Oncology Overview: Adagrasib (MRTX849) for Non-Small Cell Lung Cancer

The KRAS gene, a member of the RAS/MAPK pathway, plays an important role in cell division, differentiation, and apoptosis.¹ Approximately 35% of patients with non-small cell lung cancer (NSCLC) harbor KRAS mutations. This subset of patients with NSCLC often has poor responses to chemotherapy and poor overall prognoses.¹

Researchers once thought KRAS was undruggable due to a relatively shallow, smooth surface—with the exception of the GTP/GDP-binding pocket.¹ Structural biology advances led to the discovery of KRAS G12C mutation pocket, which could be exploited for target-based drug binding.

The KRAS protein converts GTP into GDP molecules, and binding to GTP causes downstream intracellular signal transduction. Substitution of glycine to cysteine at codon 12 (G12C) favors the activated form of KRAS (GTP bound) causing uncontrolled cell proliferation and growth. Approximately 14% of patients with NSCLC harbor KRAS G12C mutations.¹

In February, the FDA accepted a new drug application (NDA) for the use of adagrasib (MRTX849) to treat patients with NSCLC harboring KRAS G12C mutation who have previously received at least 1 systemic therapy.² The FDA accepted the adagrasib NDA based on the phase 2 registration-enabling cohort of the KRYSTAL-1 study.

Clinical Trial

In the phase 2 KRYSTAL-1 cohort A study, investigators evaluated adagrasib’s clinical activity in patients with KRAS G12C-mutated NSCLC previously treated with chemotherapy and check point inhibitor therapy.³ The primary efficacy end point was objective response rate (ORR), with secondary efficacy end points of disease control, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and 1-year survival.

Trial participants (N = 116) received a 600-mg dose of adagrasib orally twice daily. Out of the total patients enrolled, 98.3% had previously received a checkpoint inhibitor following or in combination with chemotherapy. The median follow-up period was 12.9 months.

At the data cutoff, study results revealed 42.9% (48/112) of patients had a confirmed ORR. The median DOR was 8.5 months, with a median PFS of 6.4 months. Tumor shrinkage of any magnitude was observed in 79.5% of patients.

Three months later (median follow up 15.6 months), the median OS was 12.6 months. Results from the retrospective subgroup analysis from the KRYSTAL-1 phase 2 NSCLC cohort A (n = 33), revealed a 33.3% intracranial ORR in patients with previously treated, stable central nervous system (CNS) metastases.

Recently, investigators announced updated findings from a pooled analysis (N = 132) from the KRYSTAL-1 study phase 2 and phase 1/1b NSCLC cohorts.⁴ As of October 15, 2021, pooled analysis results reveal an ORR of 44% and disease control rate of 81%.

The median DOR was 12.5 months and median PFS was 6.9 months. With a January 15, 2022, data cutoff, the median OS was 14.1 months.

Mechanism of Action

Adagrasib is a small molecule covalent inhibitor of KRAS G12C.¹ It selectively and irreversibly binds to the KRAS G12C locking it in the inactive GDP bound state. This leads to inhibition of the downstream RAS pathway signaling, causing tumor cell death and shrinkage.

Dosage and Administration

Adagrasib is supplied as 25 mg, 100 mg, and 200 mg capsules.³ In the phase 2 KRYSTAL-1 cohort A clinical trial, adagrasib dose was administered at 600 mg orally twice daily. Study protocol guideline recommendations for adagrasib administration include taking the medication on an empty stomach—following an overnight fast or at least 2 hours after the previous meal and at least 1 hour before the next meal.

Patients were advised to take the medication with at least 200 mL of water and to swallow the capsules whole. Patients did not take an additional replacement dose if they vomited after dosing.

If a patient missed a dose, the dose was skipped if more than 4 hours had elapsed since the expected dosing time.

Adverse Effects

In the phase 2 KRYSTAL cohort A, 113 patients (97.4%) experienced treatment related adverse effects (TRAEs) with grade 1 or 2 in 52.6%, and grade 3 or higher in 44.8% of patients.³ Approximately 6.9% of patients discontinued the drug due to TRAEs. The most common TRAEs were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), and fatigue (40.5%).

