Yale Research Highlights Unmet Needs for Patients With Melanoma Who Progress or Relapse After Immunotherapy Treatment

A retrospective cohort study by Yale Cancer Center researchers of nearly 200 patients with melanoma who died after receiving treatment with immunotherapy highlights a need to improve outcomes for patients after the treatment.

The study of 183 patients with metastatic melanoma who died between 2009 and 2023 following immunotherapy treatment investigated sites of metastases at death in addition to settings and mechanisms of death.

“Notably, the associations identified between the sites of metastases and causes of death may inform management for patients with end-stage melanoma,” the study said.

Many factors concerning melanoma mortality are poorly understood, posing an obstacle to optimal care and the development of new treatment approaches. The study notes that despite the successes of immunotherapy in decreasing melanoma mortality, many patients continue to experience treatment resistance. The study, in describing factors associated with melanoma mortality, demonstrates the ongoing need for therapeutic advancements.

Primary authors of the study, published in Pigment Cell & Melanoma Research, are Daniel Y. Lee, MD, internal medicine resident, and Madeline McNamara, Yale School of Medicine student; senior author is Jeffrey Ishizuka, MD, DPhil, assistant professor, medical oncology, and PI of the Ishizuka Lab at Yale Cancer Center.

Melanoma is the deadliest skin cancer, claiming 57,000 lives annually worldwide. The advent of immune checkpoint inhibitors pushed the five-year overall survival among patients with metastatic melanoma from 5% to more than 50%, and novel immunotherapies for metastatic melanoma continue to be developed. But not everyone benefits from the treatment.

The study found that 87.9% of patients in the cohort who died with metastatic melanoma did so from melanoma-specific causes, paralleling findings in other studies. Even among the patients in the cohort who died more than five years after the diagnosis of metastatic disease, most deaths (76.2%) were attributable to melanoma.

“While the prognosis of patients with metastatic melanoma has dramatically improved, there remains an unmet need to improve outcomes for patients who progress or relapse after treatment with immunotherapy. Precise characterization of settings and mechanisms of death in this high-risk group may refine interventions and management for these patients,” Lee said.

The majority (53.0%) of patients received ipilimumab plus nivolumab as first line treatment, and 80.9% of patients received both anti-PD1 and anti-CTLA4 treatment at some point during treatment. Of the 35 patients who received only anti-PD1 during treatment, limitations to the use of combination therapy in subsequent treatment lines included rapid disease progression (37.1%), toxicity concerns due to comorbidities (31.4%), prior severe immune adverse related events (17.1%), patient choice (5.7%), clinical trial involvement (5.7%), and one patient with no evidence of disease who died of causes unrelated to melanoma. Of the 93 patients with stage II or III disease at diagnosis, 13 patients (7.1%) received adjuvant systemic therapy. A third of patients were enrolled in a clinical trial at some point in their care.

The majority (60.6%) of patients in the cohort were enrolled in hospice prior to death. As expected, patients with acute causes of death were less likely to be enrolled in hospice and more likely to die in the hospital. Still, 80.3% of patients experienced hospitalization prior to death.

“Our findings may further support the ongoing need of early palliative care support for patients with metastatic melanoma in the immunotherapy era,” Ishizuka said.

“Despite advances in treatment in the age of immunotherapy, most patients still died due to melanoma-specific causes, highlighting the ongoing need to refine management.”

While it’s critical to consider whether immunotherapy could be toxic to a patient, Dr. Ishizuka said that the disease, not the treatment, is the issue.

“The study identified death from immunotherapy-associated toxicity as a very rare, but important event, finding instead that the vast majority of patients died instead of melanoma-related causes,” he said.

Additional Yale authors include Alexander Yang, MD, internal medicine resident, Maxim Yaskolko, undergraduate research assistant, Harriet Kluger, MD, Harvey and Kate Cushing Professor of Medicine (Oncology) and professor of dermatology, Thuy Tran, MD, PhD, assistant professor of medicine (medical oncology), Kelly Olino, MD, assistant professor of surgery (oncology), James Clune, MD, associate professor of surgery (plastic), and Mario Sznol, MD, professor of medicine (medical oncology).