Nivolumab Shows Durable Response in Heavily Pre-treated Patients with Advanced Melanoma

Nivolumab continues to show an impressive response that is both prompt and durable in patients with advanced melanoma, according to updated results from a long-term follow-up presented at the 11th International Congress of the Society for Melanoma Research on November 15, 2014.

“The median follow-up is 55 months, which represents the longest follow-up of an anti-PD-1 agent done to date,” commented F. Stephen Hodi MD, Dana-Farber Cancer, Boston, USA.

Dr Hodi opened the afternoon Immunotherapy Session by presenting an analysis of data from patients with advanced melanoma participating in a Phase I trial of nivolumab, which is a fully humanized IgG4, monoclonal antibody targeting the PD-1 immune checkpoint inhibitor that is expressed on a range of solid tumors, including up to 40% of metastatic melanoma tumors.

PD-1 expression is upregulated by gamma interferon and suppresses the patient’s immune response by binding to the CD8 molecule on T-cells, according to Dr. Hodi. Nivolumab restores the immune response that is dulled by PD-1 expression.

The trial comprised 107 patients that were ipilimumab (Yervoy)-naïve. Iplimumab also has immune response modulating activity. However, all patients had received previous treatment for melanoma and one-fourth had received up to three or more prior therapies.

The patient median age was 61 years, and nearly all (97%) patients had an ECOG performance status of 0 to 1. Patients were randomized to nivolumab at doses of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg.

Differences in response were observed at the different dose levels; the overall objective response rate (ORR) by RECIST criteria was 32% compared to 41% in patients receiving the 0.3 mg/kg dose.

“The 0.3 mg/kg dose is the one we have put through to the 3 ongoing phase III trials,” said Dr Hodi.

Both overall survival (OS) and progression-free survival (PFS) were prolonged in 17 patients receiving the 3 mg dose compared to the overall cohort of 107 patients. In the 3 mg cohort, median OS was 20 months compared to 17 months in the all dose levels cohort. The median PFS was 10 months versus 10 months in the 3 mg and overall groups, respectively. PFS at 48 and 96 weeks was achieved by 48% and 24% of patients receiving 3 mg nivolumab verses 38% and 29% of patients overall.

“The durability of response is remarkable,” commented Dr Hodi, who noted that, among the 34 overall responders, 19 (56%) patients are maintaining an ongoing response to date.

In all, 21 responders discontinued therapy for reasons other than progressive disease; of these, 11 (52%) patients showed a response for at least 24 weeks, and 7 (64%) patients remained in response for 24 to 56 weeks after discontinuing therapy.

Response to nivolumab was also rapid with 44% of all responding patients demonstrating response as early as 8 weeks, at the first tumor evaluation. The investigators also evaluated OS by type of response and found that patients with partial or complete response by RECIST had similar OS outcomes as patients with immune related-type responses.

Evaluation of PD-1 expression in archival tumor samples taken prior to treatment using the BMS/Dako immunohistochemistry assay showed that PD-L1 positive patients, defined as expression of 5% or greater, associated with more favorable outcome in 41 of the 107 patients with available tumor samples; ORR for 18 patients with PD-L1 positive tumors was 44% compared to 13 % in 23 patients who did not showed elevated PD-L1 expression. In PDL-1 expression positive and negative groups, the median OS were not reached and 13 months and the median PFS was 9 months and 2 months, respectively.

Nivolumab was well-tolerated and showed a safety profile in this trial that was consistent with previous reports.

“Nivolumab monotherapy demonstrated long-term survival that the compares favorable with the current standard of care agents and showed responses that occurred early and were durable, even after discontinuation of therapy,” Dr Hodi summarized.

Funding from Bristol-Meyers, Squibb and Ono Pharmaceuticals was reported.