On May 26, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported positive results from the registration-enabling Phase 2 cohort of the KRYSTAL-1 study evaluating adagrasib 600 mg BID in patients with non-small cell lung cancer (NSCLC) harboring the KRASG12C mutation who have received at least one prior systemic therapy (Press release, Mirati, MAY 26, 2022, View Source [SID1234615094]). Findings will be presented on June 3 at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, as an oral presentation during the "Lung Cancer – Non-Small Cell Metastatic" session from 2:24 to 2:36 PM ET/ 1:24 to 1:36 PM CT (Abstract #9002).

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Summary of Clinical Results from Phase 2 Registration-Enabling Study
As of October 15, 2021, 116 patients were enrolled and treated in the study. Of the patients enrolled, 98% had prior treatment with a PD-1/L1 inhibitor following or in combination with chemotherapy. Median follow up was 12.9 months.
Of the patients evaluable for response (n=112), initial results showed that the objective response rate (ORR) by Blinded Independent Central Review (BICR) was 43%, the disease control rate (DCR) was 80%, the median duration of response (DOR) was 8.5 months (95% confidence interval [CI]: 6.2 – 13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI: 4.7 – 8.4).
With a January 15, 2022 data cutoff, the median overall survival (OS) was 12.6 months (95% CI: 9.2 – 19.2).
The safety profile of adagrasib in this study was consistent with prior reports and no new safety signals were observed. The most frequent treatment related adverse events (TRAEs) included gastrointestinal events and fatigue. The majority of TRAEs were Grade 1–2 (53%) with Grade 3–4 TRAEs observed in 43% of patients. Two Grade 5 TRAEs were observed. TRAEs led to discontinuation of therapy in only 7% of patients.
"The positive and encouraging data from this trial further support the scientific rationale for targeting the KRASG12C mutation with adagrasib, which fully and continually inhibits mutant KRASG12C throughout the entire dosing period," says Alexander I. Spira, M.D., Ph.D., FACP, Co-Director, Virginia Cancer Specialists Research Institute. "This important dataset demonstrates positive clinical activity with adagrasib across molecular and clinical subgroups, including patients with treated and stable CNS metastases."

The Company also presented results from an exploratory, retrospective subgroup analysis from the Phase 2 NSCLC cohort of the KRYSTAL-1 study evaluating adagrasib in patients with KRASG12C-mutated NSCLC and stable, previously treated central nervous system (CNS) metastases (n=33). These results showed CNS-specific activity, including a 33% intracranial (IC) ORR by response assessment in neuro-oncology-brain metastases (modified RANO-BM). The IC DCR was 85% (95% CI: 68 – 95).

"The exploratory, retrospective subgroup analysis of adagrasib in patients with stable and previously treated CNS metastases showed intracranial tumor regression," added Dr. Spira. "These data are encouraging and contribute to the rapidly advancing science seeking to better understand how KRASG12C inhibitors like adagrasib can help improve patient outcomes."

Updated Findings from Pooled Analysis of KRYSTAL-1 NSCLC Cohorts
In addition to these results, the Company reported updated findings from a pooled analysis in a total of 132 patients from the KRYSTAL-1 study, including the registrational Phase 2 and Phase 1/1b NSCLC cohorts evaluating adagrasib at a dose of 600mg BID.

As of October 15, 2021, results from this pooled analysis showed an ORR of 44% and a disease control rate of 81% based on central independent review. The median DOR was 12.5 months and the median PFS was 6.9 months. With a January 15, 2022 data cutoff, (median duration of follow-up of 15.9 months) the median OS was 14.1 months. The safety and tolerability profile was consistent with the above reported findings for adagrasib in patients with advanced NSCLC. The Company plans to present full results from this pooled analysis at a future medical congress.

"The data from the registrational lung cancer cohort of KRYSTAL-1, including the clinical activity shown in patients with stable, previously treated CNS metastases, further support adagrasib’s unique profile," says Charles M. Baum, M.D., Ph.D., president, founder and head of research and development, Mirati Therapeutics, Inc. "Mirati is at the forefront of KRAS research, and we are pleased with the meaningfully positive clinical outcomes patients are experiencing with adagrasib, both in previously treated lung cancer and in other tumor settings."

On June 6, 2022, during an oral presentation at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting, the Company will present new, late-breaking results from the Phase 1b cohort of the KRYSTAL-1 study evaluating adagrasib in active, untreated CNS metastases (Abstract #LBA9009).

The adagrasib New Drug Application is currently being reviewed by the U.S. Food and Drug Administration (FDA) for Accelerated Approval (Subpart H) as a treatment for patients with NSCLC harboring the KRASG12C mutation who have received at least one prior systemic therapy. Adagrasib has also received Breakthrough Therapy Designation status from the FDA for the same indication. The Company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel who have been previously treated for metastatic NSCLC with a KRASG12C mutation.

Virtual Investor Event
Mirati Therapeutics will host an Investor Event on Monday, June 6, 2022, at 8:00 PM ET/7:00 PM CT.

Company executives will provide an overview of the adagrasib clinical data presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting and the Company’s broader lung cancer strategy, including in earlier lines of therapy.

Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

Central Nervous System (CNS) Metastases in KRAS-Mutated Lung Cancer
The brain, along with the bone, adrenals, and liver are common sites of extra-thoracic metastases in NSCLC.[1]−3 CNS metastases occur in 27−42% of patients with KRASG12C-mutated NSCLC at diagnosis.1,4−6 Additionally, patients with CNS metastases and KRAS-mutated NSCLC may have poor outcomes, with median overall survival (OS) of approximately five months.7-9

About Adagrasib (MRTX849)
Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24–48 hours. Adagrasib is being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.

Mirati has an Expanded Access Program (EAP) for investigational adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, including patients with treated or untreated CNS metastases, in the U.S. Learn more about the EAP at Mirati.com/expanded-access-policy.