Combined Immunotherapies Show Promise in Metastatic Melanoma

The results of two studies indicate that combining antibodies against the programmed death 1 (PD-1) receptor with an antibody against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) improved treatment outcomes for patients with advanced melanoma, without a significant increase in adverse events.

Histopathologic image of malignant melanoma; source: KGH, Wikimedia Commons

The first study, led by Jedd D. Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center, looked at both sequential and concomitant treatment with the anti–PD-1 antibody nivolumab and ipilimumab.

The second study, led by Omid Hamid, MD, of the University of California, Los Angeles, looked at the anti–PD-1 antibody lambrolizumab in patients with advanced melanoma with or without prior treatment with the anti–CTLA-4 ipilimumab.

The results of the two studies, which were presented this year at the annual meeting of the American Society of Clinical Oncology (ASCO), were recently published in the New England Journal of Medicine.

“Escape from immune surveillance is a recognized feature of cancer; therefore, the development of therapies to enhance tumor immunity is a rational treatment strategy,” Dr. Wolchok and colleagues wrote. “Immune checkpoint blockade is one approach that has induced regressions in several types of cancer.”

Prior research has shown that CTLA-4 and PD-1 “appear to play complementary roles in regulating adaptive immunity.”

Therefore, in the study by Dr. Wolchok and colleagues, 53 patients were administered doses of nivolumab and ipilimumab every 3 weeks for four doses followed by nivolumab alone every 3 weeks for four doses, followed by combined treatment given every 12 weeks for up to eight doses. Thirty-three patients who had already received ipilimumab were administered nivolumab alone.

Patients in the concurrent group had an objective response rate of 40%, with 65% of all patients showing some level of clinical activity. Isolating data from patients who received the maximum tolerated dose of both drugs, 53% of patients had an objective response rate. The objective response rate for patients given sequential therapy was 20%.

In the study by Dr. Hamid and colleagues, 135 patients were given the anti–PD-1 lambrolizumab every 2 to 3 weeks with tumor response assessed every 12 weeks. Overall, 38% of patients had a confirmed response. Among those patients that received 10 mg/kg every 2 weeks, 52% of patients had a confirmed response.

The researchers observed no difference in patients treated with lambrolizumab who received prior ipilimumab and those who did not.

“Surprisingly and importantly, the use of ipilimumab and either one of two PD-1 monoclonal antibodies-whether the PD-1 and CTLA-4 antibodies were given sequentially or together-resulted in a rate and severity of adverse events that were no higher than those observed with the individual drugs alone,” James L. Riley, PhD, of the University of Pennsylvania, wrote in an editorial accompanying the studies.

Grade 3 or 4 adverse events occurred in 53% of patients who received concurrent nivolumab and ipilimumab, a frequency that the researchers said was similar to that seen with monotherapy. Only 13% of patients in the trial of lambrolizumab reported drug-related grade 3 or grade 4 adverse events.

“Moreover, in an age of personalized medicine, CTLA-4 and PD-1 antibody therapies appear to be rather impersonal-that is, not currently known to require a particular tumor or patient genotype to be effective,” Dr. Riley wrote. “The success of combining these two therapies opens the door to adding other immune modulators, including CD25 or CD40 antibodies, effective cancer vaccines, or conventional therapies that target tumor survival and growth.”