small cell lung cancer, 3-4% of colorectal cancer, and 1-2% of several other cancers.

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(s).

In 2023, Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization for KRAZATI as a targeted treatment option for adult patients with KRASG12C-mutated advanced non-small cell lung cancer and disease progression after at least one prior systemic therapy followed by the European Commission (EC) in 2024.

KRAZATI continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including non-small cell lung cancer and colorectal cancer.

In 2022, the FDA granted breakthrough therapy designation for KRAZATI in combination with cetuximab in patients with KRASG12C-mutated advanced colorectal cancer whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.

For Prescribing Information, visit KRAZATI.

About KRYSTAL-12

KRYSTAL-12 is an open-label, multicenter, randomized Phase 3 study evaluating KRAZATI compared to standard-of-care chemotherapy alone, in patients with KRASG12C-mutated non-small cell lung cancer. The primary endpoint of the study is PFS as assessed by BICR. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), and safety.

INDICATION

KRAZATI is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer, 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(s).

IMPORTANT SAFETY INFORMATION

GASTROINTESTINAL ADVERSE REACTIONS

In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 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 for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death
In the pooled safety population, 6% of 366 patients with at least one 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 taking 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
In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% 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 1 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). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified
ADVERSE REACTIONS

The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite
FEMALES AND MALES OF REPRODUCTIVE POTENTIAL

Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential
Please see U.S. Full Prescribing Information for KRAZATI.