HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.
Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.
In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).
A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.
The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).
It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.
He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.
However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.
"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.
In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).
At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.
Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.
"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.
He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.
Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).
Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."
Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.