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Krazati (adagrasib) - 2 indications
Scroll down for more information on each indication:
- KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC); approved December of 2022
- KRAS G12C-mutated locally advanced or metastatic colorectal cancer; approved June of 2024
General Information
Krazati (adagrasib) is an inhibitor of the RAS GTPase family.
Krazati is specifically indicated:
1) as a single agent 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;
2) In combination with cetuximab, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecanbased chemotherapy.
These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials.
Krazati is specifically indicated:
1) as a single agent 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;
2) In combination with cetuximab, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecanbased chemotherapy.
These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials.
Dosing/Administration
Krazati is supplied as capsules for oral administration.
- Select patients for treatment 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 as a single agent in NCSLC 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
Adverse effects associated with the use of Krazati in combination with cetuximab in CRC, may include, but are not limited to, the following:
- rash
- nausea
- diarrhea
- vomiting
- fatigue
- musculoskeletal pain
- hepatotoxicity
- headache
- dry skin
- abdominal pain
- decreased appetite
- edema
- anemia
- cough
- laboratory abnormalities, including: decreased
lymphocytes, decreased potassium, decreased magnesium, decreased hemoglobin,
increased aspartate aminotransferase, increased lipase, decreased albumin, and
increased alanine aminotransferase
Indication 1 - KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)
approved December of 2022
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.
Indication 2 - KRAS G12C-mutated locally advanced or metastatic colorectal cancer
approved June of 2024
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 KRYSTAL-1, a multicenter, single-arm expansion cohort trial. Eligible patients were required to have locally advanced or metastatic KRAS G12C-mutated CRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and a VEGF inhibitor, if eligible. Patients were treated with adagrasib 600 mg twice daily plus cetuximab administered either biweekly (500 mg/m2 every two weeks) or weekly (400 mg/m2 initial dose followed by 250 mg/m2 weekly). Tumor assessments were performed every 6 weeks. Adagrasib discontinuation required cetuximab discontinuation, however patients could continue adagrasib if cetuximab was discontinued.
The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 assessed by blinded independent central review. In the 94 enrolled patients, ORR was 34%, all responses were partial responses, and median DOR was 5.8 months. Thirty-one percent of responding patients had a DOR of at least 6 months.
Approval Date: 2022-12-01
Company Name: Mirati Therapeutics
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