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Update on Targeting KRAS in Colorectal Cancer

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The ESMO World Congress on Gastrointestinal Cancer (“World GI”) is an annual highlight for international oncology professionals dedicated to improving the lives of patients with malignancies of the GI tract. The conference discusses the latest clinical advances and mechanistic insights across gastrointestinal cancers. One of the highlights for us this year was continued progress on experimental cancer drugs to inhibit KRAS. Not only are KRAS mutations recognized as one of the most common drivers for several cancers, but the protein has been labeled as “undruggable” due to a lack of molecular binding pockets for inhibitors. The concept to “drug the undruggable” continues to be a hot area we track in our conference coverage.

At World GI, Amgen presented new data from the Phase 1 CodeBreak100 trial. The study assessed AMG510, a direct inhibitor of G12C-mutant KRAS, in patients with colorectal cancer (CRC) harboring the G12C mutation.

Findings:

  • We noted improvements over prior reports. For instance, there was a 7% response rate at World GI, vs 0% response rate at ASCO 2019. However, we still see that AMG510 is less effective in CRC than non-small cell lung cancer (NSCLC)
  • A majority of CRC patients did see a temporary halt in tumor growth. Although it is difficult to base any strong conclusions on this finding, we still find this result encouraging
  • We view the AMG510 readout to be consistent with previously reported data for key competitor MRTX849 (Mirati). Thus the lesser benefit in CRC versus NSCLC may be due to underlying disease biology

Moving forward, we expect combination strategies will be key to induce both deeper responses and more durable benefit (e.g. going beyond 4 months median progression free survival in CRC). More comprehensive blockade of signaling pathways (e.g. Mirati’s combination trial with Novartis’ SHP2 inhibitor TNO155), exploiting synthetic lethality (potentially with glutaminase inhibitors in KRASmut KEAP1/NRF2 deficient cancers), or targeting complementary mechanisms (e.g. AMG in CodeBreak101 in combination with EGFR and MEK inhibitors) are all intriguing options we see being actively explored.

 

Sources: 1) ESMO World GI 2020, Abstract #SO-24; 2) ASCO Annual Meeting 2019, Abstract #3003; 3) WCLC 2019, Abstract #OA02.02; 4) https://www.mirati.com/wp-content/uploads/2019/10/AACR-NCI-EORTC-Clinical-Data-Presentation_Janne_October-2019-1-1.pdf

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