Therapy offers hope for advanced melanoma

Nivolumab , a newly developed checkpoint protein inhibitory antibody directed against programmed death-1, or PD-1, with significant clinical activity against melanoma, can treat other malignancies outside of melanoma and renal cell carcinoma, which is one of the big advances with the treatment, according to Jeffrey Weber M.D., Ph.D., senior member of the H. Lee Moffitt Cancer Center, and director, Donald A. Adam Comprehensive Melanoma Research Center in Tampa Bay, Fla.

"For the first time, it shows activity/benefit in cancers like non small-cell lung cancer," Dr. Weber says in an interview with Dermatology Times. "It is very effective in melanoma, but it appears to have efficacy in other histologies."

Another progressive step with the administration of nivolumab is that it is producing responses in patients who have not experienced success with ipilimumab therapy, Dr. Weber points out.

"Patients who were previously treated with multiple regimens, including those who failed ipilimumab, which is the established immunotherapy, had benefit," Dr. Weber says.

In a phase I study of 90 patients with unresectable stage III or IV melanoma, nivolumab, administered with or without a vaccine, was well-tolerated and induced responses lasting up to 140 weeks.¹

"Our goal is to enrich the response rate," Dr. Weber says. "It is now one out of three  (patients who respond). If we can increase the response rate to two out of three, it would save a lot of healthcare dollars."

Dr. Weber notes that there was no difference between patients in the study who were administered the vaccine and those who were not, pointing out that the vaccine was intended as an immunological marker and not a therapeutic intervention.

Predictive biomarkers

To increase the response rate, Dr. Weber and colleagues are on the hunt for appropriate biomarkers that would assist in predicting response.

"We noticed that high pre-treatment myeloid suppressor cell levels were associated with poor outcomes," Dr. Weber explains.

"Another important point is that we didn't see the same toxicity that occurred with the use of ipilimumab,” he says. “You can safely administer the PD1 inhibitor with a patient who had toxicity with ipilimumab, even if it was severe. There is not really any cross-reactive toxicity."

The most recent data from the second line Phase III trial CA209-037, which evaluated nivolumab compared to dacarbazine or carboplatin/paclitaxel in patients with unresectable or metastatic melanoma who had been previously treated, suggest greater responses (32% vs. 11%) favouring nivolumab. A complete response was seen in 3% of nivolumab patients and 0% of chemotherapy patients.

Of 405 patients, 272 received nivolumab, and the balance received chemotherapy. The co-primary endpoints of the investigation were objective response rates in the first 120 subjects assessed after at least 24 weeks of follow-up, and overall survival. Of 38 who did respond, 36 continued to respond at six months, with most responders to the monoclonal antibody still in remission.

Investigators also found grade 3/4 adverse events were much more frequent in the chemotherapy arm compared to the nivolumab arm (31% vs. 9%).

Overall data on survival are pending but the Phase III data that have emerged should definitively exclude single-agent chemotherapy as an option for treating advanced melanoma, according to Dr. Weber.

Toxicity of nivolumab

Patients taking agents such as nivolumab, may rarely develop serious dermatological toxicities, according to a medical oncologist involved in clinical  trials where the therapy has been administered.

"When a patient gets a serious rash, the clinician has to make an executive decision about whether to hold the drug or continue the drug," says Dr. Weber, adding that PD-1 antibody is given every other week in most trials.

Skin eruptions that develop with the use of nivolumab and would be classified as grade one or two will likely improve with symptomatic treatment and topical steroid therapy, but patients can experience significant eruptions and rashes, according to Dr. Weber.

"The key issue is that you can sometimes see significant skin toxicities with nivolumab, with patients developing erythematous eruptions on sites like the chest, belt line, and groin," Dr. Weber says.

"Medical oncologists will be helped by their dermatologist colleagues in these situations," Dr. Weber says. "If medical oncologists are concerned with allergic eruptions or eruptions to the drug, they (dermatologists) can be helpful with the management of these (toxicities)."

Indeed, because many immunological agents produce skin manifestations, it's worthwhile for dermatologists to be aware of the latest immunological therapies, Dr. Weber says.

Toxic epidermal necrolysis

One of the rare but possible skin complications with immunotherapy occurs with the use of ipilimumab, another immune checkpoint inhibitor, and is the development of toxic epidermal necrolysis.

"It occurs in fewer than one in 1,000 patients," Dr. Weber says. "If you see that, it is a real problem. It is very rare, but you have to recognize when it is an issue."

Dr. Weber has received honoraria from Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab.Dr. Weber has received honoraria from Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab.

1 Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31(34):4311-8.