Kirsten rat sarcoma (KRAS)G12C mutations occur in 3%-4% of cases of colorectal cancer and are a negative predictor of cetuximab (Erbitux®; Lilly & Co/Merck KGaA) efficacy. MRTX849 (Adagrasib; Mirati Therapeutics) is a 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. [1]

MRTX849 irreversibly and selectively binds KRASG12C, locking it in its inactive state. The drug was optimized for favorable PK properties, including a long half-life (∼24 hours). Durable inhibition of KRASG12C may be particularly important in CRC due to signaling pathways that create a susceptibility to feedback reactivation of KRAS. EGFR signaling is implicated in this reactivation, providing a rational co-targeting strategy for KRAS-mutant CRC.

The investigational agent is investigated in KRYSTAL–1, an open-label Phase 1/2 multiple expansion cohort trials evaluating MRTX849 as monotherapy and in combination with other anticancer therapies in patients with advanced solid tumors harboring a KRASG12C mutation.

KRYSTAL–1 is a multicohort Phase 1/2 study evaluating MRTX849 (adagrasib)in patients with KRASG12C -mutant advanced solid tumors. CRC cohorts include MRTX849 600 mg BID monotherapy (Phase 1/2) and MRTX849 600 mg BID + cetuximab 400 mg/m2 followed by 250 mg/m2 QW; or 500 mg/m2 Q2W (Phase 1b). Endpoints include safety, PK, and clinical activity.

Interim results
Results from a cohort of the Phase 1/2 KRYSTAL–1 study evaluating the investigational agent MRTX849 at the 600mg BID dose as both monotherapy and in combination with cetuximab in patients with heavily pretreated colorectal cancer harboring a KRASG12C mutation, showed that MRTX849 alone and with cetuximab demonstrated significant clinical activity and broad disease control in these patients.

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The findings (Abstract # LBA6) were presented as a late-breaking oral presentation during the Presidential Symposium II session at the European Society for Medical Oncology Congress (ESMO) 2021.

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“Patients living with KRAS-mutated colorectal cancer face a significant medical need for new treatment options,” said Jared Weiss M.D., lead study investigator and associate professor of medicine, division of oncology at University of North Carolina-Chapel Hill.

“The positive results presented today show that MRTX849 alone or in combination with cetuximab may improve clinical outcomes in patients with colorectal cancer harboring a KRASG12C mutation.”

Clinical Results
As of May 25, 2021, 80% of patients enrolled in the MRTX849 monotherapy arm (n=46) received at least two prior lines of systemic anticancer therapies, and had a median follow-up of 8.9 months. Of the evaluable patients (n=45), results showed an investigator-assessed response rate (RR) of 22%, including one unconfirmed partial response (PR), and a disease control rate (DCR) of 87%; the median duration of response (DOR) was 4.2 months. In all enrolled patients, the median progression-free survival (PFS) was 5.6 months (95% Confidence Interval, CI: 4.1,8.3).

As of July 9, 2021, 90% of patients enrolled in the MRTX849 plus cetuximab arm (n=32) received at least two prior lines of systemic anticancer therapies and had a median follow-up of 7 months. Of the evaluable patients (n=28), results showed an investigator-assessed RR of 43%, including two unconfirmed PRs and a DCR rate of 100%. After the data cutoff date, of the two unconfirmed PRs, follow-up scans showed one patient had a confirmed PR, and the second patient progressed. At the time of the analysis, 63% (20/32) of enrolled patients remained on treatment.

MRTX849 monotherapy and in combination with cetuximab was well-tolerated in this study, with a manageable safety profile. Grade 3/4 treatment-related adverse events (TRAEs) were observed in 30% of patients treated with MRTX849 alone, and in 16% of patients treated with the combination. Treatment-related adverse events led to treatment discontinuation in 6% of patients who received combination therapy and in none (0%) of those who received MRTX849 monotherapy. No Grade 5 TRAEs were observed in either treatment arm.

“MRTX849 represents Mirati’s scientific commitment to the discovery and development of novel targets that may lead to new treatment options for people with cancer,” said Charles M. Baum, M.D., Ph.D., president and chief executive officer, Mirati Therapeutics.

“The results presented at ESMO support further study of MRTX849 in KRAS-mutated colon cancer, including with our ongoing, global registrational Phase 3 trial, KRYSTAL–10, comparing MRTX849 plus cetuximab to the standard of care chemotherapy in second-line KRASG12C-mutated colorectal cancer.”

Clinical trials
Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1 – (NCT03785249)

Highlights of prescribing information
Cetuximab (Erbitux®; Lilly & Co/Merck KGgA) – (Prescribing Information)

Reference
[1] Weiss J, Yaeger RD, Johnson ML, Spira A, Klempner SJ, Barve MA, Christensen JG, Chi A, Der-Torossian H, Velastegui K, Kheoh T, Ou SI. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. A Late-Breaking Abstract (LBA6) Presented during the 2021 ESMO Congress. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741

Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Photo Courtesy: European Society for Medical Oncology (ESMO). Used with Permission.

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