Adagrasib shows promising clinical activity in heavily pretreated KRAS-mutated CRC

The selective KRAS^G12C inhibitor adagrasib, as monotherapy or combined with cetuximab, was well tolerated and demonstrated promising clinical activity in heavily pretreated patients with KRAS-mutant colorectal cancer (CRC), first results of the KRYSTAL-1 trial showed.

KRAS^G12C mutations, which occur in 3–4% of CRC, act as oncogenic drivers and are a negative predictor of cetuximab efficacy. Adagrasib is a KRAS^G12C inhibitor that irreversibly and selectively binds KRAS^G12C, locking it in its inactive state. Durable inhibition of KRAS^G12C may be particularly important in CRC due to signalling pathways which create a susceptibility to feedback reactivation of KRAS. EGFR signalling is implicated in this reactivation, providing a rational co-targeting strategy for KRAS-mutant CRC.

KRYSTAL-1 (NCT03785249) is a multicohort phase 1/2 study evaluating adagrasib in patients with KRAS-mutant advanced solid tumours. CRC cohorts include adagrasib 600 mg twice daily monotherapy and adagrasib 600 mg twice daily plus cetuximab. Endpoints include safety, pharmacokinetics, and clinical activity. Dr Jared Weiss (University of North Carolina at Chapel Hill, NC, USA) presented the first results [1].

At data cut-off, 46 patients with CRC (50% female; median age 58 years; 3 median prior lines of therapy) had received adagrasib monotherapy (median follow-up 8.9 months). Among the 45 patients evaluable for clinical activity, the response rate was 22% (10/45, including 1 unconfirmed partial response who remains on study) and disease control rate was 87% (39/45). Median duration of response was 4.2 months; median PFS was 5.6 months. Treatment-related adverse events of any grade occurred in 91% and grade 3/4 events in 30% of patients, with no grade 5 events.

Conversely, 32 patients with CRC (53% female; median age 60 years; 3 median prior lines of therapy) were treated with adagrasib plus cetuximab (median follow-up 7 months). Among the 28 patients evaluable for clinical activity, the response rate was 43% (12/28, including 2 unconfirmed partial response who remain on study) and disease control rate was 100% (see Figure). Data are still unmature for duration of response and PFS. Treatment-related events of any grade occurred in 100% and grade 3/4 events in 16% of patients, with no grade 5 events.

Figure: Overall response of CRC patients on adagrasib plus cetuximab in KRYSTAL-1 [1]



“Adagrasib is well tolerated as monotherapy and combined with cetuximab and demonstrates promising clinical activity in heavily pretreated patients with KRAS^G12C-mutant CRC,” concluded Dr Weiss. The phase 3 KRYSTAL-10 trial (NCT04793958) currently evaluates adagrasib/cetuximab combination versus chemotherapy in the second-line setting in patients with KRAS^G12C-mutant CRC.

Similar data with another KRAS^G12C inhibitor, sotorasib, combined with panitumumab were also presented [2].

1. Weiss J, et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) withcolorectal cancer (CRC) harboring a KRASG12C mutation. Abstract LBA6, ESMO Congress 2021, 16–21 September.
2. Fakih M, et al. CodeBreaK 101 subprotocol H: Phase Ib study evaluating combination of sotorasib (Soto), a KRASG12C inhibitor, and panitumumab (PMab), an EGFR inhibitor, in advanced KRAS p.G12C-mutated colorectal cancer (CRC). Abstract 434P. ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November 202117 May 2024