AMG 510 First to Inhibit “Undruggable” KRAS

Amgen's novel small-molecule inhibitor AMG 510 has become the first drug to show activity in patients with KRAS^G12C-mutant solid tumors. In a phase I trial, AMG 510 elicited partial responses in half of patients with non–small cell lung cancer (NSCLC) and led to stable disease in patients with colorectal or appendix cancer. The striking results were presented at the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL, in June (J Clin Oncol 37, 2019 [suppl; abstr 3003]).

“This is a population of patients that has not had targeted therapies, and the fact that they're now potentially being included in that approach is really a remarkable thing,” said Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute/Harvard Cancer Center in Boston, MA, who was not involved in the trial.

KRAS alterations are the most prevalent oncogenic driver mutations in cancer. However, researchers have long considered KRAS undruggable due to its small size and relatively smooth surface—with few deep pockets where molecules can bind—as well as how rapidly and tightly it binds to GTP in its active state. AMG 510 binds to KRAS^G12C via the cysteine amino acid that replaces glycine when the mutation occurs, locking it in an inactive state. “This mutation occurs in approximately 13% of patients with NSCLC, and approximately 3% of colorectal and appendix, and 1% to 3% of other solid tumors,” said Marwan Fakih, MD, of City of Hope Comprehensive Cancer Center in Duarte, CA, who presented the results.

Researchers enrolled 35 patients with KRAS^G12C-mutant solid tumors who had received at least two prior therapies in the trial: 14 patients with NSCLC, 19 with colorectal cancer, and two with appendix cancer. Five of 10 evaluable patients with NSCLC who received AMG 510 had a partial response and are still being treated; four more experienced stable disease. Additionally, 14 of 18 evaluable patients with colorectal or appendix cancer had stable disease. Adverse events were mild, mostly classified as grade 1 and 2.

“This is the clinical proof-of-concept that you can target KRAS^G12C, and you can get a clinical response, but even bigger than that is the potential impact here,” Jänne said, noting that 40% of patients with KRAS-mutant NSCLC have a KRAS^G12C mutation. “I think that the fact that you're seeing five responses here is pretty stunning, actually.”

Kwok-Kin Wong, MD, PhD, of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center in New York, NY, who was also not involved in the trial, agreed. “I think this is an amazing day for targeted therapy,” he said. However, Wong wants to know the duration of response, pointing out that, as with other targeted therapies, patients will likely develop resistance. “The future is trying to figure out what combinations would give you a durable response,” he said.

Wong also wants to know why patients with NSCLC responded better than those with colorectal cancer, as well as how patients with other KRAS-mutant malignancies, such as pancreatic cancer, might respond.

Amgen is not the only company pursuing targeted therapies for KRAS mutations: Mirati Therapeutics is conducting a phase I trial on its KRAS^G12C inhibitor, MRTX849, and Dicerna is developing a therapy that targets KRAS^G12D, the most common KRAS mutation. –Catherine Caruso

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