Built for the challenge of KRAS^G12C: A new treatment option for 2L KRAS^G12C-mutated NSCLC

Non-small cell lung cancer (NSCLC) patients and providers now have a new treatment option following the U.S. Food and Drug Administration’s approval of KRAZATI^® (adagrasib), Mirati Therapeutics’ KRAS^G12C inhibitor for the treatment of adult patients with KRAS^G12C-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). This new therapy will be available to patients in the form of a selective oral small molecule therapy, designed to meet the challenge of KRAS^G12C.

The approval of KRAZATI has the potential to impact patients affected by this historically challenging to target mutation as well as the oncology community who has worked tirelessly to identify and provide treatment options.

The KRAS^G12C mutation is the most commonly occurring KRAS mutation in NSCLC and accounts for ~50% of all KRAS mutations in NSCLC.^1,2 KRAS^G12C accounts for ~14% of patients with NSCLC adenocarcinomas histology, making it almost as prevalent as EGFR mutations, which affect around 15% of NSCLC patients.^1,3 However, KRAS has been challenging to target due to the protein’s smooth surface providing few binding pockets for small molecules, and high binding affinity for GTP.^4,5 KRAZATI 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.⁶

Recently, the oncology community has seen a rise in targeted therapies either on their own or in combination with other treatments, including chemotherapy, surgery and radiation therapy.⁷ The development and approval of KRAZATI marks an important advancement forward for targeted therapies, as it offers an additional treatment option for adult patients with KRAS^G12C-mutated advanced NSCLC who have received at least one prior systemic therapy.

A Phase 2 registration-enabling study evaluated KRAZATI 600 mg orally twice daily in 116 patients with KRAS^G12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least one measurable lesion as defined by Response Evaluation criteria in Solid Tumors (RECIST v1.1). The trial demonstrated an objective response rate of 43% (95% CI: 34-53) with 80% (95% CI: 71-87) of patients achieving disease control (percentage of patients who have achieved complete response, partial response, or stable disease). The median DOR was 8.5 months (95% CI: 6.2 – 13.8).

KRAZATI was evaluated in a pooled patient population as a single agent at 600 mg orally twice daily in 366 patients with NSCLC and other solid tumors enrolled in KRYSTAL-1 and KRYSTAL-12. The most common (≥ 25%) adverse reactions were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, acute kidney injury, edema, dyspnea, and decreased appetite. The most common Grade 3 or 4 (≥ 2%) laboratory abnormalities were decreased lymphocytes, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils and increased alkaline phosphatase. Permanent discontinuation of KRAZATI due to an adverse reaction occurred in 13% of patients.

The approval of KRAZATI marks an important development in the NSCLC treatment landscape for patients with previously treated KRAS^G12C-mutated advanced NSCLC, as well as their caregivers and providers. As we look forward to the future of targeted oncology, Mirati is excited to continue discovering, designing and delivering therapies that have the potential to transform the lives of patients living with cancer. We are relentlessly focused on developing best-in-class targeted therapies, and the approval of KRAZATI is just one milestone in our journey to meaningfully impact the lives of patients with cancer.

Learn more about KRAZATI here.

KRAZATI (adagrasib) Important Safety Information

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

• KRAZATI can cause severe gastrointestinal adverse reactions.
• 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.
• 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, which may lead to drug-induced liver injury and hepatitis.
• 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.
• 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.

Adverse Reactions

• The most common adverse reactions (≥20%) are diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.

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.

References

1. Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: Striking a moving target. JCI Insight. 2018;3(15):e120858.
2. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187.
3. 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.
4. Ghimessy A, Radeczky P, Laszlo V, et al. Current therapy of KRAS-mutant lung cancer. Cancer Metastasis Rev. 2020;39(4):1159-1177.
5. Lu S, Jang H, Muratcioglu S, et al. Ras conformational ensembles, allostery, and signaling. Chem Rev. 2016;116(11):6607-6665.
6. KRAZATI (adagrasib) prescribing information, Mirati Therapeutics.
7. American Cancer Society. Targeted Therapy. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/targeted-therapy.html. Accessed August 9, 2022.