p100 Vaccination Prior to IL-2 Improves Response Rates, Progression-free Survival in Advanced Melanoma

gp100 Vaccination Prior to IL-2 Improves Response Rates, Progression-free Survival in Advanced Melanoma


In what Discussant Antoni Ribas, MD, of the University of California, Los Angeles, characterized as “a rare positive study” in the field of metastatic melanoma, a multi-institutional phase III trial has demonstrated substantial improvements in overall response rate (ORR) and progression-free survival (PFS) in patients treated with the investigational peptide gp100:209-217(210M) prior to high-dose interleukin-2 (IL-2) compared with those treated with high-dose IL-2 monotherapy.

Although the primary endpoint (ORR) and one secondary endpoint (PFS) were achieved, the other secondary endpoint — overall survival (OS) — was not, leaving open the question of whether the trial justifies adopting this therapeutic strategy as a practice standard.

Among 86 evaluable patients randomly assigned to receive tandem therapy and 91 treated with only IL-2, ORR favored dual treatment by 22.1% to 9.7% (p = 0.022), according to investigator assessment. A recent independent radiologic assessment reduced the rates (18.6% vs. 6.5%) but confirmed the significance (p = 0.013). The ORR was most pronounced among patients with pulmonary metastases.

Dual treatment also was associated with 2.9 months of PFS compared with 1.6 months for IL-2 monotherapy (p = 0.010). Although there was a trend toward improved OS with peptide plus IL-2 (17.6 months vs. 12.8 months), it did not achieve statistical significance.

Historical comparisons of the gp100 vaccine strategy date back to 1998, when the Surgery Branch of the National Cancer Institute (NCI) reported a 42% response rate to gp100 followed by high-dose IL-2 in a small phase II study. In subsequent small phase II trials using gp100 plus IL-2 on varying schedules, response rates ranged from 12.5% to 23.8%. Data from the current trial, presented by Douglas Schwartzentruber, MD, of the Goshen Center for Cancer Care, during Saturday’s Melanoma Oral Abstract Session (CRA9011) affirmed the response rate to tandem treatment from phase II trials and demonstrated the superiority of tandem peptide plus high-dose IL-2 therapy in a head-to-head prospective phase III comparison of ORR and PFS.

The trial enrolled patients with measurable stage III locally advanced melanoma or stage IV M1a, M1b, and M1c disease. Patients were stratified by cutaneous/subcutaneous disease and involvement of other sites. Because the peptide used is specific for HLA-A0201 disease, this was an entry requirement. Exclusion criteria included brain metastases, illness precluding IL-2 treatment, and prior exposure to IL-2 and/or gp100.

Underlying the tandem therapy approach is the assumption that vaccine induces antitumor T cells and that IL-2 induces T-cell proliferation and sensitizes them to tumor antigen, thus modulating the immune response. The modification of gp100 at the second site is thought to improve immunogenicity. In the two trial arms, intravenous IL-2 was given on the same schedule and at the same dosage. The gp100 peptide was administered in Montanide ISA 51 subcutaneously in the treatment group only.

Because of the inconclusive results for OS, further clinical investigation of this strategy is warranted. However, it took 7 years to accrue the requisite population for confirming efficacy measured by ORR and PFS, leading Dr. Ribas to conclude that it is “uncertain that anyone will want to undertake a confirmatory phase III trial for OS.” Thus, although this trial produced a positive outcome, it cannot be considered definitive, and the future of this tandem strategy remains uncertain.

Figure: Progression-free survival rates

Figure: Overall response.