Melanoma's Progress, Persistent Gaps, and the Toxicity Criteria That Needed to Change: Igor Puzanov, MD

Immunotherapy has transformed melanoma care, with annual US melanoma deaths falling from approximately 15,000 to around 7700, says Igor Puzanov, MD, MSCI, FACP, senior vice president of clinical investigation at Roswell Park Comprehensive Cancer Center, in an interview with The American Journal of Managed Care^® for the 2026 annual meeting of the American Society of Clinical Oncology. Puzanov, who has worked in early-phase melanoma drug development since 2005, is clear-eyed about what remains unsolved.

The EMT Problem: When Tumors Go Invisible

The most pressing unanswered question in melanoma, as Puzanov frames it, is not resistance in general but a specific biological phenomenon when a subset of tumors undergo epithelial-mesenchymal transition (EMT) and adopt stem-cell-like properties and primitive neural characteristics that render them largely invisible to the immune system. These tumors are not destroyed by checkpoint inhibitors because the very process of transformation strips the cell-surface markers that T cells use to recognize and attack them, which is a biologic parallel to how stem cells protect themselves from immune clearance.

The clinical significance extends beyond melanoma. Gastrointestinal malignancies have remained largely refractory to checkpoint therapy, except in specific biomarker-selected subgroups. Puzanov argues that if researchers can identify what drives EMT and reverse-engineer the transition, those same interventions could restore immune visibility in solid tumors that currently fail immunotherapy across oncology.

Updating CTCAE for the Immunotherapy Era

Puzanov also discusses the Common Terminology Criteria for Adverse Events (CTCAE), which was built for chemotherapy toxicity. Therefore, its grading schema does not map cleanly onto the distinct immune-related adverse events that checkpoint inhibitors generate. Puzanov and colleagues have worked to revise CTCAE grading criteria for immunotherapy-specific toxicities—an effort that has reached some consensus but remains incomplete in contested areas.

The highest-stakes example is immune checkpoint inhibitor–associated cardiotoxicity, which is rare, occurring in less than 1% of patients, but catastrophic when it does occur, as it carries a mortality rate of 30% to 50% if not identified and managed immediately and aggressively. Prospective trial evidence is difficult to generate because the event rate is too low, says Puzanov, and the cases are too geographically dispersed.

In the absence of randomized data, expert consensus recommendations now call for weekly troponin monitoring during the first 6 weeks of checkpoint therapy, since clinically symptomatic cardiotoxicity typically represents severe myocardial damage that is harder to reverse once symptoms emerge. Early detection through biomarker surveillance is the only available lever for improving outcomes in this rare but high-lethality complication.