Targeted therapy with adagrasib in addition to immunotherapy with pembrolizumab for advanced lung cancer with the KRAS G12C mutation

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. In some people, a change in the KRAS gene—known as the KRAS G12C mutation—is found. This mutation causes cancer cells to continuously receive growth signals and multiply uncontrollably. Standard treatments for advanced NSCLC often include immunotherapies such as pembrolizumab, chemotherapy, or combinations of these. Pembrolizumab (KEYTRUDA®) helps the immune system better recognize and attack cancer cells. Adagrasib (MRTX849) is a targeted therapy that specifically blocks the KRAS G12C mutation and is designed to slow tumor growth. Pembrolizumab is administered as an intravenous infusion, while adagrasib can be taken orally in tablet form.

The goal of this Phase 2/3 study is to investigate the efficacy of the combination of adagrasib and pembrolizumab compared to pembrolizumab monotherapy. The study consists of a Phase 2 and a Phase 3 portion. In Phase 2 of the study, researchers will investigate how effective adagrasib is—either alone or in combination with pembrolizumab—and how well-tolerated the treatments are. To this end, patients will be divided into three cohorts. Patients with low PD-L1 expression are randomly assigned to receive either adagrasib alone or the combination of adagrasib and pembrolizumab. PD-L1 is a surface protein on cancer cells that plays a role in suppressing the immune system. Patients with higher PD-L1 expression will receive the combination therapy. In Phase 3 of the study, the combination of adagrasib and pembrolizumab will be directly compared with pembrolizumab alone in patients with a KRAS G12C mutation and high PD-L1 expression. The study will examine whether the combination therapy is more effective, how well it is tolerated, how long the disease remains under control, and what impact the treatment has on quality of life. The study is open-label, which means that both the patients and the treating physicians know which therapy is being administered. The primary objective of the study is to determine whether the combination therapy can delay disease progression and improve survival.

Patients with advanced or metastatic NSCLC with a KRAS G12C mutation who have not yet received any drug treatment for their advanced disease are eligible to participate. Patients with active or certain untreated brain metastases, brainstem involvement, frequent seizures, or neurological symptoms caused by brain metastases are not eligible to participate in the study. Also excluded are individuals who require higher doses of corticosteroids due to brain metastases or who have received high-dose radiation to the lungs within the last six months.