'Undruggable' oncogene inhibited in promising cancer trial

A novel agent that targets a mutated form of the KRAS gene — the most commonly altered oncogene in human cancers and one long considered ‘undruggable’ — shrank tumours in most patients in a clinical trial with manageable side effects, according to a study reported at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The KRYSTAL-1 (NCT03785249) phase I/II trial tested the agent, adagrasib (MRTX849), in patients with non-small lung cancer (NSCLC), colorectal cancer and other solid tumours such as pancreatic, endometrial and ovarian cancer. Adagrasib targets a KRAS mutation called G12C, which is associated with a poor prognosis and lack of response to standard treatments. The mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC, 3–4% of colorectal cancers and 2% of pancreatic cancers.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its ability to send cell-growth signals and leading to cancer cell death. Until recently no KRAS inhibitor had moved beyond preclinical testing, but in 2018 adagrasib was among several KRAS inhibitors approved by the US FDA for study in clinical trials.

Dr Pasi A Jänne, Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, reported that of 51 patients with NSCLC participating in the KRYSTAL-1 phase I/II trial, 45% had an objective response, meaning their tumours shrank by 30% or more and did not grow or spread to other parts of the body. The disease control rate was 96%, meaning that 49 of the patients had a partial or complete response or stable disease.

Among the 14 patients in the phase I/Ib cohort who had been followed for a longer period of time (median time of 9.6 months), an objective response was seen in six (43%). Five of these six patients were still in ongoing treatment as of the cut-off date, with four of these six patients on the treatment for more than 11 months.

“KRAS G12C patients are a population for which there are no proven targeted therapies,” said Dr Jänne. “Once chemotherapy or immune therapy fails in a patient, treatment options are limited.

“The fact that we are seeing responses in 45% of patients with adagrasib is incredibly meaningful, as it opens up the possibility of a new treatment option for this subset of lung cancer patients.”

Of 18 patients with colorectal cancer who could be evaluated, three (17%) had a confirmed objective response and two of them continue to receive treatment. Disease control was seen in 17 of the patients (94%) and 12 of these patients continue to be treated, including 10 of 18 patients on treatment for greater than four months.

Among the six patients with other solid tumours who could be evaluated, a partial response was confirmed in one patient each with endometrial cancer, pancreatic cancer, ovarian cancer and cancer of the bile duct (cholangiocarcinoma). Two appendiceal cancer patients who were treated achieved stable disease. All six patients remain on the treatment.

The researchers are also looking at combining adagrasib with other targeted therapies, such as pembrolizumab for NSCLC, cetuximab for colon cancer, investigational SHP-2 inhibitor, TNO-155, in either NCSLC or colon cancer and afatinib for NSCLC.

Image credit: ©stock.adobe.com/au/royaltystockphoto

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