Adagrasib monotherapy effective in patients with pancreatic and other gastrointestinal tumours harbouring a KRAS G12C mutation

At ASCO GI 2022, Prof. Bekaii-Saab discussed the updated results of the ongoing phase I/II KRYSTAL-1 trial in KRAS^G12C-mutated gastrointestinal cancers. In this study, adagrasib monotherapy was found to be well tolerated and demonstrated encouraging clinical activity in pre-treated patients with pancreatic ductal adenocarcinoma (PDAC) and other gastro-intestinal tumours harbouring a KRAS^G12C mutation.

KRAS mutations occur in approximately 90% of pancreatic cancers and approximately 2% of these are KRAS^G12C mutations. Adagrasib, an investigational agent, is a KRAS^G12C inhibitor that irreversibly and selectively binds KRAS^G12C, locking it in its inactive state. This drug has been optimised for favourable pharmacokinetic (PK) properties, including long half-life (̃24 h), extensive tissue distribution, dose-dependent PK, as well as central nervous system penetration. Maintaining continuous exposure of adagrasib above a target threshold enables inhibition of KRAS-dependent signalling for the complete dose interval and maximises depth and duration of antitumour activity. Previously reported data demonstrated clinical activity with adagrasib in patients with various KRAS^G12C-mutated solid tumours, including non-small cell lung cancer, colorectal cancer (CRC) and other tumours such as pancreatic ductal adenocarcinoma (PDAC), ovarian and endometrial cancers, and cholangiocarcinoma.

Study design

KRYSTAL-1 is a multicohort phase I/II study evaluating adagrasib in patients with KRAS^G12C-mutant advanced solid tumours. All patients had unresectable or metastatic disease without available treatment with curative intent or available standard of care. At ASCO GI 2022, preliminary data from patients enrolled in a phase II cohort evaluating single-agent adagrasib administered orally at 600 mg twice daily in previously treated patients with unresectable or metastatic solid tumours (excluding non-small cell lung cancer and colorectal cancer), including pancreatic and other GI cancers with a KRAS^G12C mutation were reported. Study endpoints include clinical activity, safety, and PK.

Results

In total, 42 patients were enrolled in the KRYSTAL-1 cohort of “other solid tumours”, of whom 30 patients had KRAS^G12C-mutant gastro-intestinal (GI) tumours (12 PDAC, 8 biliary tract, 5 appendiceal, 2 gastro-oesophageal junction, 2 small bowel, and 1 oesophageal). Median age of these patients was 65.5 years, 40% were female and 67% were white. Most patients (80%) had an ECOG performance status of 1. Patients had received a median of two prior lines of therapy (range 1-5). In a preliminary analysis with a median follow-up of 6.3 months, 27 patients with GI tumours were evaluable for clinical activity and partial responses (PRs) were seen in 41% (11/27, including 3 unconfirmed PRs). The disease control rate (DCR) was 100%.

Of the twelve enrolled patients with PDAC (median follow-up 8.1 months), ten were evaluable for clinical activity. Of those, partial responses (PR) were seen in five patients (50%, including one unconfirmed PR) and the DCR was 100%. Median time to response (TTR) was 2.8 months and median duration of response (DOR) was 6.97 months. In this population, the median progression-free survival (PFS) was 6.6 months and treatment was ongoing in 50% of patients.

Among the 17 evaluable patients with other GI tumours, six achieved PR (35%; two unconfirmed) with a DCR of 100%. Responses were observed in patients with biliary tract cancer (4/8 patients, 50%), gastro-oesophageal junction cancer and small bowel cancer (1 PR each). Median TTR was 1.3 months and median DOR was 7.85 months in this cohort of patients with other GI tumours. Median PFS was 7.85 months and eleven patients (65%) were still receiving treatment. In the overall cohort of patients with GI cancers, treatment-related adverse events (TRAEs) of any grade occurred in 87% of patients, the most frequent being nausea (50%), vomiting (40%), diarrhoea (37%), and fatigue (33%). Grade 3 events occurred in 27% of patients, with no grade 4 or 5 events. No TRAEs led to discontinuation.

Conclusion

Adagrasib monotherapy demonstrated promising clinical activity and 100% disease control in previously treated patients with PDAC and other GI (non-colorectal) tumours harbouring a KRAS^G12C mutation. In addition, adagrasib monotherapy was well tolerated and has a manageable safety profile. Further exploration of adagrasib is ongoing in the KRYSTAL-1 trial and a newly initiated early access program is available to this patient population.

Reference

Bekaii-Saab T, Spira AI, Yaeger R, et al. KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients (Pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. Presented at ASCO GI 2022; Abstract 519.