Challenges in Conducting Clinical Research on Patients With Advanced Melanoma.

Unprecedented advances in the treatment of melanoma and the large number of investigational therapies entering clinical studies not only represent outstanding achievements, but also create major challenges for clinical research in melanoma. The challenges for accrual and for developing important new data in trials include the relatively low incidence of melanoma compared with other diseases, a shrinking pool of patients for trials because of the high efficacy of standard of care therapy, requirements for larger studies and longer duration of follow-up to detect signals of activity or establish efficacy, and suboptimal predictive biomarkers for the vast number of new combinations and new agents. The cost of new treatments remains a major concern, particularly because current standard of care involves doublets of targeted therapy or immune therapy, and clinically meaningful further increases in efficacy may require development of triplets or larger multidrug combinations. Toxicities of the current doublets, particularly for immune therapy, may limit development of some multidrug regimens or may require novel solutions such as sequencing or alternating schedules. The activity of first-line therapies may push development of new drugs or combinations into the second-line setting or into subgroups with suboptimal response to the first-line doublets as identified by predictive clinical variables or tissue biomarkers.