Adagrasib Elicits Intracranial Response in NSCLC With KRAS G12C Mutations, Untreated CNS Metastases

Adagrasib (Krazati) has demonstrated intracranial activity among patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) with untreated central nervous system (CNS) metastases, according to findings from the phase 1b cohort of the KRYSTAL-1 trial (NCT03785249). These data were recently published in the Journal of Clinical Oncology.¹

At the August 1, 2022, data cutoff, efficacy-evaluable patients who received the agent (n = 19) achieved an intracranial objective response rate (ORR) of 42% (95% CI, 20.3%-66.5%) by RECIST 1.1 criteria, including 3 complete intracranial responses and 5 partial intracranial responses. Additionally, the intracranial disease control rate (DCR) was 90% and the median time to response was 2.1 months.¹

In preclinical models, adagrasib has shown the ability to penetrate the CNS, cause intracranial tumor regression, and, ultimately, extend survival. The agent locks KRAS G12Cin an inactive state by binding to the protein in an irreversible and selective manner. It boasts a half-life of approximately 24 hours, considerable tissue distribution, and dose-dependent pharmacokinetics.²

Previously, findings from KRYSTAL-1 supported the accelerated approval of adagrasib by the FDA. The agent was given the green light from the agency for the treatment of patients with KRAS G12C–mutated NSCLC who had previously undergone at least 1 previous line of systemic therapy on December 12, 2022.³

KRYSTAL-1 is an ongoing open-label, nonrandomized trial evaluating adagrasib, both as a monotherapy and as part of a combination, for the treatment of patients with advanced KRAS G12C–mutated solid tumors. The coprimary end points were safety, pharmacokinetics, and clinical activity measured by ORR. Secondary end points include establishing the maximum-tolerated dose and identifying dose-limiting toxicities. Overall survival (OS) and estimated 1-year survival rate were also assessed.⁴

Patients in the published cohort had neurologically stable, asymptomatic KRAS G12–-mutated NSCLC with untreated CNS metastases. To be eligible for the trial, they also needed to have an ECOG performance status of 1 or less. Those with other active cancers, a history of intestinal disease, or have undergone major gastric surgery were not included.^1,4

Adagrasib monotherapy was given at the recommended phase 2 dose of 600 mg. The agent was administered orally twice daily. The efficacy-evaluable population included all patients who were treated with at least 1 dose and underwent baseline and on-study disease assessments, and the safety population included all patients who received at least 1 dose.¹

At baseline, the median patient age was 66 years (range, 47-89). Most patients were women (52%), White (84%), had an ECOG performance status of 1 (72%), were past smokers (68%), and had received a checkpoint inhibitor (80%) and/or a platinum-based agent (68%) as part of a prior regimen. In terms of prior lines of therapy, the median number was 1; patients received either 0 (16%), 1 (60%), 2 (12%), or at least 3 (12%) treatments.

Additional findings from the trial showed that, at a median follow-up of 13.7 months (95% CI, 8.5-not evaluable [NE]), the median intracranial progression-free survival (PFS) was 5.4 months (95% CI, 2.7-NE) and the median OS was 11.4 months (95% CI, 5.5-14.9). The median duration of response (DOR) was 12.7 months and treatment remained ongoing for over 10 months among 2 patients who were still responding.

All patients who experienced an intracranial response also underwent a dose modification during the study; 4 responders recorded their initial response at the second on-study scan. The systemic ORR was 30%, including a median DOR of 5.6 months and a median PFS of 5.3 months. Patients evaluable for intracranial activity by mRANO-BM criteria (n = 20) experienced a confirmed intracranial ORR of 35% and an intracranial DCR of 85%.

In the safety population (N = 25), all patients experienced an any-grade treatment-related adverse effect (TRAE); 40% of these were grade 3 in severity, 1 patient had grade 4 neutropenia, and no grade 5 events were reported. The most common any-grade TRAEs included nausea (88%), diarrhea (76%), vomiting (60%), increased alanine transaminase (40%), and increased aspartate transferase (40%). These respective events also occurred at grade 2 severity at rates of 32%, 8%, 8%, 12%, and 12%, and grade 3 severity at rates of 12%, 0%, 16%, 8%, and 4%.

Dose reductions because of TRAEs were reported in 32% of patients, 56% experienced a dose interruption, and 2 patients discontinued treatment. Patients discontinued therapy because of grade 3 acute pancreatitis and grade 2 fatigue.

Any grade CNS-specific TRAEs consisted of dysgeusia (24%), dizziness (20%), ataxia (8%), aphasia (4%), confused state (4%), encephalopathy (4%), headache (4%), and insomnia (4%). There were no grade 4 or greater CNS-specific TRAEs; 3 patients had grade 3 dizziness and 1 experienced grade 3 encephalopathy.

Investigators noted that their study was limited by its exploratory nature, narrow follow-up period, and small patient population. They concluded that, in addition to the encouraging intracranial responses that were observed, “Adagrasib had a manageable safety profile with few CNS-specific TRAEs. These findings support continued clinical development of adagrasib for patients with KRAS G12C–mutated NSCLC.”¹

References

1. 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. Published online June 16, 2023. doi:10.1200/JCO.23.00046
2. Sabari JK, Velcheti V, Shimizu K, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRASG12C-mutant non-small cell lung cancer. Clin Cancer Res. 2022;28(15):3318-3328. doi:10.1158/1078-0432.CCR-22-0383
3. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed June 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc
4. Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. ClinicalTrials.gov. Updated January 9, 2023. Accessed June 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03785249