MRTX849 Active in KRAS G12C+ NSCLC and CRC

Pasi A. Janne, MD, PhD

The investigational KRAS G12C inhibitor MRTX849 demonstrated clinical activity in patients with non—small cell lung cancer (NSCLC) and colorectal cancer (CRC), according to preliminary results of a phase I/II trial presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.^1,2

Findings showed that at the highest dose of 600 mg twice daily, 3 of 5 evaluable patients with KRAS G12C—positive NSCLC and 1 of 2 evaluable patients with KRAS G12C—positive CRC achieved a partial response (PR), and the remaining patients had stable disease.

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

MRTX849 is an orally available small molecule designed to potently and selectively inhibit KRAS G12C; KRAS G12C mutations are present in approximately 14% of all patients with NSCLC adenocarcinoma, 4% of those with CRC, and in subsets of other malignancies. KRAS G12C—mutant tumors have been described as having a poor prognosis and are typically resistant to therapy, and patients with these mutations have limited therapeutic options, Mirati Therapeutics, the developer of the agent, explained in the press release.

In the ongoing, first-in-human, open-label, multicenter phase I/II trial (NCT03785249), investigators enrolled 17 patients with KRAS G12C—mutant cancers, including NSCLC (n = 10), CRC (n = 4), and other tumor types (n = 3). There are 5 cohorts of varying doses, including 150 mg, 300 mg, 600 mg, and 1200 mg, all orally and once daily, and 600 mg orally twice daily. The accelerated titration design of the study includes single-patient dose-escalation cohorts. Approximately 200 patients will be enrolled on the trial.

To be eligible for enrollment, patients must have an unresectable or metastatic histologically confirmed KRAS G12C—mutant solid malignancy along with adequate organ function. Those with active brain metastases, a history of intestinal disease or major gastric surgery, or another active cancer were excluded from entering on the trial.

The primary endpoints are safety and pharmacokinetics (PK); secondary endpoints include maximum-tolerated dose (MTD) and tumor response via RECIST v1.1 criteria. Tolerability and pharmacodynamics (PD) are additional study objectives. As of the data cutoff date of October 11, 2019, 12 patients across all dose levels were evaluable for response with ≥1 radiographic scan. Treatment duration across all dose levels ranged from 6.7 to 38.6 weeks for patients with NSCLC and 9.9 to 30.1 weeks for patients with CRC.

Additional data showed that across all dose levels, 3 out of 6 patients with NSCLC and 1 of 4 patients with CRC achieved a PR. Moreover, 2 responding patients—1 with NSCLC and 1 with CRC—achieved confirmed PRs and continued to experience tumor shrinkage after their first scan. The other 2 patients with NSCLC who had PRs remain on study, but have not yet had confirmatory scans.

Regarding PK, results showed that the twice-daily dose of 600 mg led to drug levels that meet or exceed those likely to lead to full inhibition of KRAS G12C signaling.

Treatment-related adverse events were mostly of grade 1 severity. There was 1 patient who experienced a dose-limiting toxicity (DLT) at the 1200 mg daily dose due to capsule burden intolerance, and another patient experienced a DLT at the 600-mg twice daily dose, which was due to grade 3/4 isolated amylase/lipase increase.

The company noted in the press release that the MTD has not yet been established and further dose escalation may be explored in the study. Enrollment into dose expansion at the 600-mg twice-daily dose is ongoing.

"Patients whose tumors carry the KRAS G12C mutation have a poor prognosis, are resistant to standard of care treatment and have no available targeted therapeutic options," Charles M. Baum, MD, PhD, president and chief executive officer of Mirati Therapeutics, stated in the press release. "Early efficacy and safety data from this phase I/II trial demonstrate the potential of a potent and effective KRAS therapy. We look forward to investigating MRTX849 in patients with a variety of KRAS G12C—mutated cancers and bringing the hope of a targeted therapy to them."

Preclinical data highlighting the efficacy with MRTX849 were simultaneously published with the phase I/II data during the conference.^2,3 Out of 26 KRAS G12C—positive cell line- and patient-derived xenograft models from multiple tumor types, results showed that the agent demonstrated pronounced tumor regression in 17 (65%) models.

Moreover, comprehensive PD and pharmacogenomic profiling in sensitive and partially resistant non-clinical models recognized mechanisms that are involved in limiting antitumor activity, which included KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence, the authors noted in their article. These factors included RTKs activation, bypass of KRAS dependence, and genetic cell cycle dysregulation. The authors also suggested that MRTX849 could be combined with agents that target RTKs, mTOR, or cell cycle, as these approaches showed enhanced response and marked tumor regression in models, including those that were MRTX849-refractory.

References

1. Mirati Therapeutics Presents First Clinical Data of Phase 1/2 Trial of MRTX849 at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets And Cancer Therapeutics. Mirati Therapeutics. Published October 28, 2019. https://bit.ly/2q4kGNW. Accessed October 28, 2019.
2. Jänne P. A phase 1 clinical trial evaluating the pharmacokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRASG12C inhibitor, in advanced solid tumors. Presented at: 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA.
3. Christensen JG, Hallin J, Engstrom LD, et al. The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients [published online ahead of print October 28, 2019]. Cancer Discov. doi: 10.1158/2159-8290.CD-19-1167.