Adagrasib is an investigational agent that irreversibly and selectively binds to KRASG12C, locking it in its inactive state. The phase I/II KRYSTAL-1 study demonstrates that adagrasib alone or in combination with cetuximab provides encouraging antitumour activity and safety in heavily pre-treated patients with KRASG12C-mutant colorectal cancer (CRC).
KRASG12C mutations occur in approximately 3-4% of colorectal cancers (CRC), act as oncogenic drivers and are a negative predictor of cetuximab efficacy. The KRAS protein cycles between GTP-on and GDP-off states and has a protein resynthesis half-life of approximately 24 hours. Adagrasib is a covalent inhibitor of KRASG12C that irreversibly and selectively binds KRASG12C in its inactive, GDP-bound state. It was optimised for favourable pharmacokinetic properties, including a long half-life. Combining adagrasib with cetuximab, an EGFR inhibitor, may enhance inhibition of KRAS-dependent signalling or overcome adaptive feedback to improve outcomes.
KRYSTAL-1 study design
KRYSTAL-1 is a multicohort phase I/II study evaluating adagrasib in patients with KRASG12C-mutant advanced solid tumours. All patients had unresectable or metastatic disease without available treatment with curative intent or available standard of care. CRC cohorts include adagrasib 600 mg twice daily (BID) monotherapy (N= 2 in phase I/Ib and N= 44 in phase II) and adagrasib 600 mg BID plus cetuximab 400 mg/m2 (N= 32) followed by 250 mg/m2 once a week (QW); or 500 mg/m2 every two weeks (Q2W) (phase Ib).
As of 25 May 2021, 46 patients with CRC had received adagrasib monotherapy (median follow-up 8.9 months). Median age of these patients was 58 years, 50% was female and they received a median of three prior lines of systemic anticancer therapy. Among the 45 patients who were evaluable for clinical activity, the response rate was 22% (10/45, including 1 unconfirmed partial response who remains on study). Stable disease was observed in 64% (29/45) of patients, resulting in a disease control rate (DCR) of 87%. No apparent association between response rate and molecular status was shown in an exploratory analysis. The median duration of response (DoR) was 4.2 months and the median time to response was 1.4 months. At the time of analysis, 40% of patients remain on treatment. Median progression-free survival was 5.6 months with a 6-month PFS rate of 42%. Treatment-related adverse events (TRAEs) of any grade occurred in 91% of patients while 30% of patients experienced grade 3-4 TRAEs. No grade 5 events were reported and no TRAEs led to discontinuation. The most frequent TRAEs of any grade were diarrhoea (63%), nausea (57%) and fatigue (46%).
As of 9 July 2021, 32 patients with CRC were treated with adagrasib plus cetuximab (median follow-up 7 months). Median age of these patients was 60 years, 53% was female and they received a median of three prior lines of systemic anticancer therapy. Among the 28 patients evaluable for clinical activity, the response rate was 43% (12/28, including 2 unconfirmed partial responses who remain on study). Stable disease was reported in 57% of patients and the DCR was 100%. Median time to response was 1.3 months and at the time of analysis, 71% of patients remain on treatment. TRAEs of any grade occurred in all patients and grade 3/4 events in 16% of patients, with no grade 5 events. The most frequent TRAEs of any grade were nausea (63%), diarrhoea (56%) and vomiting (50%).
Adagrasib monotherapy demonstrated promising clinical activity and broad disease control in heavily pre-treated patients with CRC harbouring a KRASG12C mutation. In addition, also the combination of adagrasib and cetuximab showed encouraging clinical activity in this patient population. Adagrasib is tolerable and has a manageable safety profile, both as monotherapy and combined with cetuximab. Adagrasib and cetuximab are now being evaluated in the second-line setting in KRYSTAL-10, a phase III trial in patients with KRASG12C-mutant mCRC.
Weiss J, Yaeger R, Johnson ML, et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Presented at ESMO 2021; Abstract LBA6.