Efficacy vs Toxicity With Immunotherapy

Treatment selection must carefully balance efficacy against toxicity profiles unique to each immunotherapy regimen. Atezolizumab-bevacizumab combines immunotherapy-related adverse events with VEGF-specific toxicities including proteinuria and hypertension, particularly concerning for long-term treatment. Dual checkpoint inhibitor regimens carry substantially higher frequencies and severity of immunotherapy-related adverse events, with more grade 3 to 4 toxicities than single-agent immunotherapy or atezolizumab-bevacizumab combinations.

Nivolumab-ipilimumab uses higher-dose ipilimumab (IPI3 NEVO1 regimen) given 4 times, compared with durvalumab-tremelimumab’s single CTLA4 dose, resulting in higher immune-related adverse event rates in CheckMate 9DW vs HIMALAYA. Yarchoan explains the rationale: a randomized phase 2 trial testing different ipilimumab-nivolumab combinations found the higher ipilimumab dose numerically associated with best survival, leading to its selection for phase 3 testing. While nearly 30% of patients experienced grade 3 to 4 immune-related adverse events, this rate remains lower than the response rate, providing meaningful clinical benefit despite toxicity risks.

Anti-CTLA4 therapy demonstrates remarkable activity in hepatocellular carcinoma (HCC). Single-agent PD-1 inhibitors achieve 13% to 18% response rates, while adding ipilimumab increases responses to 36%—nearly doubling the benefit. This substantial delta reflects CTLA4’s significant contribution, unusual among tumor types. The liver’s immunosuppressive microenvironment may explain this activity, as CTLA4 acts as a priming agent potentially overcoming impaired immune activation. Despite toxicity concerns, the meaningful efficacy gains justify anti-CTLA4 use, particularly for patients seeking long-term survival benefits and potentially curative outcomes that weren’t previously achievable with single-agent checkpoint inhibitors or tyrosine kinase inhibitors alone.