Three PD-1 inhibitors are in midstage clinical development for metastatic melanoma and other solid tumors: nivolumab, pembrolizumab, and pidilizumab (PIDI). PIDI, also known as CT-011, is a humanized anti-PD-1 antibody that is being developed as a treatment for hematologic malignancies and solid tumors. Two phase 2 trials of PIDI in aggressive and indolent lymphomas, including a study in combination with rituxumab in follicular lymphoma, demonstrated clinical activity that correlated with PD-1 and PD-L1 expression on lymphocytes.1
Atkins and colleagues reported results of a phase 2 multicenter, randomized, open-label study to evaluate the safety and efficacy of PIDI in patients with metastatic melanoma (ASCO 2014; Abstract 9001). Eligibility criteria included measurable disease, clearly progressive metastatic disease, and at least 3 prior systemic therapies. Patients with stabilized brain metastases were allowed in the trial. Prior ipilimumab (IPI) was allowed, but prior treatment with PD-1, PD-L1, or PD-L2 inhibitors was precluded. Patients were randomized to 2 dose levels of PIDI: 1.5 mg/kg or 6 mg/kg every 2 weeks for 27 doses. Patients were stratified by PIDI dose and by prior IPI receipt.
A total of 103 patients with metastatic melanoma were randomized, including 75% high risk (M1c), 16% with stable brain metastases, 30% with elevated lactate dehydrogenase, and 33% with disease spread to 3 or more organs. Most (77%) had received prior systemic therapy for metastatic melanoma, including 51% prior IPI, 8% prior BRAF inhibitor, and 44% prior biologics (cytokines). Approximately half of the population (45%) had not responded to their most recent therapy.
In this trial, the objective response rate (ORR; using immune-related response criteria) associated with PIDI was 6%. The ORR increased to 10% among patients treated with 1.5 mg/kg PIDI who had received prior IPI. The rate of immune-related stable disease was higher among patients who had received prior IPI compared with IPI-naïve patients (54% vs 21%, respectively), and median progression-free survival was slightly longer (2.8 vs 1.9 months, respectively).
At 12 months, the overall survival (OS) rate with PIDI was 64.5% (90% confidence interval [CI], 56-72), with insignificant differences between PIDI doses, BRAF mutation status, and irrespective of therapies given before study entry or after study withdrawal. Among patients with M1c disease, 12-month OS was 67% (90% CI, 57-75).
The most frequent adverse events (AEs) observed with PIDI in this large phase 1 trial included fatigue (43%), diarrhea (23%), and arthralgia (21%). Serious AEs included pneumonia (5%) and dyspnea (3%).
Despite low response rates, PIDI therapy resulted in substantial 12-month survival in heavily pretreated patients with metastatic melanoma. The 12-month survival appears comparable to that of other anti-PD-1 antibodies in this patient population. Further studies of PIDI in patients with metastatic melanoma are warranted, preferably using higher doses or in combination with other therapeutics.
1. Westin JR, Chu F, Zhang M. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15(1):69-77.
