Updated results from the KRYSTAL-7 Phase 2 study evaluating adagrasib (Krazati®; previously known as MRTX849 being developed my Mirati Therapeutics*), an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C, combined with pembrolizumab (Keytruda®; Merck & Co/MSD) in patients for the treatment of first-line NSCLC harboring a KRASG12C mutation at the European Society of Medical Oncology Congress (ESMO 2023).

The data demonstrates a manageable safety profile and early signs of durability of adagrasib in combination with a checkpoint inhibitor in the first-line NSCLC setting.

Clinical Results

  • In patients with PD-L1 TPS ≥50%, adagrasib and pembrolizumab demonstrated an overall response rate (ORR) of 63% and disease control rate (DCR) of 84% and promising early signs of durability. The 63% confirmed response rate compares favorably to pembrolizumab monotherapy which has demonstrated an ORR of 39-45%.1,2
  • A median progression free survival has not been reached at 10.1 months median follow up.
  • The safety profile of the adagrasib and pembrolizumab combination was consistent with either agent as monotherapy, with a low rate of treatment related adverse events (TRAEs) leading to discontinuation of both drugs in only 4% of patients.
  • Treatment related hepatic events occurred in <10% of patients and were predominantly low grade. No patients discontinued both adagrasib and pembrolizumab due to ALT/AST increase or hepatic-related TRAEs.

“The Data presented to date indicate that adagrasib prescribed following or in combination with immunotherapy offers a tolerable safety regimen for first-line NSCLC patients with a KRASG12C mutation,” said Marina C. Garassino, M.D., professor of medicine, UChicago Medicine. “Adagrasib is the only KRASG12C inhibitor to be feasibly combined concurrently or following immunotherapy with a well-managed hepatoxicity profile, and still exhibits positive efficacy signals.”

“We are pleased to see these significant findings, which further support the initiation of a global Phase 3 study evaluating the combination of adagrasib plus immunotherapy in the first-line setting for KRASG12C-mutated NSCLC with PD-L1 TPS ≥50% for the benefit of patients,” said Alan Sandler, M.D., chief medical officer, Mirati Therapeutics.

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“Potential combinability with an immunotherapy, in addition to encouraging clinical activity in other tumor types and demonstrated central nervous system (CNS) penetration, reinforces our confidence in the differentiation of adagrasib from other potential treatment options and the benefit it offers to patients,” Sandler added.

Mirati Therapeutics plans to initiate a Phase 3 clinical study to evaluate adagrasib in combination with pembrolizumab in the first line setting for KRASG12C-mutated NSCLC with PD-L1 TPS ≥50%. Initial patient enrollment is expected by year-end 2023.

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Note: *On October 8, 2023,  Bristol Myers Squibb (BMS) and Mirati Therapeutics announced that the two companies entered into a definitive merger agreement under which Bristol Myers Squibb has agreed to acquire Mirati for $58.00 per share in cash, for a total equity value of $4.8 billion.

Clinical trials
Phase 2 Trial of MRTX849 Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination in Patients With a KRAS G12C Mutation KRYSTAL-7

Highlights of Prescribing Information
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]

References
[1] Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4. PMID: 30955977.
[2] Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8. PMID: 27718847.

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

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