Adagrasib Approved in Europe for Pretreated KRAS G12C+ Advanced NSCLC

The European Commission has granted conditional marketing authorization to adagrasib (Krazati) for use in adult patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation whose disease progressed following at least 1 prior systemic treatment.¹

The decision is supported by data from the phase 2 registration-enabling cohort of the phase 1/2 KRYSTAL-1 study (NCT03785249), in which the agent elicited an objective response rate (ORR) of 43% (95% CI, 34%-53%) in evaluable patients (n = 112); this included a complete response rate of 0.9% and a partial response rate of 42%.2 The median duration of response (DOR) was 8.5 months (95% CI, 6.2-13.8), with 58% of patients continuing to respond for at least 6 months.

“Krazati offers an efficacious and tolerable therapeutic option for patients living with advanced KRAS G12C–mutated NSCLC and this approval expands the potential treatment options available,” Martin Reck, MD, PhD, of Lung Clinic Grosshansdorf in Germany, stated in a press release.1 “With its differentiated profile, Krazati offers an impactful treatment option for patients living with lung cancer. This approval will assist physicians in tailoring treatment approaches for patients.”

The multicenter, single-arm, open-label expansion cohort KRYSTAL-1 study included those with locally advanced or metastatic KRAS G12C­–mutated NSCLC who had prior exposure to a platinum-based chemotherapy regimen and an immune checkpoint inhibitor.2 To participate, patients were required to be at least 18 years of age, have an ECOG performance status of 0 or 1, and have at least 1 measurable lesion by RECIST v1.1 criteria.

Participants were administered oral adagrasib at a twice-daily dose of 600 mg. Treatment continued until progressive disease or intolerable toxicity.

Confirmed ORR and DOR by blinded independent central review and RECIST v1.1 criteria served as the trial’s primary efficacy outcome measures.

In the efficacy population, the median patient age was 64 years (range, 25-89). A little more than half of patients were female (55%), and the majority were White (83%) and had an ECOG performance status of 1 (83%). Moreover, 97% of patients had adenocarcinoma and 89% had metastatic disease.

The median number of prior systemic therapies received was 2, with a range of 1 to 7 lines. Notably, 43% of patients received 1 prior line of treatment, 35% received 2 prior lines, 10% received 3 prior lines, and 12% received 4 or more prior lines. Ninety-eight percent of patients had received previous platinum-based therapy and immune checkpoint inhibition.

Updated data from the study were presented during the 2023 World Conference on Lung Cancer.³ At a median follow-up of 26.9 months, the median overall survival (OS) with adagrasib was 14.1 months (95% CI, 9.2-18.7) in evaluable patients (n = 132); the 1- and 2-year OS rates were 52.8% and 31.3%, respectively. The median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.7) in evaluable patients (n = 128), with PFS rates of 35.0% and 13.9% at 1 and 2 years, respectively. Additionally, the ORR was 43% and the disease control rate was 80%. The median DOR was 12.4 months (95% CI, 7.0-15.1).

Subgroup data on baseline comutations were also released. The median OS experienced by patients whose tumors harbored TP53 (n = 42), CDKN2A (n = 12), STK11 (n = 44), and KEAP1 (n = 25) mutations was 18.7 months (95% CI, 11.3-27.0), 13.0 months (95% CI, 1.6-20.8), 9.2 months (95% CI, 5.0-12.7), and 5.7 months (95% CI, 3.6-9.2), respectively. In these respective groups, the median PFS was 8.7 months (95% CI, 5.0-12.1), 8.4 months (95% CI, 1.2-11.9), 4.2 months (95% CI, 3.9-6.1), and 4.1 months (95% CI, 2.7-5.6).

Moreover, in the 26 patients who had baseline central nervous system metastases, the median OS was 14.7 months (95% CI, 7.5-19.3) and the median PFS was 6.9 months (95% CI, 4.1-11.9).

The safety of adagrasib was explored in 116 patients enrolled in KRYSTAL-1.² Fifty-seven percent of patients experienced serious toxicities, and 11% experienced fatal events. Thirteen percent of patients experienced adverse effects (AEs) that resulted in discontinuation. AEs resulted in dose reductions or interruptions for 28% and 77% of patients, respectively.

The most common AEs experienced by 20% or more of patients included diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation. Moreover, the most common laboratory abnormalities occurring in at least 25% of patients were increased aspartate aminotransferase, creatinine, alanine aminotransferase, and lipase, as well as decreased lymphocytes, sodium, hemoglobin, albumin, platelets, magnesium, and potassium.

In December 2022, the FDA granted accelerated approval to adagrasib for use in adult patients with KRAS G12C­­–mutated, locally advanced or metastatic NSCLC, as determined by a FDA-approved test, who previously received at least 1 systemic treatment.₄ The decision was based on data from KRYSTAL-1.

Conditional marketing authorization for the agent is valid in all 27 European Union member states as well as Iceland, Norway, and Liechtenstein. The authorization follows the positive opinion issued by the Committee for Medicinal Products for Human Use in November 2023.⁵

References

1. European Commission approves Krazati (adagrasib) as a targeted treatment option for patients with advanced non-small cell lung cancer (NSCLC) with a KRASG12C mutation. News release. Mirati Therapeutics, Inc. January 10, 2024. Accessed January 10, 2024. https://ir.mirati.com/press-releases/press-release-details/2024/European-Commission-Approves-KRAZATI-adagrasib-as-a-Targeted-Treatment-Option-for-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-NSCLC-with-a-KRASG12C-Mutation/default.aspx
2. Adagrasib (Krazati). Prescribing information; Mirati Therapeutics, Inc.; 2022. Accessed January 10, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf
3. Gadgeel SM, Jänne PA, Spira AI, et al. KRYSTAL-1: two-year follow-up of adagrasib (MRTX849) monotherapy in patients with advanced/metastatic KRASG12C-mutated NSCLC.Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.
4. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed January 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc
5. Mirati Therapeutics receives positive opinion from CHMP for KRAZATI (adagrasib) as a targeted treatment option for patients with advanced non-small cell lung cancer (NSCLC) with a KRASG12C mutation following a re-examination procedure. News release. Mirati Therapeutics, Inc. November 10, 2023. Accessed January 10, 2024. https://ir.mirati.com/press-releases/press-release-details/2023/Mirati-Therapeutics-Receives-Positive-Opinion-from-CHMP-for-KRAZATI-adagrasib-as-a-Targeted-Treatment-Option-for-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-NSCLC-with-a-KRASG12C-Mutation-Following-a-Re-Examination-Procedure/default.aspx