ASCO: Amgen's closely watched KRAS drug, first to clinic, shrinks NSCLC, curbs colorectal tumors

“AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” said David Reese, M.D., Amgen’s R&D chief. (Amirah Al Idrus)

CHICAGO—It’s been 30 years in the making, but the first clinical data from a KRAS inhibitor is finally here. In a small phase 1 study, Amgen’s prospect, AMG 510, stopped tumor growth in the majority of patients with non-small cell lung cancer (NSCLC) and colorectal cancer, shrinking the tumors of half of the lung cancer patients. 

The results, unveiled Monday at the annual meeting of the American Society of Clinical Oncology, follow data from a handful of patients that Amgen teased earlier this month. At the time, only 10 patients had been on the drug long enough to be evaluated. Now, the company is sharing how 32 patients fared on AMG 510. 

The study enrolled 35 patients with advanced KRAS-mutated cancers: 14 with NSCLC, 19 with colorectal cancer and two with cancer of the appendix. KRAS mutations turn up in up to one-quarter of all cancers, about 13% of NSCLC cases and up to 5% of colorectal cancers. Unlike patients with other mutations, such as HER2 or BRAF, patients with KRAS-mutated cancers still don’t have a treatment tailored to their mutation, largely due to the lack of obvious binding sites on the KRAS protein 

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“AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” said David Reese, M.D., Amgen’s R&D chief, in a statement. “By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state.” 

RELATED: Amgen posts early clinical data on closely watched KRAS drug

The study tested four doses of AMG 510, ranging from 180 mg to 960 mg, in patients whose tumors had spread despite having undergone at least two previous treatments. The drug shrank tumors in five of the 10 evaluable NSCLC patients and stopped tumor growth in another four, showing it could control the disease in 90% of patients. 

“These heavily pretreated patients have received multiple lines of therapy before, which makes their treatment more challenging,” Sanket Agrawal, general manager of the KRAS program at Amgen, told FierceBiotech. 

Without their own targeted therapy, patients with KRAS mutations are treated with the general standard of care: chemotherapy and sometimes, checkpoint inhibitors. Agrawal pegs the response rate for these difficult-to-treat patients at around 20%. 

As for the 18 evaluable colorectal cancer patients, 13 of them—nearly three-quarters—saw their tumors stop growing. But, Agrawal pointed out, these results come from patients who have been treated with the two lowest doses of AMG 510. The higher doses might do even better. 

“We have only treated one patient so far at the highest dose in colorectal. We haven’t treated enough patients to see what the response would be,” he said. “Stable disease in the earlier, lower-dose cohorts is encouraging.” 

RELATED: New insight into KRAS mutations may improve cancer drug development

Nine patients quit the study, mostly because their disease got worse, Agrawal said. Otherwise, AMG 510 looks to be well tolerated. Nearly 70% of the side effects were mild, and no serious treatment-related side effects were seen. Nor did the drug cause any dose-limiting toxicities, namely side effects serious enough to stop a patient from stepping up to a higher dose. 

In this study, Amgen tested AMG 510 as a single agent to be used after the patient has exhausted other treatments. But it’s looking to move earlier in the lines of treatment and plans to start a phase 1b study combining AMG 510 with checkpoint inhibitors. 

It’s a logical move, Agrawal said, as Amgen’s preclinical data from cell lines show that AMG 510 “appears to have what I would call an immune-priming effect.” The hope is to see this “synergistic effect” between AMG 510 and a checkpoint inhibitor in the clinic.

Editor's note: This story has been edited to update Sanket Agrawal's title.

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