Emerging Approaches in Advanced Melanoma Include Progress in Adjuvant Therapy, Novel Vaccines

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Emerging approaches in advanced melanoma include adjuvant targeted therapy/immunotherapy, new immunotherapy treatment algorithms, and novel vaccines. The progress on each was reviewed by presenters at the 2015 World Cutaneous Malignancies Congress.

State-of-the-Art Adjuvant Therapy
Despite advancements in progression-free survival (PFS) in treatment-naive unresectable melanoma with the use of targeted agents and immunotherapy, “we still need ways to prevent and delay development of metastatic disease,” said Vernon K. Sondak, MD.

Adjuvant interferon alpha at various doses and for various durations has improved relapse-free survival in almost every study, with a median 17% improvement in disease-free survival (P <.00001) (Cochrane Database Syst Rev. 2013;6:CD008955). Delaying recurrence with high-dose interferon for 1 year translates into a significantly improved 2-year overall survival (OS) (Cancer. 2006;106:1431-1442). Improving survival at 2 years may allow patients to benefit from further advancements in approved therapies for melanoma, which are coming at a rapid pace, said Sondak, Chair, Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL. Toxicity with high-dose interferon is high, and treatment duration is 1 year in the adjuvant setting, so alternatives are desired, he said.

Adjuvant peginterferon alpha-2b for stage III melanoma had a slightly positive benefit versus observation on recurrence-free survival (RFS) (J Clin Oncol. 2012;30:3810-3818), but biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin (IL)-2, and interferon alpha-2b given for 3 months significantly improved RFS, but not OS, and with more toxicity compared with interferon alpha-2b alone given for 1 year (J Clin Oncol. 2014;32:3771-3778). A Cochrane review demonstrated an improvement in OS of 9% with adjuvant interferon (P = .003) compared with observation (Cochrane Syst Rev. 2013;6:CD008955).

Ipilimumab improved OS compared with placebo (P = .003) in patients with previously treated stage IV melanoma (N Engl J Med. 2010;363:711-723). Three years of adjuvant ipilimumab improved RFS from 34.8% in the placebo group to 46.5% in the active treatment group (P = .0013), but with a substantial increase in grade 3 immune-related adverse events and 5 deaths resulting from the drug-related adverse events (Lancet Oncol. 2015;16:522-530).

A clinical trial is comparing ipilimumab at 2 dosages (10 or 3 mg/kg) with high-dose interferon alpha-2b in the adjuvant setting, with OS as the end point. Several studies are also under way using BRAF inhibitors alone or in combination with MEK inhibitors, but toxicity and resistance are major concerns potentially limiting this approach, said Sondak. Results from these trials are not anticipated for several years.

The use of programmed death-1 (PD-1) inhibitors as adjuvant therapy is also being tested in clinical trials with nivolumab and pembrolizumab, but accrual for these trials will take several years.

Immunotherapy Update

The current status of immunotherapy in advanced melanoma was reviewed by Steven O’Day, MD, Director of Immuno-Oncology at Providence St. John’s Health Center, Santa Monica, CA.

At present, first-line immunotherapy is preferred in advanced melanoma, and PD-1 inhibition has been shown superior to cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition. Phase 2 studies show 2-year OS rates of 29% to 42% with ipilimumab.

“We now know that at least 1 immuno-oncology agent, ipilimumab, induces long-term survival in some patients [in advanced melanoma],” said O’Day. Three-year OS from a meta-analysis of >4000 patients treated with ipilimumab was 21%, and some patients were still alive at 5 and even 10 years (Eur J Cancer. 2013;49[suppl 2]. Abstract 24LBA).

Responses with ipilimumab are durable, he said, but immune toxicities are prevalent. Management of grade 3/4 toxicity may require use of high-dose steroids or discontinuation of ipilimumab.

Other inhibitors of the PD-1 immune checkpoint include nivolumab and pembrolizumab, which target PD-1, and the investigational MEDI4736 and MPDL3280A, which are engineered human IgG1 molecules that target the PD-1 ligand PD-L1.

Nivolumab monotherapy improved OS as first-line therapy compared with chemotherapy, with a median duration of response of 22 months at the 3-mg/kg dose. In the CheckMate 003 trial, median OS was 17.3 months with nivolumab in patients with previously treated advanced, unresectable melanoma (J Clin Oncol. 2014;32[suppl]. Abstract 9002). Sixty-five percent of patients in CheckMate 003 had prior immunotherapy, but no CTLA-4 or PD-1 inhibitors.

