| Sumario: | Background: Adagrasib, a KRASG12C inhibitor selected for favorable properties, including a long half-life (23 hr), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration, has demonstrated clinical activity in patients with KRASG12C-mutated non--small cell lung cancer (NSCLC) with an objective response rate (ORR) of 43% and a median overall survival of 12.6 months, including patients with CNS metastases (intracranial ORR per modified response assessment in neurooncology brain metastases, 33%). Objective: To report additional practice-informing safety analyses from KRYSTAL-1 cohort A, a registrational phase 2 cohort, evaluating adagrasib capsules 600 mg orally twice daily in patients with previously treated NSCLC. Methods: KRYSTAL-1 is a multicohort phase 1/2 study of adagrasib in patients with advanced solid tumors harboring a KRASG12C mutation. Analyses reported here include time to onset (TTO), time to resolution (TTR), and the management of treatment-related adverse events (TRAEs), including gastrointestinal (GI)-related TRAEs. Results: As of October 15, 2021, 116 patients (female, 56%; median age, 64 y; Eastern Cooperative Oncology Group performance status 1, 84%) received adagrasib; median follow-up was 12.9 months (95% CI, 11.8-13.5), and median treatment duration was 5.7 months (range, 0-19.6 mo). Any grade TRAEs occurred in 97% of patients: grade 1-2, 53%; grade ≥3, 45%. Overall, >92% of new-onset TRAEs occurred within the first 3 cycles; few new grade ≥3 TRAEs occurred after cycle 3. TRAEs led to dose reduction, interruption, and discontinuation in 52%, 61%, and 7% of patients, respectively. GI-related TRAEs occurred in 85%, leading to dose reductions in 20%. Median TTO of GI TRAEs was 3 days (interquartile range, 1-12 d) and of increased alanine transaminase/aspartate aminotransferase levels was 22 days (interquartile range, 15-35 d); median TTR of these TRAEs after initial occurrence was 14 days (range, 5-43 d) and 12 days (range, 7-21 d), respectively. GI TRAEs were manageable with antidiarrheals (48%) and antiemetics/antinauseants (87%). Conclusions: Adagrasib demonstrated a manageable adverse event profile in pretreated patients with KRASG12C-mutated NSCLC. Most TRAEs were low grade, occurred early in treatment, and resolved quickly, resulting in a low (7%) discontinuation rate. Funding: This study (NCT03785249) was sponsored by Mirati Therapeutics, Inc. Third-party medical writing support, under the direction of the authors, was provided by Hannah Preston, BSc, of Ashfield MedComms, an Inizio company, and was funded by Mirati Therapeutics, Inc. This abstract was previously presented at the European Society for Medical Oncology (ESMO) Conference 2022; Final Publication Number: 1133P. The study was previously published in Zhang J, et al. Annals Oncol. 2022;33(suppl 7):S1068-S1069. doi: http://doi.org/10.1016/j.annonc. 2022. 07.1257. Data previously published in Zhang J, Johnson M, Barve M, et al. Oncologist. 2023;28(4):287-296. Reused with permission.
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