Conference Coverage

Sotorasib is a ‘triumph of drug discovery’ in cancer



KRAS, one of the most frequently mutated oncogenes in human cancer, has long been thought to be “undruggable,” but early results from a clinical trial of the experimental KRAS inhibitor sotorasib (Amgen) suggest that at least one KRAS mutation common in non–small cell lung cancers (NSCLC) has a soft underbelly.

In the phase 1 CodeBreaK 100 trial, sotorasib, an investigational first-in-class inhibitor of the KRAS p.G12C mutation, showed encouraging activity against advanced NSCLC and other solid tumors.

Among patients with NSCLC, 19 (32.2%) of 59 had a confirmed objective response to sotorasib monotherapy, and 52 (88.1%) had disease control, reported David S. Hong, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“Sotorasib also demonstrated durable disease control in heavily pretreated patients with non–small cell lung cancer,” said Dr. Hong.

He presented secondary efficacy endpoint results from the trial in an online presentation during the European Society of Medical Oncology Virtual Congress 2020. The study was also published simultaneously online in the New England Journal of Medicine.

The trial met its primary endpoint of safety of sotorasib, with no dose-limiting toxicities or treatment-related fatal adverse events, and treatment-emergent grade 3 or higher adverse events occurring in less than 20% of patients.

“The safety profile is more favorable than that of other targeted agents, and I think the reason why you have a quite safe compound here is that sotorasib is very specific in its binding to KRAS G12C, and KRAS G12C is only present in the tumor,” coinvestigator Marwan G. Fakih, MD, a medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said in an interview. Fakih was co–lead author of the report in the New England Journal of Medicine.

A real “triumph”

Sotorasib is “a triumph of drug discovery,” commented Colin Lindsay, MD, from the University of Manchester (England), the invited discussant.

“We know that KRAS, over many years, over 3 decades, has been very difficult to target,” he said.

“The early development of KRAS G12C–targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach,” write Patricia M. LoRusso, DO, from the Yale Cancer Center in New Haven, Conn., and Judith S. Sebolt-Leopold, PhD, from the University of Michigan Rogel Cancer Center, Ann Arbor, in an accompanying editorial.

The KRAS, which stands for Kristen rat sarcoma viral oncogene homologue, p.G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form. The mutation has been identified in approximately 13% of NSCLC tumors, in 1% to 7% of colorectal cancers, and in other solid tumors.

But the mutation has been considered too difficult to target because of KRAS’ strong binding affinity for guanosine triphosphate (GTP), an essential building block of RNA synthesis, and by a lack of accessible drug binding sites.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form, Dr. Fakih explained.


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