Unveiling of KRAS Inhibitor Clinical Data Initiates Mirati, Amgen comparisons

By Rajaneesh K. Gopinath, Ph.D.

Mirati’s KRAS G12C inhibitor data from a Phase 1/2 trial involving patients with advanced solid tumors was presented at the AACR-NCI-EORTC International Conference held at Boston. Preliminary data suggests that MRTX849 demonstrated clinical activity, including objective responses, in patients.

The KRAS oncogene is one of the most prevalent in human cancers and it is also the most frequently mutated isoform of RAS oncogenes. Due to the lack of traditional binding pockets on the KRAS protein, various attempts to develop small molecule-based therapies failed, giving it an “undruggable” tag. The common mutations found in the KRASgene are primarily at codons 12, 13, or 61. Mutation of the glycine 12 amino acid to any of the six possible amino acids, leads to RAS activation and eventually cancer growth. Among those six, Glycine to Cysteine (KRAS-G12C) mutation is one of the most common, constituting 10%–20% of all KRAS G12 mutations found in cancers.

In the last ASCO conference, Amgen has presented the blockbuster results of a phase 1 study evaluating its novel investigational KRAS G12C inhibitor, AMG 510 at four different doses. Out of the 10 lung cancer patients enrolled, an overall response rate (ORR) of 50% was achieved. In the follow-up data presented at WCLC conference it announced that out of the 23 evaluable patients, 7/13 who received the highest dose exhibited shrinkage in tumor, which constitutes an ORR of 54%.

At the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, the data of the phase ½ trial of Mirati’s KRAS G12C inhibitor MRTX849 were presented. The study tested 5 dosages of the inhibitor in the 17 enrolled patients that comprised of 10 patients with lung cancer, 4 patients with colorectal cancer, and 3 patients with other tumor types. Across all dose levels, 3/6 patients with lung cancer, 1/4 patients with CRC achieved a partial response. Two responding patients, one each from the two cancer types achieved confirmed partial responses, both with continuing tumor shrinkage. The data from MRTX849 are encouraging but have to be met with guarded enthusiasm.

“There are currently no effective targeted therapies for patients with KRAS-mutant cancers,” said Pasi A. Jänne, M.D., Ph.D., Director of The Lowe Center for Thoracic Oncology at the Dana Farber Cancer Institute and MRTX849-001 investigator. “KRAS mutations are the most common oncogenic alteration in all of the human cancers, and as such, finding a therapeutic approach for this subset of cancers would have a tremendous clinical impact for cancer patients.”

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804475/
2. https://www.amgen.com/media/news-releases/2019/06/amgen-announces-first-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-amg-510-at-asco-2019/
3. https://www.amgen.com/media/news-releases/2019/09/amgen-announces-new-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-in-larger-patient-group-at-wclc-2019/

Author

Rajaneesh K. Gopinath