Adagrasib demonstrates promising efficacy in pre-treated patients with NSCLC harbouring a KRAS G12C mutation
Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable safety profile in the phase I–Ib part of the KRYSTAL-1 study. In the registrational phase II cohort in patients with previously treated KRASG12C-mutated non-small cell lung cancer, adagrasib now demonstrated clinical efficacy without new safety signals.
KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of patients with non-small cell lung cancer (NSCLC), predominantly adenocarcinoma. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib is optimised for favourable pharmacokinetic (PK) properties, including long half-life (23 h), dose-dependent PK, and central nervous system penetration. It has demonstrated objective response and favourable tolerability in the phase I/Ib setting.
Study Design
KRYSTAL-1 is a multi-cohort phase I/II study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumours harbouring a KRASG12C mutation. At ASCO 2020, Prof. Spira reported the first disclosure from all patients enrolled in Cohort A, a phase II cohort with registrational intent, evaluating adagrasib given 600 mg orally twice daily (capsule, fasted) in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-(L)1 therapy, either concomitantly or sequentially. Treated, stable CNS metastases were allowed. Study objectives include evaluating efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]), safety, pharmacokinetics and exploratory correlative analyses. Objective tumour response was assessed per RECIST v1.1 by blinded independent central review (BICR).
Results
As of the 15 October 2021 data cut-off, 116 patients with NSCLC harbouring a KRASG12C mutation were enrolled and treated, with a median follow-up of 12.9 months. Baseline characteristics include median age 64 years, 56% female, and 16%/84% with ECOG PS 0/1; 98% of patients received adagrasib following prior treatment with both immunotherapy and chemotherapy, with a median of 2 prior systemic therapies. Among the 112 evaluable patients, the ORR (by BICR) was 43% (48/112) and the disease control rate was 80% (89/112). One patient achieved a complete response. Responses were deep, with 75% of responders achieving more than 50% tumour reduction. Among 48 patients with a response, median time to response was 1.4 months and median DOR was 8.5 months (95%CI 6.2–13.8). As of the data cut-off date, 24 patients with a response (50%) were still receiving treatment and 33% (16/48) are still in response. The median PFS was 6.5 months (95%CI 4.7–8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. Median OS was 12.6 months (95%CI 9.2–19.2) with a 6- and 12-month OS of 71% and 51%, respectively. Results were consistent among all exploratory subgroups analysed.
Among patients with treated, stable CNS metastases, the intracranial (IC) ORR was 33% with a median IC DOR of 11.2 months. The IC DCR was 85% and the median IC PFS was 5.4 months. Confirmed ORRs in patients with co-occurring alterations in STK11, KEAP1, TP53, and CDKN2A were 40.5%, 28.6%, 51.4%, and 58.3%, respectively. Confirmed ORRs were similar across PD-L1 expression subgroups (46.8% for PD-L1 < 1%, 44.4% for PD-L1 1-49%, 41.7% for PD-L1 ≥50%).
Treatment-related adverse events (TRAEs) of any grade occurred in 97% of patients, grade ≥3 TRAEs in 43%. There were two grade 5 TRAEs (cardiac failure [N= 1] and pulmonary haemorrhage [N= 1]). TRAEs led to dose reduction in 52% of patients, dose interruption in 61% of patients and study drug discontinuation in only 7% of patients. The most commonly reported (≥25%) TRAEs (any grade) were diarrhoea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT/AST increased (28%/25%) and blood creatinine increased (26%).
Conclusion and future directions
In this registrational phase II cohort, adagrasib demonstrated promising clinical activity as well as a manageable safety profile in patients with previously treated NSCLC harbouring a KRASG12C mutation. A confirmatory phase III trial (KRYSTAL-12) is evaluating adagrasib versus docetaxel in previously treated patients with KRASG12C-mutant NSCLC. Thus far, adagrasib has demonstrated responses across 9 tumour types, across NSCLC-relevant molecular subsets and patients with NSCLC with either stable/treated or untreated CNS metastases.
Reference
Spira AI, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at ASCO 2022; Abstract 9002.
