Conference Coverage

Adding low-dose ipi to pembro seems safer, still effective for advanced melanoma



Low-dose ipilimumab plus pembrolizumab given immediately after progression on a PD-1 antibody alone demonstrated antitumor activity and tolerability in patients with advanced melanoma in a phase 2 study, according to an investigator.

The investigator, Daniel Olson, MD, of the University of Chicago, presented the study results as part of the American Society of Clinical Oncology virtual scientific program.

Pembrolizumab plus ipilimumab at 1 mg/kg generated a response rate of 27%, Dr. Olson reported. This is higher than the 15% response rate observed in historical controls who received ipilimumab alone after primary PD-1 failure (Lancet Oncol. 2019 Sep;20[9]:1239-1251), he noted.

“Treatment-related grade 3 to 4 toxicity occurred in 27% of patients” in the current trial, Dr. Olson added. He said this compares favorably to ipilimumab given at 3 mg/kg in combination with a PD-1 antibody first line, which produced a grade 3/4 adverse event rate of 59% in a prior trial (N Engl J Med 2017; 377:1345-1356).

Preserving efficacy while limiting toxicity

“The combination of PD-1 and CTLA-4 blockade is an incredibly potent combination, not only in melanoma, but across cancer types,” said Douglas Johnson, MD, an assistant professor at Vanderbilt University in Nashville, Tenn., and the discussant on Dr. Olson’s presentation.

Dr. Johnson noted, however, that the combination produces a high incidence of serious immune-related adverse events.

The goal of recent research has been finding a way to preserve the efficacy but limit the toxicity. The tack taken in the current study was to wait until primary PD-1 antibody failure to initiate the combination, then do so with an ipilimumab dose lower than the standard 3 mg/kg used in melanoma.

“The response rate was quite good,” Dr. Johnson said. “I think these are very favorable results.”

“It does seem like the sequential approach does decrease the total number of toxicities compared to using both agents in the front line,” he added. “Should we use 1 mg/kg or 3 mg/kg [ipilimumab] in this sort of sequential-type approach? I would say, at this point, they’re still both viable.”

However, for “patients who really need an upfront response ... we might favor giving combination upfront,” Dr. Johnson said.

Patients and treatment

The trial (NCT02743819) enrolled 70 patients with unresectable or metastatic melanoma that had progressed on a PD-1 antibody after a median treatment duration of 4.8 months. Patients had no prior exposure to a CTLA4 antibody.

Prior to entry, 86% of subjects had been treated with a PD-1 antibody alone, 14% with a PD-1 antibody in a non-CTLA4 antibody combination, and 7% with BRAF-directed therapy prior to PD-1 antibody treatment.

The patients’ median age was 64 years, and 67% were men. Overall, 89% of subjects had cutaneous melanoma, 10% acral melanoma, and 1% mucosal melanoma.

Half of patients had stage IV M1c or M1d disease. Ten percent had treated brain metastases at baseline, 24% had liver metastases, 28% had baseline lactate dehydrogenase (LDH) above the upper limit of normal, and 29% had BRAF mutations.

The patients were treated with ipilimumab at 1 mg/kg every 3 weeks for four doses. They received pembrolizumab at 200 mg every 3 weeks for up to 2 years.


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