KEY TAKEAWAYS
- The KRYSTAL-1 registrational phase II trial assessed the efficacy of adagrasib in previously treated KRASG12C -mutated NSCLC pts.
- The study’s primary endpoints were ORR, PFS, OS, safety, and exploratory correlative analyses.
- Adagrasib exhibits clinical activity and manageable tolerability in pts previously treated for KRASG12C-mutate NSCLC.
This study assessed the efficacy of adagrasib (ada) 600 mg orally BID in previously treated KRASG12C -mutated NSCLC patients (pts), with a primary focus on objective response rate [ORR], progression-free survival [PFS], overall survival [OS], safety, and exploratory correlative analyses. The mutation allele frequency clearance (MAFC)-evaluable population, comprising pts with detectable circulating tumor (ct) DNA at baseline, cycle 2 day 1, and cycle 4 day 1 (C4D1), underwent an exploratory clinical response analysis. The KRASG12C ctDNA was quantified using a digital droplet polymerase chain reaction.
Based on data as of October 15, 2021, Cohort A included 116 pts with a median follow-up of 12.9 months. The median age of the pts was 64 years, and 56% were female. The median number of prior systemic therapies was 2. According to the blinded independent central review (BICR), the objective response rate (ORR) was 42.9%, and the disease control rate was 79.5%.
The median progression-free survival (PFS) was 6.5 months (95% CI 4.7–8.4), and with longer follow-up (cutoff 15 Jan 2022), the median overall survival (OS) was 12.6 months (95% CI 9.2–19.2). Among the pts, 97% experienced treatment-related adverse events (TRAEs), with diarrhea (63%), nausea (62%), vomiting (47%), and fatigue (41%) being the most common. Grade 3–4 TRAEs occurred in 43% of pts, with serum lipase increase (6%) and anemia (5%) being the most common. Two grade 5 TRAEs occurred, and 8 (7%) TRAEs led to discontinuation. In MAFC-evaluable pts (n = 35), the ORR by BICR was 60% (21/35), and all responses correlated with MAFC >90% by C4D1.
Promising developments have emerged in the cancer field regarding ada’s potential to treat pts with KRASG12C-mutated NSCLC. It has proven to be effective, with manageable tolerability. Further analysis would determine whether the clinical response of ada is linked to MAFC in ctDNA. A phase III trial is underway to compare ada monotherapy with docetaxel in previously treated pts withKRASG12C -mutated NSCLC.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03785249
Jänne, P.A., Spira, A., Riely, G.J., Gadgeel, S., Heist, R., Ou, S.I., Johnson, M.L., Sabari, J., Velastegui, K., Christensen, J.G., Yang, W., Anderes, K., Chao, R., Paweletz, C. Journal of Thoracic Oncology (2023) .