Investigators also reported lab abnormalities of increased ALT (27.6%), increased blood creatinine level (25.9%), and increased AST levels (25%) in patients. TRAEs also lead to dose reduction (51.7%), and dose interruption (61.2%) in patients. The majority of patients reported nausea, vomiting, and diarrhea within the first 2 to 3 cycles. The median time to resolution for GI TRAEs was 2.1 weeks, and 1.7 weeks for increased AST and ALT levels.³

Dose Modifications

Investigators followed the study protocol sequential dose reductions for management of adverse effects:³

• 600 mg twice daily (usual dose)
• 400 mg twice daily
• 600 mg once daily
• 400 mg once daily

Management of AEs according to study protocol:³

• For specific grade 3 or 4 hematological toxicities (grade 4 anemia, grade 4 neutropenia ≥8 days, grade 3 or 4 febrile neutropenia, grade 3 thrombocytopenia with bleeding, and grade 4 thrombocytopenia), hold until ≤ grade 1 or return to baseline, then decrease 1 dose level.
• For other grade 3 or 4 hematologic toxicities, hold until ≤ grade 1 or return to baseline and may resume at the same dose level.
• For specific grade 3 or 4 GI-related TRAEs (grade 3 nausea >72 hours, grade 3 or 4 vomiting >24 hours, grade 3 diarrhea >48 hours despite therapy), hold until ≤ grade 1 or return to baseline then decrease 1 dose level. For grade 4 diarrhea, despite therapy discontinue study treatment.
• For grade 3 increased AST or ALT, hold until ≤ grade 1 or return to baseline then decrease 1 dose level. Discontinue treatment for grade 4 elevated ALT, AST.
• For grade 3 or 4 creatinine increased ≤ 22 days, hold until ≤ grade 1 or return to baseline then decrease 1 dose level or resume at same dose. For grade 3 or 4 creatinine increased > 22 days, discontinue treatment.
• For QTcF prolongation> 500 msec and increase >60 msec on at least 2 ECGs> 22 days, discontinue study treatment.
• Decrease in LVEF ≥20% from baseline and below LLN or symptomatic left ventricular systolic dysfunction, discontinue treatment.
• For grade 2 pneumonitis, hold until ≤ grade 1 or return to baseline if treatment is resumed decrease by 1 dose level lower. For grade 2 recurrent pneumonitis, discontinue study treatment.

Drug Interactions

Adagrasib is metabolized by CYP3A4.³ Patients on strong CYP3A4 inducers or inhibitors were switched to an alternative medication or obtained the study monitor approval.

Adagrasib is a potential inhibitor of P-gp and CYP2B6, CYP2C9, and CYP3A4. In the clinical trial, drugs with a narrow therapeutic indices that are P-gp or CYP2B6, CYP2C9, or CYP3A4 substrates were used with caution. Patients were also instructed to avoid grapefruit juice, curcumin, and St John’s Wort during the treatment period.³

In the phase 2 KRYSTAL cohort A, patients avoided medications with QTc prolonging activity. Female patients on hormonal contraceptives were monitored closely for signs of thrombotic events due to the potential of adagrasib to inhibit CYP3A4 and increase exposure to hormonal contraceptive levels.

Concomitant medications

Antacids should be administered 2 hours before and more than 2 hours after adagrasib dose (adagrasib solubility is maximal at low pH). H2 antagonist should be administered 2 hours after adagrasib dosing. Patients should not take proton pump inhibitors during adagrasib treatment and for 7 days before.³

Study protocol recommendations for anti-emetics include using a medication without QT prolongation. If an alternative is not available, oral ondansetron 4 mg every 6 hours for a daily total dose of 16 mg is permitted in patients without underlying cardiac issues.³

Warnings and Precautions

Patients with cardiac abnormalities of unstable angina pectoris, congestive heart failure ≥ NYHA class 3, and QTc >480 msec or family history or medical history of Long AT Syndrome were excluded from the study.³

Prescribers should monitor patients for hepatotoxicity due to the potential for increased liver enzymes, and should monitor for new or worsening pulmonary symptoms because pneumonitis is a reported TRAE.

About the Author

Bisni Narayanan, PharmD, MS, works as a Supervisor for Pharmacy Operations at the Outpatient Pharmacy Services, an integrated specialty pharmacy embedded within the Yale New Haven Health System.

References

1. Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol. 2021;32(9):1101-1110.
2. U.S. Food and Drug Administration (FDA) Accepts Mirati Therapeutics' New Drug Application for Adagrasib as Treatment of Previously Treated KRASG12C-Mutated Non-Small Cell Lung Cancer. Mirati Therapeutics. News release. Feb 15, 2022. Accessed June 11, 2022. Mirati Therapeutics Inc. - U.S. Food and Drug Administration (FDA) Accepts Mirati Therapeutics' New Drug Application for Adagrasib as Treatment of Previously Treated KRASG12C-Mutated Non-Small Cell Lung Cancer
3. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation [published online ahead of print, 2022 Jun 3]. N Engl J Med.
4. Investigational adagrasib delivers positive results in registration-enabling study of patients with KRASG12C-mutated advanced non–small cell lung cancer. Mirati Therapeutics. News release. May 26, 2022. Accessed June 11, 2022. Mirati Therapeutics Inc. - Investigational Adagrasib Delivers Positive Results in Registration-Enabling Study of Patients with KRASG12C-Mutated Advanced Non-Small Cell Lung Cancer