CHMP Recommends Adagrasib for Pretreated KRAS G12C+ Advanced NSCLC

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After a re-examination procedure, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion on the conditional marketing authorization application for adagrasib (Krazati) in the treatment of adult patients with KRAS G12C–mutated advanced non–small cell lung cancer (NSCLC) whose disease progressed following at least 1 prior systemic treatment.¹

In July 2023, CHMP had issued a negative opinion regarding the application, stating that although the agent demonstrated a positive risk-benefit profile, it did not meet certain requirements for approval.² At the time of the initial decision, Mirati Therapeutics, the drug developer, stated that they disagreed with the opinion and would request a formal re-evaluation.

The application is supported by data from the phase 1/2 KRYSTAL-1 trial (NCT03785249) in which the agent induced an objective response rate (ORR) of 43% (95% CI, 34%-53%), with most patients with a disease control rate (DCR) of 80% (95% CI, 71%-87%).2 The median duration of response (DOR) was 8.5 months (95% CI, 6.2-13.8). Data from a pooled efficacy analysis of 132 patients from the phase 1/1b and registrational phase 2 NSCLC cohorts of the trial showed that adagrasib elicited an ORR of 44% and a DCR of 81% by blinded independent central review (BICR) assessment. In this group, the median DOR was 12.5 months (95% CI, 7.3-not evaluable).

At a median follow-up of 26.9 months, adagrasib (n = 132) resulted in a median overall survival (OS) of 14.1 months (95% CI, 9.2-18.7); the 1-year and 2-year OS rates were 52.8% and 31.3%, respectively.³ In 128 evaluable patients, the median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.7); the PFS rates at 1 year and 2 years were 35.0% and 13.9%, respectively.

“Today’s positive opinion from the CHMP for [adagrasib] marks an important step on the path to providing access to a potentially best-in-class therapeutic option to patients living with this difficult-to-treat disease,” Alan Sandler, MD, chief medical officer of Mirati Therapeutics, Inc.1 “We look forward to approval from the European Commission and the opportunity to positively impact the lives of eligible patients living in the European Union.”

Patients with locally advanced or metastatic NSCLC harboring a KRAS G12C mutation were enrolled to the multicenter, single-arm, open-label study. Patients had received a prior platinum-based regimen and an immune checkpoint inhibitor. They needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and at least 1 measurable lesion by RECIST v1.1 criteria.

Participants were given 600 mg of adagrasib twice daily until progressive disease or intolerable toxicity. Tumor assessments were performed every 6 weeks. Major efficacy outcome measures included confirmed ORR and DOR by BICR assessment and RECIST v1.1 criteria. Secondary end points included PFS, 1-year survival rate, OS, and safety. An exploratory end point included clinical activity in those with central nervous system metastases.

Baseline characteristics were consistent with those previously reported; those who comprised the efficacy population had a median age of 64 years (range, 25-89). The majority of patients were female (55%), White (83%), had an ECOG performance status of 1 (83%), metastatic disease (89%), adenocarcinoma (97%), and had received both prior platinum and anti PD-1/PD-L1 therapy (98%).2 The median number of prior systemic therapies received was 2 (range, 1-7) with 1 (43%), 2 (35%), 3 (10%) or at least 4 (12%) lines given.

Previous data published in the Journal of Clinical Oncology showed that at a data cutoff date of August 1, 2022, adagrasib elicited an intracranial ORR of 42% (95% CI, 20.3%-66.5%) by RECIST v1.1 criteria in efficacy-evaluable patients (n = 19).⁴ Three patients experienced complete intracranial responses and 5 experienced partial intracranial responses. The intracranial DCR was 90%. Moreover, the median time to response was 2.1 months.

Additionally, data from an exploratory analysis showed that adagrasib elicited an ORR of 68% in a subset of patients with KRAS G12C–mutated NSCLC who had at least 90% mutation allele frequency clearance (n = 31).⁵ In the 11 patients who had MAFC below 90% (n = 4), the ORR with the agent was 0%.

In December 2022, the FDA granted an accelerated approval to adagrasib for use in adult patients with KRAS G12C–mutated locally advanced and metastatic NSCLC based on KRYSTAL-1 data.⁶

In terms of safety, the most common adverse events occurring in at least 20% of patients were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.³

The most common laboratory abnormalities occurring in at least 25% of patients were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.

“This is an important day for the oncology community as we step closer to a new therapeutic option being available to patients living with KRASG12C mutated NSCLC in the European Union,” Martin Reck, MD, PhD, of the Lung Clinic Grosshansdorf in Germany, added in the press release.¹ “Every patient has a slightly different case so as more options become available physicians will better be able to tailor their treatment for each patient.”

References

1. 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 November 13, 2023. 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
2. Mirati Therapeutics provides update on regulatory review in the European Union of KRAZATI (adagrasib) for the treatment of advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation. News release. Mirati Therapeutics, Inc. July 21, 2023. Accessed November 13, 2023. https://ir.mirati.com/press-releases/press-release-details
3. Adagrasib (Krazati). Prescribing information; Mirati Therapeutics, Inc.; 2022. Accessed November 13, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf
4. Negrao MV, Spira AI, Heist RS, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRASG12C–mutated non–small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. 2023;41(28):4472-4477. doi:10.1200/JCO.23.00046
5. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed November 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc