General Information

Krazati (adagrasib) is an inhibitor of the RAS GTPase family.

Krazati is specifically indicated for the treatment of adult patients with KRAS G12C-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.

Krazati is supplied as capsules for oral administration.

Select patients for treatment of locally advanced or metastatic NSCLC with Krazati based on the presence of KRAS G12C mutation in plasma or tumor specimens. If no mutation is detected in a plasma specimen, test tumor tissue.

The recommended dosage of Krazati is 600 mg orally twice daily until disease progression or unacceptable toxicity. Take Krazati at the same time every day with or without food. Swallow tablets whole. Do not chew, crush or split tablets.

If vomiting occurs after taking Krazati, do not take an additional dose. Resume dosing at the next scheduled time. If a dose is inadvertently missed, it should be skipped if greater than 4 hours have elapsed from the expected dosing time. Resume dosing at the next scheduled time.

Mechanism of Action

Krazati (adagrasib) is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibits tumor cell growth and viability in cells harboring KRAS G12C mutations and results in tumor regression in KRAS G12C-mutated tumor xenograft models with minimal off-target activity.

Side Effects

Adverse effects associated with the use of Krazati may include, but are not limited to, the following:

nausea

diarrhea

vomiting

fatigue

musculoskeletal pain

hepatotoxicity

renal impairment

edema

dyspnea

decreased appetite

laboratory abnormalities, including decreased lymphocytes, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils and increased alkaline phosphatase

Clinical Trial Results

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.

Accelerated approval was based on the phase 2 registration-enabling cohort of the KRYSTAL-1 study, evaluating Krazati 600 mg capsules administered orally twice daily in 116 patients with KRASG12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor. The primary efficacy endpoints were confirmed ORR and DOR as evaluated by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST v1.1).

The trial demonstrated an ORR of 43% with 80% of patients achieving disease control. The median DOR was 8.5 months. In a pooled efficacy analysis (n=132) including Phase 1/1b NSCLC and registrational Phase 2 NSCLC cohorts from the KRYSTAL-1 study evaluating adagrasib as a single agent at 600 mg capsules orally twice daily, adagrasib showed an ORR of 44% and a disease control rate of 81% based on blinded independent central review, a median DOR of 12.5 months and median overall survival of 14.1 months.