Background and Objective <p>Companion diagnostics (CDx) are critical to precision medicine. Developing and commercializing new CDx faces regulatory and economic challenges. This study aims to illustrate the utility of an early health technology assessment in quantifying the unmet clinical need and commercial opportunity created by the limited accuracy of existing programmed cell death ligand 1 CDx.</p> Methods <p>The study uses an early health technology assessment and market sizing to assess the potential value of a novel programmed cell death ligand 1 CDx for non-small cell lung cancer (NSCLC). Decision tree-based cost-effectiveness models were used to evaluate clinical and economic outcomes for improved programmed cell death ligand 1 testing in atezolizumab-treated patients with stage II–IIIA and metastatic NSCLC from a US payer perspective in 2023 US Dollars. Three strategies were examined: standard care, new CDx for cytology specimens only, and new CDx for all patients. Commercial opportunities from the perspectives of diagnostics and pharmaceutical manufacturers were assessed using headroom and threshold analyses.</p> Results <p>Headroom analyses indicated that a new CDx is not cost effective for metastatic NSCLC but holds significant value for stage II–IIIA NSCLC. Assuming perfect sensitivity and specificity, the incremental cost-effectiveness ratio for the new CDx in stage II–IIIA NSCLC was $57,650/quality-adjusted life-year and $54,950/quality-adjusted life-year for cytology specimens only and all patients, respectively. A threshold analysis showed that at a $500 price point, the new CDx is cost effective at sensitivity levels of 0.9 for all patients and 0.8 for cytology only. The total addressable US market for the CDx manufacturer was estimated at $2.6 million per year with a $500/test kit price.</p> Conclusions <p>A novel, highly accurate CDx for stage II–IIIA NSCLC could provide significant value to patients, payers, and manufacturers.</p>