Systemic Therapy in Metastatic Melanoma

Hodi and colleagues conducted a phase 3 trial of ipilimumab, including 676 patients who progressed after prior treatment for stage III or IV melanoma, and found that median OS was significantly better in the ipilimumab groups: 10 months in the ipilimumab plus gp100 peptide vaccine group vs 6.4 months in the gp100 vaccine alone group; 10.1 months in the ipilimumab alone group vs 6.4 months in the gp100 vaccine alone group. ¹³ In another phase 3 trial comparing ipilimumab plus dacarbazine to dacarbazine alone, the ipilimumab group had a significantly improved OS (11.2 months vs 9.1 months). ¹ Survival rates with ipilimumab were prolonged for up to 3 years compared with the dacarbazine plus placebo group. However, the combination was associated with increased incidence of hepatotoxicity, thereby limiting its use.

A long-term survival analysis of 10 prospective and 2 retrospective studies of ipilimumab showed a median OS of 11.4 months and a long-term survival that began at 3 years with a plateau at 10 years of 21%, which was independent of prior therapy or ipilimumab dose. ¹⁴ The immune-related AEs of ipilimumab are secondary to its activity against the host antigens and include dermatitis, enterocolitis, hepatitis, and endocrinopathies. ¹⁵

A recent phase 2 trial studied the combination of ipilimumab with granulocyte-macrophage colonystimulating factor in 245 patients with stage III and IV melanoma. Median OS after 13 months was significantly higher with the combination compared with ipilimumab alone. The 1-year survival rate was 69% with
the combination and 53% with ipilimumab alone. There was no difference in the overall response rate (ORR) or progression-free survival (PFS) between the 2 groups. However, the AEs were significantly reduced with the combination (45% vs 58%). ¹⁶ The dose of ipilimumab used in the trial was higher than the approved dose, making it difficult to apply the results in practice without further studies on the combination.

Anti-PD-1 Antibodies

Programmed death 1 ligands (PD-L1 and PD-L2) are expressed by tumor or stromal cells to inhibit the T-cell mediated antitumor activity. These ligands bind to the PD-1 protein on the surface of activated T cells to mediate their immunosuppressive effects. Interruption of this interaction by either anti-PD-1 antibodies or anti-PD-L1 antibodies facilitates tumor cell killing by activated T cells. ¹⁷

Pembrozilumab and nivolumab are the 2 anti-PD-1 monoclonal antibodies that have been approved for treatment of metastatic melanoma. In a phase 1 trial
of pembrolizumab, 411 patients with advanced melanoma (consisting of both ipilimumab-naïve [IPI-N] and ipilimumab-treated [IPI-T] patients), ORR was 40% in IPI-N and 28% in IPI-T patients with a 1-year OS of 71% in all patients. Median PFS was 24 weeks in IPI-N and 23 weeks in IPI-T pts. ¹⁸ There was no difference in outcomes and safety profiles across the various dosing regimens. ^18,19 Of note, pembrolizumab had antitumor activity irrespective of the PS, lactate dehydrogenase levels, BRAF (B-Raf proto-oncogene, serine/threonine kinase) gene mutation, metastatic stage, and number and type of prior therapy. In a subgroup analysis, 173 patients who had progression after treatment with ipilimumab were randomly assigned to pembrolizumab 2 mg/kg every 3 weeks (q3w) or 10 mg/kg q3w dosing regimens. Both groups had no significant difference in the ORR (26% in both) and safety profiles. ²⁰