This is a randomized, open-label, active-controlled, parallel-group, multicenter study of JNJ-90301900 as radioenhancer in combination with chemoradiation followed by durvalumab for locally advanced and unresectable Stage IIIA and IIIB NSCLC (according to the Eighth Edition Lung Cancer Stage Classification).

A 3-arm randomized JNJ-90301900 dose optimization and proof-of-concept Part 2 (JNJ-90301900 at 22% and 33% GTV in Arms A and B, respectively, as an intratumoral radioenhancer added to cCRT followed by cIT compared with Arm C control treatment of cCRT only followed by cIT). Participants will be randomized 1:1:1 to experimental Arms A and B and control Arm C to evaluate the efficacy and safety of 2 dose levels of JNJ-90301900.

Intratumoral injection of a radioenhancer.

• Candidate for SOC treatment of study cancer by cCRT followed by consolidation durvalumab treatment as determined by the investigator and per local guidelines at screening.
• Life expectancy > 6 months
• Pathologically proved NSCLC within 3 months of randomization
• Locally advanced stage IIIA or IIIB
• At least one target lesion per RECIST 1.1 for intratumoral injection.
• At least 50% of gross tumor volume is accessible for injections (GTV max = 909 mL)

• History of uncontrolled illness
• Any of the following within 3 months prior to randomization: severe or unstable angina, myocardial infarction, major thromboembolic events, clinically significant ventricular arrhythmias or heart failure. Uncomplicated deep vein thrombosis is not considered exclusionary
• QTcF interval > 480 msec
• Other cancers within the last 36 months
• History of immunodeficiency or organ transplant with immunosuppression