Pembrolizumab as second-line therapy following ipilimumab improved PFS compared with chemotherapy, and with less toxicity, in the KEYNOTE 002 study. In a comparison with ipilimumab as first-line therapy (KEYNOTE 006), pembrolizumab conferred a benefit in OS while being less toxic. Long-term data from KEYNOTE 001, conducted in ipilimumab-treated and ipilimumab-naive patients with advanced melanoma, demonstrated durable antitumor activity, promising long-term OS, and a manageable safety profile with pembrolizumab (J Clin Oncol. 2015;33[suppl]. Abstract 9005). Median OS was 22.8 months, with 49% of patients alive at 2 years, in the overall population. In newly diagnosed, ipilimumab-naive patients, median OS was 31.1 months, and 60% were alive at 2 years.

Combination anti–PD-1/anti–CTLA-4 immunotherapy is superior to anti–CTLA-4 therapy alone. The combination of nivolumab and ipilimumab was superior to ipilimumab alone; median PFS was not yet reached in the combination arm and was 3.0 months in the ipilimumab-alone arm (P <.0001) (J Clin Oncol. 2015;33[suppl]. Abstract LBA1). In patients with PD-L1 expression <5%, the combination of PD-1 and CTLA-4 blockade was more effective than either alone.

Emerging Vaccines

The potential role of oncolytic immunotherapies in the treatment of advanced melanoma was discussed by Robert H. I. Andtbacka, MD, Associate Professor of Surgery, Department of Surgery at the University of Utah School of Medicine, Salt Lake City.

Several intralesional agents are in development, including plasmid IL-12 electroporation (IL-12 EP), talimogene laherparepvec (T-VEC), and coxsackievirus A21 (CVA21). These vaccines have been shown to exhibit an effect on injected and uninjected tumors.

Lesions suitable for intratumoral injections are dermal lesions, subcutaneous lesions, and superficial lymph nodes. The goals of injectable intralesional therapy are local disease control, induction of systemic host immune antitumor activity, durable response, and limited systemic toxicity.

Plasmid-encoded DNA IL-12 EP was associated with a complete response rate of 45% in treated lesions and an overall response rate of 59% in untreated lesions in an interim analysis of a phase 2 study of patients with advanced melanoma (J Clin Oncol. 2014;32[suppl]. Abstract 9025). IL-12 EP was safe and well tolerated across multiple treatment cycles; the vast majority of adverse events were grade 1/2, and there were no reports of treatment interruptions, hospitalizations, or discontinuations due to treatment-related adverse events.

T-VEC has dual mechanisms of action; it was designed to produce local and systemic antitumor effects. In the OPTiM phase 3 study (J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.3377), the durable response rate was 16.3% in patients randomized to T-VEC compared with 2.1% in those randomized to granulocyte-macrophage colony-stimulating factor (GM-CSF) (P <.0001). In T-VEC responders, the complete response rate was 41%. Responses in uninjected lesions demonstrate a systemic effect of T-VEC, said Andtbacka. An exploratory subgroup analysis revealed a particular benefit in patients with limited visceral disease (hazard ratio, 0.57; P <.001). The risk of developing visceral and bone metastasis in patients treated with T-VEC was 59% lower compared with GM-CSF.

T-VEC in combination with ipilimumab was associated with a 50% overall response rate in a phase 1b study of 18 patients with stage II/IV melanoma (J Clin Oncol. 2015;33[suppl]. Abstract 9063). The number of total and activated T cells increase after T-VEC and combination treatment (J Clin Oncol. 2014;32[suppl]. Abstract 9029).

Intralesional CVA21 was studied in unresectable stage IIIC-IV M1c melanoma in the CALM phase 2 study (J Clin Oncol. 2015;33[suppl]. Abstract 9030). The primary end point was achieved, with 21 of 57 (36.8%) evaluable patients having an immune-related (ir) PFS at 6 months, and a median irPFS of 4.2 months. The overall response rate was 28.1%, and 19.3% had a durable response (≥6 months). The 1-year survival rate was 75.4%.

In patients treated with immune checkpoint inhibitors, CVA21 induced notable changes within the tumor microenvironment by inducing increases in immune cell infiltrates and expression of PD-L1.

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