Recently, KRASG12C inhibitors have demonstrated promising clinical activity in patients with KRASG12C-mutated advanced non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur uncommonly in solid tumours other than NSCLC and CRC and adagrasib may represent a matched treatment option for this rare cohort of pretreated patients with KRASG12C-mutated solid tumours according to the results from the KRYSTAL-1 study.
The KRYSTAL-1 results provide clinical evidence that KRASG12C can be therapeutically targeted across diverse tumour types, with activity observed for adagrasib in this tumour-agnostic patient population. Next generation sequencing for all tumour types is necessary to identify potential treatment targets, and testing for KRASG12C mutations across solid tumours remains critical to identify patients who may benefit from treatment with adagrasib according to Dr. Tanios S. Bekaii-Saab of the Department of Medical Oncology and Hematology, Mayo Clinic in Scottsdale, AZ, US, and colleagues who published the findings on 26 April 2023 in the JCO.
A phase II cohort study, KRYSTAL-1 evaluated the clinical activity and safety of adagrasib, a potent covalent KRASG12C inhibitor, in patients with advanced solid tumours, excluding NSCLC and CRC, harbouring a KRASG12C mutation. To date, this study is the largest phase II tumour agnostic dataset to evaluate KRASG12C-mutated solid tumours, excluding NSCLC and CRC.
The authors wrote in the background that KRASG12C occurs in approximately 14% of patients with NSCLC and 3-4% of those with CRC. KRASG12C mutations have also been identified, though less frequently, in other solid tumours, including appendiceal (3-4%), pancreatic (1-3%), small bowel (1-3%), biliary tract (1%), endometrial (1-2%), and ovarian cancer (1-2%).
Adagrasib is an oral, small molecule, covalent inhibitor that irreversibly and selectively binds KRASG12C, trapping it in its inactive guanosine diphosphate-bound state. Adagrasib was selected for favourable properties, including a long half-life of 23 hours, dose-dependent pharmacokinetics, and central nervous system penetration. Adagrasib is currently being evaluated in KRYSTAL-1, a phase I/II multiple expansion cohort study of patients with advanced solid tumours harbouring a KRASG12C mutation.
Data reported previously from other cohorts of this study demonstrated clinical activity and tolerability of adagrasib in previously treated patients with KRASG12C-mutated NSCLC and CRC. Based on these data, the US Food and Drug Administration (FDA) granted accelerated approval for adagrasib in previously treated KRASG12C-mutated NSCLC in December 2022. The FDA has also granted breakthrough therapy designation for adagrasib in combination with cetuximab, for the treatment of patients with KRASG12C-mutated CRC. In the latest article published in the JCO, the study team reports data from a phase II cohort of KRYSTAL-1 evaluating adagrasib monotherapy in patients with advanced solid tumours, excluding NSCLC and CRC, harbouring a KRASG12C mutation.
In this phase II cohort of the KRYSTAL-1 study, the researchers evaluated adagrasib 600 mg orally twice daily in patients with KRASG12C-mutated advanced solid tumours, excluding NSCLC and CRC. The primary endpoint was objective response rate. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival, and safety.
As of 1 October 2022, 64 patients with KRASG12C-mutated solid tumours were enroled and 63 patients treated with median follow-up of 16.8 months. The median number of prior lines of systemic treatment was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 patients (35.1%), all partial responses, including 7 of 21 (33.3%) in pancreatic and 5 of 12 (41.7%) in biliary tract cancers.
The median DoR was 5.3 months (95% confidence interval [CI] 2.8 to 7.3) and median PFS was 7.4 months (95% CI 5.3 to 8.6).
Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3 to 4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. The most frequently occurring TRAEs are aligned with those reported previously in patients with pretreated NSCLC or heavily pretreated CRC.
The authors commented that this study is limited by its non-randomised, single-arm design. KRASG12C mutations in solid tumours other than NSCLC and CRC are rare, resulting in heterogenous populations and small patient numbers for each of the tumour types in this study. However, the responses observed in tumour types such as pancreatic, where mutation analysis is not routinely conducted, underscore the importance of more consistent genomic testing.
Ongoing biomarker analyses may provide additional information on the mechanisms of primary and secondary resistance to KRASG12C inhibitors, and may be used to identify other drug targets, or combinations thereof, for specific patient populations. In particular, there is a rationale for combining adagrasib with other inhibitors targeting different points of the RAS/MAPK signalling pathway, such as the combination of adagrasib and cetuximab in KRASG12C-mutated CRC. Based on this rationale, adagrasib is being evaluated in exploratory combinations in other solid tumours, including pancreatic cancer.
The findings were previously presented in part at ASCO GI 2022.
This study was sponsored by Mirati Therapeutics, Inc. and was also supported by the Cancer Center Core Grant to Memorial Sloan Kettering.
Bekaii-Saab TS, Yaeger R, Spira AI, et al. Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation. JCO; Published online 26 April 2023, DOI: 10.1200/JCO.23.00434