Cancer associated fibroblasts layer on tumor microenvironment
3D rendering of cancer-associated fibroblasts CAF layer on tumor microenvironment.[Marcin Klapczynski/Getty Images]

KRAS inhibitors made substantial progress this week as both Mirata (adagrasib for colorectal cancer) and Amgen (sotorasib for pancreatic cancer) shared positive trial results in the New England Journal of Medicine. Mirata also netted an FDA Breakthrough Therapy Designation (BTD) for adagrasib (KRAZATI) in combination with cetuximab in patients with KRASG12C-mutated, advanced colorectal cancer.

This BTD was based in part from results from the Phase Ib cohort of the KRYSTAL-1 trial, which appeared this week in NEJM. This Phase I/II study evaluated small molecule adagrasib (MDF849) as monotherapy or combined with cetuximab in patients KRAS positive metastatic colorectal cancer. The data showed promising clinical activity and demonstrated a favorable tolerability profile with reversible adverse events.

“Preclinical studies and early clinical data indicate that the combination of a KRAS inhibitor and an anti-EGFR antibody could be an effective strategy to mitigate EGFR reactivation,” said Rona Yaeger, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center and study author. “These results provide a strong rationale for continued development of this combination regimen.”

A Phase III trial evaluating adagrasib in combination with cetuximab in patients with KRASG12C-mutated colorectal cancer in the second line setting compared with standard chemotherapy is currently ongoing.

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) has long been one of cancer drug developers most enticing targets. The KRAS protein is part of a normal signaling pathway regulating growth and proliferation of cells, but activating mutations in KRAS drives abnormal growth in cancer. It is the most frequently mutated oncogene, occurring in a variety of tumor types. Approximately 90% of pancreatic tumors have KRAS mutations.

But targeting KRAS mutations with drugs is challenging due to the lack of classic drug binding sites. Researchers have explored routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. The introduction of KRAS (G12C) inhibitors have made a big difference. But despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors has been a key problem.

Referring to the sotorasib trial results, which also appeared in NEJM this week, David S. Hong, MD, said: “These are encouraging early data because they point toward establishing that KRAS inhibitors can work in pancreatic cancers, which have been difficult to crack from a targeted therapy standpoint,” Hong is the principal investigator of the trial and professor of Investigational Cancer Therapeutics at University of Texas. “We look forward to data from larger trials as we continue working to bring much-needed new therapies to these patients, he added.

Sotorasib is a small-molecule inhibitor that irreversibly binds the mutant KRAS G12C protein to lock it in an inactive state. In 2021, it was approved by the FDA for the treatment of KRAS G12C-mutated metastatic non-small cell lung cancer, based on previous data from another cohort of this study.

The pancreatic cancer cohort enrolled 38 patients with metastatic disease and a median of two prior lines of therapy. The median age of participants was 65.5, 76.3% were men and 55.3% had stage IV disease at initial diagnosis.

According to Hong, these results may be a harbinger of success for other drugs in the pipeline targeting mutant KRAS that could potentially benefit far greater numbers of patients.

“It’s gratifying to see results like this, since targeting mutant KRAS seemed virtually impossible just a few years ago. Still, we must continue our research efforts to make progress against other common KRAS mutations found in pancreatic and other cancer types,” Hong said. “Trials have recently begun on drugs targeting KRAS G12D, a much more common mutation in pancreatic cancer, as well as some pan-RAS therapies, which target multiple mutations.”

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