Benzinga | Oct 25, 2020 10:56AM EDT

Mirati Therapeutics Reports Investigational Adagrasib (MRTX849) Preliminary Data Demonstrating Tolerability and Durable Anti-Tumor Activity With 45% Confirmed ORR and 96% DCR across Phase 1/1b and Phase 2 Monotherapy Cohorts in Patients with Advanced NSCLC

Mirati Therapeutics, Inc. (NASDAQ:MRTX) today announced preliminary results from the Company's mutant KRAS selective inhibitor programs. The preliminary results included updated clinical data of adagrasib (MRTX849), the Company's KRAS G12C inhibitor, presented at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics ("ENA") and initial preclinical in vivo data of MRTX1133, the Company's selective and potent potential first-in-class KRAS G12D inhibitor.

Adagrasib is a potent and selective inhibitor of KRAS G12C, optimized for a long half-life and a significant volume of tissue distribution to maintain continuous inhibition of KRAS-dependent signaling for the complete dose interval to maximize efficacy demonstrated by the depth and duration of anti-tumor activity.

"The adagrasib preliminary data presented today showed deep and durable anti-tumor activity in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other solid tumors, providing renewed hope for patients that harbor a KRAS G12C mutation. A 45% confirmed objective response rate for adagrasib as a monotherapy in advanced NSCLC is compelling. While this data is still maturing, adagrasib also demonstrated clinically meaningful duration of treatment for NSCLC patients in the Phase 1/1b cohort," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati. "Enrollment is complete in the Phase 2 cohort of adagrasib as a monotherapy treatment for patients in 2nd / 3rd line NSCLC and we anticipate submitting a New Drug Application for accelerated approval in the second half of 2021. Adagrasib has been well tolerated as a monotherapy and in combination with pembrolizumab, cetuximab and TNO-155, a SHP-2 inhibitor. We are initiating additional registration-enabling global clinical studies of adagrasib as both a monotherapy and in combinations as we expand the program to earlier lines of therapy in NSCLC and CRC."

Adagrasib tolerability at a dose of 600 mg BID in both monotherapy and combination trials:

In a pooled assessment of 110 patients harboring a G12C mutation in NSCLC, CRC and other solid tumors, monotherapy adagrasib has been well tolerated4.5% of treatment-related adverse events led to discontinuationOver 50 patients have been treated with adagrasib in combination with either pembrolizumab (a PD-1 inhibitor) in NSCLC, cetuximab (an anti-EGFR antibody) in CRC and TNO-155 (a SHP-2 inhibitor) in NSCLC or CRCEach combination has been well toleratedThe pembrolizumab and cetuximab combination cohorts are ongoing and each have cleared the dose limiting toxicity evaluation period at the full dose of each commercial agent and at a 600 mg BID dose of adagrasibThe TNO-155 combination dose escalation and expansion cohorts are ongoing at a 600 mg BID dose of adagrasibPreliminary efficacy data as of August 30, 2020 in patients with advanced NSCLC treated with adagrasib as a monotherapy at a 600 mg BID dose:

Patients had a median of two prior systemic treatments, including all patients receiving prior treatment with platinum-based chemotherapy regimens and 92% of patients receiving prior treatment with an anti-PD-1 /L1 inhibitorEfficacy data from pooled Phase 1/1b cohort and Phase 2 registration-enabling cohort (n=51):45% (23/51) confirmed objective response rate (ORR)70% (16/23) of responders had a best tumor response greater than 40%96% (49/51) disease control rate (DCR)3.6 months median duration of follow-up65% (33/51) of patients remain on treatment83% (19/23) of responders have not progressed and remain on treatmentEfficacy data from the Phase 1/1b cohort (n=14):43% (6/14) confirmed ORR100% (14/14) DCR8.2 months median duration of treatment50% (7/14) of patients remain on treatment83% (5/6) of responders remain in response and on treatment4 of 6 responders have a duration of treatment for >11 months and all 4 patients remain on treatmentPreliminary explorative correlative analysis of co-mutations of KRAS G12C and STK11 in advanced NSCLC showed a 64% (9/14) ORR across pooled Phase 1/1b and Phase 2 cohorts:Approximately 30% of all KRAS G12C mutant NSCLC patients have a STK11 co-occurring mutationCo-occurring KRAS and STK11 mutations have been shown to be significantly correlated with poor clinical outcomes when treated with immunotherapy and platinum-based chemotherapy regimensIn a case study presented today from the ongoing clinical trial of adagrasib as a monotherapy, a heavily pre-treated NSCLC patient with an unirradiated, active brain metastases observed a 67% reduction in tumor volume including the disappearance of a metastatic brain lesion:Preclinical studies demonstrate dose-dependent brain and cerebrospinal fluid (CSF) exposureThe Phase 2 cohort of adagrasib as a monotherapy is currently enrolling additional NSCLC patients with active brain metastases to further explore this patient population which has a high unmet medical needIn a case study presented today from the ongoing clinical trial of adagrasib in combination with TNO-155 (investigational SHP-2 inhibitor) in collaboration with Novartis, a heavily pre-treated NSCLC patient treated in the combination trial of adagrasib and TNO-155 (investigational SHP-2 inhibitor) observed a 60% reduction in tumor volume:

