Could a combo treatment boost KRAS inhibitors in lung cancer?

Combining inhibitors of KRAS-G12C, mTOR and IGF1R can significantly shrink lung tumors in mice, scientists at the Francis Crick Institute have shown. (Miriam Molina-Arcas and Christopher Moore, Francis Crick Institute)

KRAS made a splash at this year’s American Society for Clinical Oncology annual meeting after Amgen’s early data for its first-to-clinic inhibitor AMG 510 triggered blockbuster chatter. Now one research team is suppressing two more tumor-related proteins, and it has early evidence that the combo could further increase KRAS inhibitors’ therapeutic effects in lung cancer.

Adding Novartis’ mTOR blocker Afinitor (everolimus) and Astellas’ investigational anti-IGF1R linsitinib to a KRAS-G12C inhibitor called ARS-1620, developed by Araxes Pharma's subsidiary Wellspring Biosciences, can significantly shrink lung tumors in mice and human cells in lab dishes, scientists from the Francis Crick Institute and The Institute of Cancer Research, London, reported in a study published in Science Translational Medicine. Wellspring inked a KRAS-G12C drug discovery and development pact with Johnson & Johnson's Janssen Biotech in 2013. The partnership's ARS-3248 was recently cleared by the FDA to start clinical testing.

Julian Downward and colleagues at Crick and ICR previously showed that combining the inhibition of the MEK enzyme and the IGF1R receptor could limit KRAS-driven lung cancer cell growth. Hoping to further improve the result, the team screened 16,019 genes to identify pathways that could be blocked to provide additional benefits.

Inhibition of mTOR emerged as a winner. In their subsequent tests in non-small cell lung cancer cell lines, the researchers found that a regimen that combines Novartis’ FDA-approved MEK inhibitor Mekinist (trametinib), Afinitor and linsitinib significantly reduced cell growth for longer period of time and led to enhanced cell death as compared to double-drug combinations. The triplet also reduced tumor progression better than the double combos in mouse models of KRAS-mutated lung tumor.

However, previous attempts to combine MEK and mTOR inhibitors were ruled out due to unacceptable adverse effects. So the scientists replaced the MEK inhibitor with a direct KRAS inhibitor ARS-1620.

“Tumors treated with the combination shrank and stayed small, whereas those treated with the G12C KRAS inhibitor alone tended to shrink at first but then start growing again after a couple of weeks,” Downward, the study’s senior author, said in a statement. The triple combinations using either ARS-1620 or Mekinist showed similar results, the researchers said in the study.

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Mutation at G12C is the most common KRAS abnormality in lung cancer, accounting for about 16% of all lung adenocarcinomas. At ASCO in June, Amgen showed its AMG 510 drug, currently the furthest KRAS-G12C inhibitor in development, shrank tumors in five of the 10 evaluable NSCLC patients and kept the disease stable in another four in a phase 1 study. The results, while promising, were from a small trial, and the treatment duration was too short to show any survival benefit or risk of developing resistance.

Meanwhile, drug development efforts in blocking IGF1R and mTOR have hit setbacks. Clinical testing of linsitinib has mostly stopped after a phase 3 flop in adrenocortical carcinoma in 2015. Last year, AstraZeneca also capped its own mTOR drug vistusertib as a monotherapy in solid tumors and in combination with Calquence for blood cancers. Merrimack Pharmaceuticals ditched its IGF-1R-HER3 bispecific antibody MM-141 after a midphase trial failure in pancreatic cancer.

Downward’s team believes the current study provides a new way to improve the effectiveness of targeting mutated KRAS proteins, which are linked to more aggressive disease. “This provides a clear direction for how better to use KRAS-G12C inhibitors in the clinic and how to attempt to circumvent the likely evolution of resistance to them when used as single agents,” the authors argue in the study.

Editor's Note: The story has been updated to include information about Wellspring Biosciences and its KRAS-G12C agreement with Janssen.