In a Phase 1/2 trial MRTX849, an investigational KRAS G12C inhibitor has demonstrated clinical activity, including objective responses in patients with non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Although a maximum targeted dose has not yet been established, dose-expansion is underway and the trial continues to enroll patients. The data was recently presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston by Mirati Therapeutics (MRTX), a clinical-stage targeted oncology company.
What are KRAS Inhibitors?
According to Mirati Therapeutics, scientists have long thought KRAS inhibitors may be a “holy grail” of cancer treatments—and the quest to create one has been going on for over three decades. Yet no KRAS inhibitors have gone beyond pre-clinical testing, making KRAS mutations the most common oncogene mutations with no targeted treatment option. The landscape, however, changed in 2018 when the first investigational new drug (IND) applications for drugs that target KRAS were submitted to the FDA including one for MRTX849 and one from Amgen.
Patient Populations for KRAS Inhibitors
KRAS mutations are the initial, driving genetic factor for the growth and development of some of the deadliest cancers reports Mirati Therapeutics from NIH sources. Patients exhibiting this mutation typically have a poor prognosis and resistance to standard of care treatment, representing an extraordinary unmet need. KRAS G12C, a specific sub-mutation, is the most frequent individual KRAS mutation in non-small cell lung cancer adenocarcinomas, accounting for 14% of new U.S. cases per year; 5% of colorectal adenocarcinomas and 2% of pancreatic cancers an annually. Collectively, KRAS G12C mutations comprise a patient population with a worldwide annual incidence of greater than 100,000 individuals.
The Mirati Phase I Study
The study evaluates the safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumors with a KRAS G12C mutation. MRTX849 is an orally-available small molecule inhibitor of KRAS G12C.
The study sponsor seeks a total of 200 participants and the estimated study completion date is April 2020. The ongoing Phase I/2 first-in-human, open-label multicenter trial has enrolled 17 patients including 10 patients with NSCLC, 4 patients with CRC and 3 patients with other tumor types. The study team has established five dose cohorts thus far including 150 mg, 600 mg, and 1200 mg taken orally twice daily. The trial enrolled single patient dose-escalation cohorts in an accelerated titration design. Trial objectives include evaluation of safety, tolerability, pharmacodynamics (PD), pharmacokinetics (PK) and tumor response evaluated using RECIST v1.1 criteria.
Participating Clinical Investigational Sites
The study sites represent critically important cancer centers including:
· UC San Diego Moores Cancer Center
· University of Colorado
·Dana Farber Cancer Institute
·Henry Ford Medical Center
·New York Perlmutter Cancer Center
·University of North Carolina
·The Sarah Cannon Research Institute
·Mary Crowley Cancer Center
·South Texas Accelerated Research Therapeutics
·University of Wisconsin Carbone Cancer Center
As presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, the findings at a high level look promising: MRTX849 demonstrated clinical activity, including objective responsiveness, in patients with non-small cell lung cancer (NSCLC) and colorectal cancer (CC).
As of the data cut-off date of October 11, 2019, 12 patients across all dose levels were evaluable for a response with at least one radiographic scan.
- At the highest dose (600 mg BID), three of five (3/5) evaluable patients with NSCLC and one of two (1/2) evaluable patients with CRC achieved a partial response (PR); the remaining patients experienced stable disease (SD).
- Across all dose levels, three of six (3/6) patients with NSCLC and one of four (1/4) patients with CRC achieved a PR. Two responding patients (1 NSCLC and 1 CRC) achieved confirmed PRs, both with continuing tumor shrinkage following their first scan. The other two patients with PRs (both NSCLC) remain on the study but have not yet had confirmatory scans.
- Clinical PK data demonstrated that the dose of 600 mg BID results in drug levels that meet or exceed those likely to lead to full inhibition of KRAS G12C signaling.
- Treatment duration across all dose levels ranged from 6.7- 38.6 weeks for patients with NSCLC and 9.9-30.1 weeks for patients with CRC as of the data cut-off.
Treatment-related adverse events (AEs) were primarily graded 1 event. One patient experienced dose-limiting toxicity (DLT) at the 1200 mg QD dose (capsule burden intolerance [12 capsules]) and one patient experienced a DLT at the 600 mg BID dose (grade 3/4 isolated amylase/lipase increase). The MTD has not yet been established and further dose escalation may be explored. Enrollment into dose expansion at the 600 mg BID dose is underway.
Clinical Investigator Comments
Pasi A. Jänne, MD, Ph.D., Director of the Lowe Center for Thoracic Oncology at the Dana Farber Cancer Institute and MRTX849-001 investigator notes “There are currently no effective targeted therapies for patients with KRAS-mutant cancers.” Pasi A. Jänne continued “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 impact on cancer patients.”
Bioscience investors are watching the study closely as they are comparing Mirati and Amgen KRAS inhibitors. A Motley Fool stock analyst author noted that Mirai stock soared in response to the recent Mirati data. At least some investors believe the Mirati experimental drug MRTX849 may work better than Amgen’s AMG 510, pushing the stock 15% higher recently.
Pasi A. Jänne, MD, Ph.D., Director of the Lowe Center for Thoracic Oncology at the Dana Farber Cancer InstituteCall to Action: For those that have a cancer diagnosis involving the KRAS mutation, these studies are of importance.