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KRYSTAL-1

A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1

Phase 1/2NCT03785249

Population
Heavily pretreated metastatic colorectal cancer with mutant KRAS G12C
Design
Open-label, nonrandomised phase 1-2 trial; this record covers the heavily pretreated metastatic colorectal cancer cohorts reported in the NEJM 2023 paper: adagrasib 600 mg orally twice daily alone, or the same dose with intravenous cetuximab given weekly (loading dose then maintenance) or every two weeks. Per the full text, the primary endpoint was objective response in the monotherapy cohort and safety in the combination cohort, with response a secondary endpoint there. The two cohorts were not randomised and are not compared.
Primary endpoint
ORR
Arms
  • Adagrasib (experimental, n = 44): Adagrasib 600 mg orally twice daily
  • Adagrasib + cetuximab (experimental, n = 32): Adagrasib 600 mg orally twice daily plus intravenous cetuximab
People
Yaeger R
Show the numbers
Results reported for KRYSTAL-1
EndpointAnalysisAdagrasib / Adagrasib + cetuximabControlEffect
ORREvaluable patients: 43 in the monotherapy cohort and 28 in the combination cohortObjective response (complete or partial response), investigator-assessed, evaluable patients (primary endpoint in the monotherapy cohort; secondary endpoint in the combination cohort)primaryYaeger 202319% (8–33%)—As of 16 June 2022, 44 patients had received adagrasib and 32 the combination; median follow-up 20.1 and 17.5 months. By blinded independent central review the response was 23% (95% CI 12 to 39) with adagrasib and 46% (95% CI 28 to 66) with the combination (full text). Nonrandomised cohorts.
DOREvaluable patients with a responseMedian duration of responseprimaryYaeger 2023median 4.3 months (2.3–8.3)—The 95% CI for the combination cohort is 5.7 months to not estimable; an interval with an open upper bound cannot be shown here.
PFSAll patients treated: 44 in the monotherapy cohort and 32 in the combination cohort (full text)Median progression-free survival (secondary endpoint)primaryYaeger 2023median 5.6 months (4.1–8.3)——
Results reported for KRYSTAL-1
EndpointAnalysisAdagrasib / Adagrasib + cetuximabControlEffect
ORREvaluable patients: 43 in the monotherapy cohort and 28 in the combination cohortObjective response (complete or partial response), investigator-assessed, evaluable patients (primary endpoint in the monotherapy cohort; secondary endpoint in the combination cohort)primaryYaeger 202319% (8–33%)—As of 16 June 2022, 44 patients had received adagrasib and 32 the combination; median follow-up 20.1 and 17.5 months. By blinded independent central review the response was 23% (95% CI 12 to 39) with adagrasib and 46% (95% CI 28 to 66) with the combination (full text). Nonrandomised cohorts.
DOREvaluable patients with a responseMedian duration of responseprimaryYaeger 2023median 4.3 months (2.3–8.3)—The 95% CI for the combination cohort is 5.7 months to not estimable; an interval with an open upper bound cannot be shown here.
PFSAll patients treated: 44 in the monotherapy cohort and 32 in the combination cohort (full text)Median progression-free survival (secondary endpoint)primaryYaeger 2023median 5.6 months (4.1–8.3)——
Illustrative — modelled from reported values, not trial data. DOR, primary.
0%25%50%75%100%051015Months (modelled)
  • Adagrasib (experimental)
  • Adagrasib + cetuximab (experimental)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsAdagrasibAdagrasib + cetuximab
0100.0%100.0%
544.7%63.4%
1019.9%40.2%
1410.5%27.9%
194.7%17.7%
Illustrative — modelled from reported values, not trial data. PFS, primary.
0%25%50%75%100%051015Months (modelled)
  • Adagrasib (experimental)
  • Adagrasib + cetuximab (experimental)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsAdagrasibAdagrasib + cetuximab
0100.0%100.0%
461.0%66.9%
932.8%40.5%
1320.0%27.1%
1712.2%18.1%
Primary publication: Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023;388(1):44-54. PubMedDOI

Appears in

Sources

  1. Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023;388(1):44-54.

    PubMedDOI