Data was from a scan on August 24, 2020Prior therapy included treatment with a non-adagrasib monotherapy G12C direct inhibitor (with initial partial response followed by disease progression) and in combination with another SHP-2 inhibitor with chemotherapy (which was discontinued due to an adverse event)Preliminary efficacy data as of August 30, 2020 in heavily pretreated patients with advanced CRC treated with adagrasib as a monotherapy at a 600 mg BID dose:

Median of 4 prior systemic treatmentsEfficacy data from pooled Phase 1/1b and Phase 2 cohorts (n=18)17% (3/18) confirmed ORR with 2 of 3 responders remaining on treatment94% (17/18) DCR67% (12/18) of patients remain on treatment55% (10/18) have a duration of treatment of >4 monthsPreliminary efficacy data as of August 30, 2020 in patients with advanced solid tumors, other than NSCLC and CRC, treated with adagrasib as a monotherapy at 600 mg BID dose from a Phase 1/1b cohort:

One patient each (n=4) with pancreatic, ovarian, endometrial and cholangiocarcinoma tumors were treated, and each patient had a confirmed partial response to therapy2 appendiceal cancer patients had stable diseaseAll 6 eligible patients remain on treatmentMRTX1133 Preclinical Summary

MRTX1133, the Company's potent, selective and reversible inhibitor of KRAS G12D, binds to and inhibits mutant KRAS protein in both its active and inactive states. MRTX1133 exhibits single digit nanomolar potency and is >1000-fold selective for KRAS G12D compared with wild-type KRAS in cellular assays. Based on preclinical analyses, MRTX1133 has a projected human half-life exceeding 50 hours and exhibits a low propensity for drug interactions or off-target pharmacology. MRTX1133 demonstrated tumor regression in multiple in vivo tumor models, including pancreatic and colorectal cancers.

"MRTX1133, a potential first-in-class compound, continues to advance toward an Investigational New Drug filing in the first half of 2021. The drug properties and antitumor activity we've observed in preclinical tumor models continue to show promise," said James G. Christensen, Ph.D., Executive Vice President and Chief Scientific Officer at Mirati. "MRTX1133 has a low predicted target plasma concentration, based on its potency and high unbound fraction, and our goal is to achieve near complete and sustained target inhibition and maximal anti-tumor activity. To ensure sustained therapeutic levels are achieved, we are pursuing both oral and parenteral routes of administration in parallel as we plan for a Phase 1 clinical trial and intend to select the route that results in the optimal KRAS G12D inhibition. We are driven by the opportunity to positively impact the lives of patients with KRAS mutant cancers who have limited treatment options."

ENA Presentations on Adagrasib Clinical Data:

Pasi A. Janne, M.D., Ph.D., Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, Professor of Medicine, Harvard University and the Scientific Director of the Belfer Center for Applied Cancer Science, presented updated data for adagrasib in NSCLC patients from MRTX849-001. The presentation is titled, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation" (LBA-03).

Melissa L. Johnson, M.D., Associate Director of the Lung Cancer Research Program at Sarah Cannon Research Institute and Partner, Tennessee Oncology, PLLC, presented updated data for adagrasib in other solid tumors harboring a KRAS G12C mutation from MRTX849-001. The presentation is titled, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors Harboring a KRAS G12C Mutation" (LBA-04).

"It's an inspiring and exciting time in the oncology field to see potential targeted therapeutic options for patients with the KRAS G12C mutation, a patient population that has historically faced limited treatment options. The clinical outcomes presented today, including the depth and maturing duration of responses in non-small cell lung cancer, colorectal cancers, and other solid tumors, along with the overall favorable safety profile, are highly encouraging," said Dr. Pasi Jnne.

Virtual Investor Event

Mirati will host a virtual investor event on October 25, 2020, at 1:30 p.m. PT/4:30 p.m. ET. Company executives will provide an overview of the adagrasib clinical data presented at the EORTC-NCI-AACR conference and share initial preclinical data for MRTX1133, the Company's KRAS G12D selective inhibitor.

Investors and the general public are invited to listen to a live webcast of the event through the "Investors" section of the Mirati corporate website at http://ir.mirati.com/events-and-presentations. Materials related to the webcast will be available at the same website prior to the event. A replay of the event will be available shortly after the conclusion of the event.