A drug in early clinical development that targets an “undruggable” mutation in cancers has potential to join the growing class of therapies that treat cancers as genomic rather than tissue-specific diseases, a clinical trial investigator said.
Thousand Oaks, California-based Amgen plans to present Phase I data on the drug, AMG 510, at the American Society of Clinical Oncology meeting in Chicago next month. The drug targets KRAS G12C mutations, which are expressed in a variety of solid tumors – especially non-small cell lung cancer (NSCLC) and colorectal cancer – but have previously evaded drug therapies because their structure makes them difficult to inhibit. The oral presentation will include updates on data included in an abstract made public Wednesday that showed the drug, as a single agent, produced partial remissions in two NSCLC patients and stabilized the disease of six patients, including two with NSCLC and four with colorectal cancer.
“Any time you see responses with a targeted monotherapy drug, that is big,” said trial investigator Dr. Marwan Fakih, an oncologist at City of Hope in Duarte, California, said in a phone interview. The updated data at ASCO – which Fakih will present on June 3 – will include patients with NSCLC, colorectal cancer and a third cohort of patients who were enrolled regardless of tumor type, as long as it expressed a KRAS G12C mutation.
KRAS G12C is not the most common KRAS mutation – estimated to occur in 13 percent of lung cancers and 1-3 percent of other solid tumors – but Fakih said its particular configuration makes it more druggable than other KRAS mutations. Although KRAS plays a major role in cancers, RAS proteins in general have been seen as “undruggable” because they do not have pockets that drugs can effectively bind to.
Based on the results so far, it’s possible that AMG 510 could become tumor-agnostic, Fakih added. In other words, any patient with a solid tumor exhibiting a KRAS G12C mutation would be eligible to receive the drug, rather than it being limited to those with tumors affecting a particular tissue of the body. Other drugs with tumor-agnostic labels include Merck & Co.’s PD-1 inhibitor Keytruda (pembrolizumab), for microsatellite instability-high and mismatch repair-deficient tumors and also Eli Lilly & Co.’s Vitrakvi (larotrectinib), for NTRK fusion-positive solid tumors. The big question, Fakih said, is whether AMG 510 will be given as a monotherapy or in combination with certain drugs, and whether those combinations will be different based on tumor type.
Amgen spokeswoman Trish Hawkins noted in an email that the company is currently moving ahead with combining the drug with a PD-1 checkpoint inhibitor in its expansion study, based on preclinical data it presented at the American Association for Cancer Research conference earlier this year showing AMG 510 inflamed tumors and enhanced their sensitivity to checkpoint inhibitors.
Photo: Alaric DeArment, MedCity News