Discussing the melanoma studies at the Plenary Session, Kim Margolin, MD, of the University of Washington Fred Hutchinson Cancer Research Center in Seattle, noted that while the new therapies are welcomed, they are not without their challenges.

“Ipilimumab now shows a survival benefit in first-line therapy, compared with [dacarbazine]… Checkpoint blockade—ie, enhancement of autologous antitumor immune responses—works!” she noted.

“And vemurafenib, which is a transformation advance based on a rational approach to melanoma molecular biology, showed a survival benefit in the first-line setting as well,” she said. “Regression was seen in over 80% of patients. There was rapid relief of symptoms, median progression-free survival of 7 months, and an early survival benefit.”

She added that in other studies, for a subset of patients with progressive disease in limited sites, continuation of vemurafenib treatment beyond progression was shown to be potentially beneficial after local therapy.¹ Relapse may be different than in other therapies, she said.

Notable Toxicities

These treatments were not without side effects, however. Notable adverse events with ipilimumab are hepatotoxicity, endocrine abnormalities, and immune-mediated adverse reactions, for which ipilimumab already carries a “black box” warning. Grade 3/4 increases in liver enzymes were observed in approximately 20% of patients.

“In view of the increased hepatotoxicity with ipilimumab and dacarbazine in combination, and the lack of therapeutic advantage to the chemotherapy component, there is no reason to use these drugs together,” she noted.

With vemurafenib the problems include cutaneous toxicity, gastrointestinal upset, and arthralgias. Skin toxicities include hyperkeratotic follicular eruption, extreme sun sensitivity, tender calluses of the extremities, squamous cancers, and keratoacanthomas.

Optimizing Clinical Use

The issue in the clinic is how to best use these new agents, Dr. Margolin said. The BRAF inhibitor might be prescribed for immediate cytoreduction and symptom relief, or possibly as a bridge to other therapies, ie, surgery or radiotherapy, she suggested. In contrast, ipilimumab works at a slower pace and might be the first option for a patient with less tumor burden and fewer symptoms. “The goal is durable benefit,” she said. “Definitive progression would trigger a switch to vemurafenib.”

“Both agents require experience and commitment by the physician and patient to manage these unique toxicities,” she added.

Future investigations will evaluate the combination of vemurafenib and ipilimumab. ■

Financial Disclosure: Dr. Margolin reported no potential conflicts of interest.

Reference

1. Kim KB, Flaherty KT, Chapman PB, et al: Pattern and outcome of disease progression in phase I study of vemurafenib (RG7204) in patients with metastatic melanoma. 2011 ASCO Annual Meeting. Abstract 8519. Presented June 6, 2011.