On April 24, 2018 Mirati Therapeutics, Inc. (Nasdaq: MRTX) (the Company or Mirati), a clinical-stage targeted oncology company, reported that a progress update on its lead development programs and announced updated, positive clinical trial data for sitravatinib, a spectrum selective kinase inhibitor, and mocetinostat, a class I and IV HDAC inhibitor (Press release, Mirati, APR 24, 2018, View Source [SID1234525643]). The Company has been evaluating sitravatinib and mocetinostat in separate Phase 2 clinical trials in combination with checkpoint inhibitor therapy in non-small cell lung cancer (NSCLC) patients whose disease had progressed following prior treatment with a checkpoint inhibitor. Both clinical trials have generated encouraging preliminary data demonstrating the potential to overcome resistance to checkpoint inhibitor therapy.
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"The majority of NSCLC patients either do not respond to checkpoint inhibitor therapy or experience disease progression following treatment. These patients have limited treatment options and generally experience poor outcomes in response to standard of care chemotherapy," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer. "The preliminary data from our Phase 2 study of sitravatinib plus nivolumab continue to highlight the promise of this combination to overcome resistance to initial checkpoint inhibitor therapy and provide a meaningful treatment option for this large and underserved patient population."
Sitravatinib is being evaluated in a Phase 2 study in combination with nivolumab (OPDVIO), an anti-PD-1 checkpoint inhibitor, in patients with NSCLC who have experienced documented disease progression following prior treatment with a checkpoint inhibitor. As of the data cutoff date of March 31, 2018:
23 patients were evaluable for response with at least one radiographic scan
Six patients achieved a Partial Response (PR) (four confirmed and two unconfirmed)
1Five of the six patients with PRs remain on study, including both patients with unconfirmed PRs; the longest treatment duration exceeds 50 weeks and is ongoing
The other patient with a PR progressed following a treatment duration that exceeded 40 weeks
19 of 23 patients demonstrated tumor reductions
To date, the combination has been well-tolerated and most adverse events (AEs) reported by investigators were Grade 1 or 2.
"The responses and duration of treatment seen with the combination of sitravatinib and a checkpoint inhibitor are very promising, notably because these patients had relapsed following prior checkpoint inhibitor therapy," said Alexander Spira, M.D., Ph.D., Director of the Virginia Cancer Specialists Research Institute. "The trial is enrolling well, and we have been pleased with the favorable tolerability of the combination."
Enrollment is accelerating, and 45 patients have been enrolled. Correlative analyses of peripheral blood and tumor tissue biomarkers are ongoing. The Company is planning to present more mature data at an oncology conference later this year. The Company expects to meet with regulatory authorities in the second half of 2018 to discuss plans for registration.
In a separate Phase 2 study, mocetinostat is being evaluated in combination with durvalumab (IMFINZI), an anti-PD-L1 checkpoint inhibitor, in patients with NSCLC who have experienced documented disease progression following prior treatment with a checkpoint inhibitor. As of the data cutoff date of March 31, 2018:
23 patients were evaluable for response with at least one radiographic scan
Three patients achieved a PR (two confirmed and one unconfirme
All three patients with PRs remain on study; the longest treatment duration exceeds 44 weeks and is ongoing
8 of 23 patients demonstrated tumor reductions.
To date, the combination has been well-tolerated, and most AEs reported by investigators were Grade 1 or 2.
31 patients have been enrolled in this ongoing trial and the Company plans to present more mature data at an oncology conference later this year.
Mirati also provided an update on the Phase 1b expansion trial for sitravatinib as a single agent. Interim clinical data will be presented in a poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held June 1 – 5, 2018 in Chicago, Illinois. The presentation, titled "Evaluation of the spectrum selective RTK inhibitor sitravatinib in renal cell carcinoma (RCC) refractory to anti-angiogenic therapy" will report data from patients with RCC treated with single agent sitravatinib.
In that same Phase 1b trial of single agent sitravatinib, enrollment continues in the cohorts of patients whose tumors harbor CBL, CHR4Q12 and RET genetic alterations in NSCLC and other tumor types. The Company plans to present more mature data for these patients at an oncology conference later this year.
MRTX849, the Company’s small molecule mutation-selective KRAS G12C inhibitor, continues to advance towards a planned Investigational New Drug (IND) submission in the fourth quarter of 2018, with the potential to generate early proof-of-concept clinical data in 2019.
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About Sitravatinib
Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being tested in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in NSCLC patients who have experienced documented disease progression following treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.
Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion trial enrolling patients whose tumors harbor CBL, CHR4Q12 and RET genetic alterations in NSCLC and other solid tumors.
About Mocetinostat
Mocetinostat is a selective Class I and IV HDAC inhibitor. Inhibition of histone acetylation is predicted to enhance the recognition of tumor cells by anti-tumor T cells and reverse immunosuppressive factors in the tumor microenvironment. The Company is conducting a Phase 2 study of mocetinostat in combination with durvalumab (IMFINZI), an anti-PD-L1 checkpoint inhibitor, in NSCLC patients who have experienced disease progression following prior treatment with a checkpoint inhibitor.
About MRTX849
MRTX849 is an orally-available small molecule that potently and selectively inhibits a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of NSCLC adenocarcinoma patients and 5% of colorectal cancer patients. Tumors characterized by KRAS G12C mutations are commonly associated with poor prognosis and resistance to therapy, and patients with these mutations have few treatment options. MTRX849 has demonstrated complete regression of KRAS G12C-positive human tumors implanted in mice. IND-enabling preclinical studies are underway, and an IND submission is expected in the fourth quarter of 2018, with early clinical proof-of-concept anticipated in 2019.