On September 9, 2023 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a commercial stage research and development, biotechnology company, reported two-year follow-up data from a pooled analysis of the Phase 1/1b Cohort and Phase 2 Cohort A for the KRYSTAL-1 study evaluating adagrasib (KRAZATI) in patients with non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation (Press release, Mirati, SEP 9, 2023, View Source [SID1234635043]).

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In the pooled analysis, adagrasib demonstrated durable efficacy with a median overall survival (OS) of 14.1 months and a 2-year OS rate of 31% in patients with previously treated KRASG12C-mutated NSCLC. Exploratory analyses suggested clinical benefit in patients with treated, stable central nervous system (CNS) metastases at baseline with clinical benefit noted across most baseline co-mutations.

In the study, adagrasib demonstrated a manageable long-term safety profile with low grade treatment-related adverse events (TRAEs). Hepatotoxicity was not observed in any patients who received adagrasib within 30 days of prior immunotherapy and, overall, there was a low rate of grade >3 hepatoxicity.

A confirmatory Phase 3 study, KRYSTAL-12, is ongoing, evaluating adagrasib vs. docetaxel in previously treated patients with KRASG12C-mutated NSCLC.

"This data reinforces the ability of adagrasib to positively impact patients as a potential best in class option," said Alan Sandler, M.D., chief medical officer, Mirati Therapeutics, Inc. "Adagrasib offers a differentiated option for KRASG12C-mutated NSCLC as evidenced by its clinical activity in the CNS and ability to sequence adagrasib immediately after prior immunotherapy. We look forward to continuing to advance adagrasib across lines of therapy in a range of tumor types for the benefit of patients living with KRASG12C-mutated cancer."

"These data continue to reinforce the benefit of adagrasib for patients living with KRASG12C-mutated NSCLC who are in need for better options than the historical standard of care chemotherapy," Shirish M. Gadgeel, MD, head, the Division of Hematology/Oncology, associate director, Patient Experience and Clinical Care, the Henry Ford Cancer Institute. "The long term overall survival for adagrasib is meaningful for patients."

In December of 2022, adagrasib was added to the National Comprehensive Center Network (NCCN) Guidelines for patients living with previously treated KRASG12C-mutant NSCLC. Following, adagrasib was added the NCCN guidelines for CNS Cancers for patients living with previously treated KRASG12C-mutant NSCLC and CNS metastases.

About KRAZATI (adagrasib)

In the U.S., KRAZATI was approved by the FDA for Accelerated Approval (Subpart H), which allows for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. KRAZATI was reviewed under the FDA Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible. Mirati submitted a Marketing Authorization Application (MAA) in the EU in May 2022. In 2021, adagrasib achieved Breakthrough Therapy Designation in the U.S. as a potential treatment for patients with NSCLC harboring the KRASG12C mutation who have received at least one prior systemic therapy. For Prescribing Information, visit Mirati.com/KRAZATI_USPI.

Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science.

KRAZATI (adagrasib) U.S. Indication

KRAZATI 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.

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).

KRAZATI (adagrasib) Important Safety Information

WARNINGS AND PRECAUTIONS

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 Full Prescribing Information.