Doubling Down on Immunotherapy in Advanced Melanoma

Almost 30% of patients with advanced melanoma that progressed on prior checkpoint inhibition responded to pembrolizumab (Keytruda) plus low-dose ipilimumab (Yervoy), according to updated findings from a prospective trial.

Overall, 20 of 70 patients had objective responses to the combination, including five complete responses. Median duration of response was 16.6 months, and the cohort had a median overall survival (OS) exceeding 2 years.

Responses occurred in multiple tumor phenotypes, and duration of prior anti-PD-1/L1 treatment did not influence likelihood of response to pembrolizumab and ipilimumab, reported Jason J. Luke, MD, of the UPMC Hillman Cancer Center in Pittsburgh, and co-authors in the Journal of Clinical Oncology.

“The combination of pembrolizumab plus low-dose ipilimumab demonstrated significant antitumor activity and tolerability in a multicenter clinical trial,” they concluded. “This study demonstrated long-term responses, suggesting that durable survival — a hallmark of immunotherapy activity — may be possible even after failure of an anti-PD-1/L1 antibody. These findings warrant further investigation and support the ongoing effort to directly compare combination of anti-PD-1 and anti-CTLA-4 antibodies with ipilimumab in the anti-PD-1/L1 antibody-refractory setting.”

Checkpoint inhibitors (primarily anti-PD-1/L1 and anti-CTLA-4) have revolutionized treatment for advanced melanoma, providing durable responses for a substantial fraction of patients. However, patients whose disease progresses during or after checkpoint inhibition have few treatment options and a poor prognosis. No prospective trials had evaluated ipilimumab alone or in combination with an anti-PD-1/L1 inhibitor in that setting, the authors noted.

A retrospective study of ipilimumab following pembrolizumab failure showed a response rate of about 15%. A more recent retrospective analysis of 355 patients showed response rates of 13% with ipilimumab and 32% with ipilimumab plus an anti-PD-1/L1 antibody.

The retrospective data provided a rationale for a prospective evaluation of the pembrolizumab-ipilimumab combination in patients whose disease had progressed on anti-PD-1/L1 therapy. Luke and co-authors reported findings from a phase II trial evaluating the combination in 70 patients who received standard-dose pembrolizumab and low-dose (1 mg/kg) ipilimumab. An initial report from the study showed that eight of 17 patients responded.

The published update included results for the entire 70-patient cohort. The median time on prior anti-PD-1/L1 therapy was 4.8 months. The authors reported that 60 patients had progressed during treatment with a PD-1/L1 inhibitor, and 10 progressed on treatment with an anti-PD-1/L1 combination. The results showed an objective response rate of 29% with the combination of ipilimumab and pembrolizumab. Three additional patients had unconfirmed responses.

Among 66 patients with archival tissue, responses occurred in 15 of 39 (38%) PD-L1-negative tumors as compared with four of 27 (15%) PD-L1-positive tumors.

Median progression-free survival was 5.0 months for the entire cohort, and median OS was 24.7 months.

Treatment-related adverse events (TRAEs) occurred in 62 of 70 patients, the most common being pruritis, rash, diarrhea, fatigue, nausea, and transaminase elevations. Grade ≥3 TRAEs occurred in 27% of patients, led by colitis/diarrhea, rash, and transaminase elevations. The only grade 4 TRAE was concurrent lipase elevation in a patient with grade 3 pancreatitis.

Following a presentation at the 2020 American Society of Clinical Oncology annual meeting, invited discussant Douglas B. Johnson, MD, of Vanderbilt University Medical Center in Nashville, found the response rate impressive, given the patient population, and the tolerability profile favorable. An upfront combination also appeared superior to sequential treatment with a PD-1/L1 inhibitor and ipilimumab, he added.

In response to the published findings, Johnson told MedPage Today via email, “This is an important study that prospectively shows that adding ipilimumab to anti-PD-1, even after failure of anti-PD-1 alone, can be a very active treatment regimen for patients in need of good options.”