Phase 3 Randomized Double‑Blind Study of MK‑1084 + Durvalumab vs Placebo + Durvalumab in Locally Advanced KRAS G12C‑Mutant Unresectable NSCLC Post‑Chemoradiotherapy

The primary objective is to compare the combination of MK-1084 and durvalumab with placebo plus durvalumab for improvement in progression‑free survival as assessed by RECIST 1.1 using blinded independent central review in participants with locally advanced, unresected KRAS G12C‑mutant non‑small cell lung cancer who have not progressed after definitive platinum‑based chemoradiotherapy.

Secondary objectives include: - Evaluation of the effect on overall survival; - Assessment of safety and tolerability of the investigational regimen; - Determination of objective response rate and duration of response per RECIST 1.1 by blinded independent central review; - Measurement of distant metastasis‑free survival as judged by the investigator; - Analysis of the mean change from baseline in global health status/quality of life, physical functioning, and role functioning.

The trial enrolled 258 participants diagnosed with locally advanced, unresected Stage II–III non‑small cell lung cancer harboring a KRAS G12C mutation. Both male and female patients were included, representing an adult population across a broad age spectrum. Eligibility required a histological or cytological confirmation of predominantly nonsquamous NSCLC, completion of definitive platinum‑based concurrent chemoradiotherapy without disease progression, and provision of tumor tissue for central testing of KRAS G12C and PD‑L1 status. Additional criteria stipulated a body weight of at least 35 kg and, for individuals with viral infections, well‑controlled HIV on antiretroviral therapy, undetectable hepatitis B viral load with antiviral treatment, or undetectable hepatitis C viral load. General health status was otherwise unrestricted, and no specific dietary, physical‑activity, or other lifestyle restrictions were imposed for enrollment.

The study is a Phase III, randomized, double‑blind, placebo‑ and active‑comparator‑controlled trial evaluating the efficacy of MK‑1084 in combination with durvalumab versus placebo plus durvalumab in participants with locally advanced, unresected Stage II‑III non‑small cell lung cancer harboring a KRAS G12C mutation who have completed definitive platinum‑based concurrent chemoradiotherapy without disease progression. Eligible subjects undergo a screening visit to confirm histologic diagnosis, KRAS G12C status, PD‑L1 expression, and other inclusion criteria; those meeting all requirements are randomized to receive either oral MK‑1084 (film‑coated tablet) plus intravenous durvalumab 1500 mg or matching placebo plus durvalumab. Following randomization, participants attend scheduled follow‑up visits for safety monitoring, radiographic assessment of progression‑free survival per RECIST 1.1 by blinded independent central review, and collection of secondary endpoint data, culminating in an end‑of‑study visit after treatment discontinuation or study completion. Participant involvement extends from the screening encounter through the final assessment, encompassing the overall trial period projected from July 2026 to July 2037. Early discontinuation may occur in accordance with protocol‑specified criteria, such as withdrawal, unacceptable toxicity, or other reasons defined by the investigators.

MK-1084 is supplied as a film‑coated tablet for oral use. The tablet contains the active substance mk‑1084 at a concentration of 0 % (v/v). Administration is performed according to the study protocol, with each dose taken by mouth. Compliance with oral dosing is monitored by pill count and patient diary entries.

Durvalumab is provided in the pharmaceutical form PHF00230MIG for intravenous infusion. The prescribed dose is 1500 mg per infusion. Infusions are administered according to the study schedule, and infusion records are used to verify adherence.

The placebo for MK-1084 contains no active substance and is presented to match the appearance of the MK-1084 tablet. It is administered orally using the same schedule as the active tablet, and compliance is tracked in the same manner as for MK-1084.

The efficacy assessment will focus on the primary endpoint of Progression-Free Survival and multiple secondary endpoints, including Overall Survival, Objective Response Rate, Duration of Response, Distant Metastasis‑Free Survival, and changes from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‑Core 30 (EORTC QLQ‑C30) Global Health Status/Quality of Life combined score, Physical Functioning combined score, and Role Functioning combined score.

Progression‑Free Survival and tumor response parameters (Objective Response Rate, Duration of Response, Distant Metastasis‑Free Survival) will be evaluated according to RECIST 1.1 criteria by a blinded independent central review. Overall Survival will be measured as the time from randomization to death from any cause. Quality‑of‑life outcomes will be captured using the EORTC QLQ‑C30 instrument, with specified item combinations calculated to generate the respective scores. All efficacy data will be analyzed using appropriate time‑to‑event and proportion analyses as defined in the statistical analysis plan.