Phase 3 Trial Launches for Keytruda, MK-1084 in KRAS-Mutant NSCLC

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A clinical trial has started to evaluate the investigational drug MK-1084 and Keytruda among some patients with metastatic non-small cell lung cancer.

Image of lungs with a tumor in the right lung.

The novel monotherapy, MK-1084, is being evaluated in a trial for patients with NSCLC who have KRAS G12C mutations.

A phase 3 clinical trial has been launched among patients with previously untreated metastatic non-small cell lung cancer (NSCLC). The trial includes patients with tumors harboring KRAS G12C mutations and PL-L1 expression to be treated with Keytruda (pembrolizumab) and the investigational drug MK-1084, the manufacturer, Merck, has announced.

The trial will enroll approximately 600 patients, and it is estimated to be completed in February of 2031, according to the trial’s listing on clinicaltrials.gov.

MK-1084, an oral selective KRAS G12C inhibitor, according to the National Cancer Institute, “selectively targets the KRAS G12C mutant and inhibits KRAS G12C-mediated signaling. This may halt proliferation and metastasis in susceptible tumor cells,” while Keytruda, Merck noted in the announcement of the trial’s initiation, increases the body’s ability to detect and fight cancer cells.

“KRAS is among the most prevalent mutations in cancer and KRAS G12C is the most common KRAS mutation in patients with non-small cell lung cancer,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in the news release. “Based on early evidence showing MK-1084 in combination with Keytruda had a manageable safety profile and promising anti-tumor activity, we are now proceeding to a larger phase 3 trial to evaluate this combination in certain patients with metastatic non-small cell lung cancer.”

Previously untreated patients participating in the multicenter trial will receive daily MK-1084 plus Keytruda once every three weeks or Keytruda plus placebo, according to Merck.

Merck noted that the primary endpoints of the trial (the main result measured at the end of a study to see if a given treatment worked) will be progression-free survival (how long a patient lives following treatment without their disease spreading or worsening) and overall survival (how long a patient lives following treatment, regardless of disease status), with key secondary endpoints of objective response rate (the percentage of patients whose disease responded partially or completely to treatment) and duration of response.

LEARN MORE: ‘There’s a Lot of Innovation’ in the KRAS-Mutant Lung Cancer Space

In a previous phase 1 study, preliminary results of which were presented at the European Society for Medical Oncology Congress 2023, MK-1084 was evaluated as a stand-alone therapy for patients with advanced, solid tumors with KRAS G12C mutations and in combination with Keytruda as a first-line treatment for metastatic non-small cell lung cancer.

Researchers stated that MK-1084 as a monotherapy and in combination with Keytruda demonstrated “manageable safety and preliminary antitumor activity in patients with previously treated solid malignancies and previously untreated NSCLC whose tumors harbored KRAS G12C mutations.”

Side effects of any cause occurred in 84% of the MK-1084 monotherapy group and 87% of the MK-1084 and Keytruda combination group, with no side effects leading to treatment discontinuation. Treatment-related side effects occurred in 51% and 73% of patients, respectively, and all were grades 1 or 2 except for one patient in the monotherapy arm with grade 3 increased blood alkaline phosphatase (a potential indicator of liver or bone disease) and two patients in the combination arm with grade 3 pruritus (itching), rash and papular rash.

The objective response rate (patients whose disease responded partially or completely to treatment) was 19% in the monotherapy arm and 47% in the combination arm, researchers reported. The study is estimated to be completed in August of 2026, according to clinicaltrials.gov.

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