Immunotherapy, Targeted Therapy Efficacy in Melanoma, and Managing Toxicities

Surgery had long been the only real treatment option for melanoma, but new therapies have significantly improved outcomes, explained speakers at an Institute for Value-Based Medicine® event cohosted by The American Journal of Managed Care® and Minnesota Oncology.

Melanoma is more prevalent in Minnesota than the rest of the country: the disease ranks as the third-most common malignancy in both males and females in Minnesota,¹ but it is the fifth-most common malignancy in the country.²

Thomas Amatruda, MD

Over the last 15 years, systemic therapy with immunotherapy and targeted therapies have significantly improved outcomes, explained Thomas Amatruda, MD, medical oncologist, Minnesota Oncology. There are options for treatment in the adjuvant, neoadjuvant, and metastatic settings, and current trials are exploring how to combine immunotherapies and targeted therapies for improved outcomes.

Anti–PD-1, anti–PD-L1, and anti–CTLA-4 antibodies can be used alone or in combination, but while combinations are more effective, they have higher toxicities. The good news is that the longer a patient goes without their disease recurring, the lower the likelihood of recurrence happening at all. There’s an 80% likelihood that a patient who achieves a complete response will stay in remissions for at least 4 years when their immunotherapy is stopped. Patients who are not in remission tend to progress when therapy stops, Amatruda explained.

Targeted therapies for BRAF are available for patients who can’t take immunotherapies. Each BRAF inhibitor available has different toxicities, but all are about equally effective with approximately a 12-month progression-free survival, he said.

But which should be used first?

The DREAMseq trial³ was stopped early because patients on immunotherapy first had a longer survival by 2 years compared with those who started on a BRAF inhibitor first.

In practice, most people use immunotherapy first, Amatruda said. The toxicity of BRAF inhibitors is one reason, but also, they tend to have a higher risk of recurrence in the third and fourth years if they are stopped. While there haven’t been specific studies looking into it, the thought is that immunotherapies give more durable responses.

Lisa Kottschade, APRN, CNP

Image Credit: Mayo Clinic

The toxicities with immunotherapies were hard to get a handle on initially, though. When chemotherapy is stopped, patients get better after a few days. But when they introduced immunotherapies, specifically ipilimumab, patients continued to get worse even after stopping the therapy, said Lisa Kottschade, APRN, CNP, FAPO, president of the Advanced Practitioner Society for Hematology and Oncology, and chief operations officer for the Midwest Melanoma Partnership.

While some of the adverse events (AEs) can be mild and moderate, some can be very severe and fatal, she said. Immune-related AEs (irAEs) occur in 15% of patients on nivolumab, 20% of patients on ipilimumab, and more than half (53%) of patients on a combination of the 2 therapies, Kottschade said.

These irAEs commonly involve the skin, gastrointestinal tract, liver, and endocrine system, and certain populations have a higher risk of developing irAEs. Among these patients at higher risk are those with a history of autoimmune conditions, but these patients are also excluded from trials of immune checkpoint inhibitors (ICIs), so there aren’t a lot of data on how to manage them.

“Patients who may have an autoimmune condition but aren't on chronic immunosuppression, high dose steroids, [or] biologics, we generally will consider treating these patients with ICI therapy,” Kottschade said. “Based on some retrospective series, their response rates may be a bit lower.”

References

1. Online Report to the Minnesota Legislature: Fiscal Year 2023. Minnesota Department of Health website. Updated April 12, 2023. Accessed October 19, 2023. https://www.health.state.mn.us/data/mcrs/cancerinmn.html

2. Lewis KG. Trends in pediatric melanoma mortality in the United States, 1968 through 2004. Dermatol Surg. 2008;34(2):152-159. doi:10.1111/j.1524-4725.2007.34032.x

3. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763