The New England Journal of Medicine

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

No therapies for targeting KRAS mutations in cancer have been approved. The KRAS G12C mutation occurs in 13% of non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C.

Sep 24, 2020


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Sotorasib showed promising anticancer activity in patients with heavily pretreated KRAS G12C mutant solid tumors.”

Key Findings

  • In the NSCLC cohort, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease).
  • The median progression-free survival was 6.3 months.

Clinical Summary

In this phase 1 trial, the safety, pharmacokinetics, and efficacy of sotorasib, a small molecule that selectively and irreversibly targets KRAS G12C, was evaluated. KRAS G12C mutation occur in 13% of non-small-cell lung cancers (NSCLC) and in 1 to 3% of colorectal cancers and other cancers.

A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease). The median progression-free survival was 6.3 months. In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months.

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Key Findings

  • In the NSCLC cohort, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease).
  • The median progression-free survival was 6.3 months.

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Key Findings24

  • Concordance between Guardant360 and tissue testing was greater than 90% for the four biomarkers with FDA-approved therapies
  • Guideline-recommended biomarker testing was completed for 95% of patients with Guardant360 vs. 31% with standard-of-care tissue testing
  • Turnaround time was ~1 week faster with Guardant360 vs. SOC tissue testing

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Key Findings25

  • 44% of eligible patients were unable to get complete genomic results from tissue biopsy
  • 2x as many patients had targetable alterations detected by Guardant360 and tissue testing (n=82) versus tissue testing alone (n=47)
  • 86% of patients had a response or stable disease based on RECIST criteria

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Key Findings26

  • The demands on tissue specimens from diagnostic stains and PD-L1 testing may leave little remaining for genomic profiling
  • Gaps in genomic biomarker testing can be overcome with new technologies

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Key Findings19

  • Guardant360 detects guideline-complete alterations in advanced NSCLC patients, including MET exon 14 skipping alterations
  • ORR and DCR equivalent in Guardant360 and tissue biopsy groups in the VISION trial MET exon 14 skipping NSCLC cohort

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Key Findings27

  • Comprehensive ctDNA testing can effectively guide therapy selection
  • Response rates to therapy selected based on Guardant360 results were consistent with those in tissue-based targeted therapy studies

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