OBJECTIVES: Assessing drug “value” is typically based on the trade-off between its clinical benefit using quality-adjusted life-years (QALYs) relative to cost. Recently, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have proposed alternative frameworks to evaluate the value of oncology drugs. This analysis applies these frameworks vs traditional cost-effectiveness analysis to compare a new immuno-oncology (IO) therapy to chemotherapy in an ultra-rare tumor. METHODS: A survival partition model was developed using the approach proposed by the Institute for Clinical and Economic Review (ICER). Under the ASCO framework, net health benefit (NHB) scores between the IO agent vs chemotherapy were compared using survival, toxicity, and bonus points. NCCN Evidence Blocks of efficacy (E), safety (S), consistency (C), quality (Q) of evidence, and affordability (A) were assessed based on benchmarking to IO therapies in other indications and other therapies in the same indication. RESULTS: Under ICER, incremental life-years were estimated to be 0.74, with a corresponding increase in QALYs of 0.59, with most gains associated with pre-progression improvement in life-expectancy. Under ASCO, the incremental NHB was estimated to be 189, comprising 157 clinical benefit points, 12 toxicity points, and 20 bonus points for improved survival at the tail of the curve. Efficacy contributed to 94% of the NHB. Under NCCN, the IO therapy scored (E:5, S:4, Q:3, C:2, A:4). Chemotherapy scored lower on all domains apart from affordability (E:1, S:2, Q:2, C:3, A:4). CONCLUSIONS: ASCO and NCCN include oncology-specific measures important to patients, whereas ICER is payer focused. Overall, multiple or more holistic value assessments should be considered to capture the true value of an IO therapy in a rare disease space.