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Supplements The Role of Immuno-Oncology in the Treatment of Advanced Melanoma

Current Landscape of Immuno-Oncology in Advanced Melanoma

Adjuvant treatment with nivolumab was compared with ipilimumab in an international, double-blind, phase 3 trial in patients with resected stage IIIB, IIIC, or IV melanoma with or without BRAF mutations (N = 906). Patients were randomized 1:1 to receive nivolumab (n = 453) or ipilimumab (n = 453).37 As of the prespecified interim analysis, the median RFS had not been reached. At 1 year, the RFS in patients receiving nivolumab was 70.5% (95% CI, 66.1%-74.5%) versus 60.8% (95% CI, 56.0%-65.2%) for ipilimumab. At 18 months, these rates were 66.4% (95% CI, 61.8%-70.6%) and 52.7% (95% CI, 47.8%-57.4%), respectively. Nivolumab resulted in significantly longer RFS versus ipilimumab, with recurrence or death reported in 34.0% and 45.5% of patients, respectively (HR, 0.65; 97.56% CI, 0.51-0.83; P <.001).37

In early clinical trials, researchers observed a correlation between pretreatment levels of tumor-expressed PD-L1 and treatment response and that PD-L1 expression varies by tumor type. Taube et al found that PD-L1 is expressed by both tumor cells and tumor infiltrating cells (TILs) in melanoma. TIL expression of PD-1 was significantly associated with tumor expression of PD-L1, thus more likely to respond to anti–PD-1 therapy.38 In the subgroup analysis of RFS according to PD-L1 expression, HRs favored patients in the nivolumab group whose PD-L1 expression was 5% or greater. In this subgroup, the 1-year RFS was 81.9% (95% CI, 74.7%-87.2%) versus 73.8% (95% CI, 65.9%-80.1%) with ipilimumab. In patients whose PD-L1 expression was ≤5%, the 1-year RFS with nivolumab was 64.3% (95% CI, 58.3%-69.7%) versus 53.7% (95% CI, 47.6%-59.4%) with ipilimumab.37 Treatment-related AEs were observed in 14.4% of patients receiving nivolumab and 45.9% receiving ipilimumab; grade 3 or 4 AEs resulting in study discontinuation were reported in 4.6% and 30.9% of patients, respectively. In this prespecified analysis, adjuvant nivolumab resulted in significant improvement in RFS compared with ipilimumab.37

Combination nivolumab plus ipilimumab was evaluated against monotherapy with each agent in an international, randomized, double-blind, phase 3 trial in treatment-naïve patients with unresectable stage III or IV melanoma with or without BRAF mutations (N = 945). Patients were randomized 1:1:1 to receive nivolumab (n = 316), nivolumab plus ipilimumab (n = 314), or ipilimumab (n = 315). Patients receiving nivolumab or ipilimumab received matched placebo.39 The median PFS with nivolumab plus ipilimumab was 11.5 months (95% CI, 8.9-16.7) compared with 6.9 months (95% CI, 4.3-9.5) with nivolumab alone and 2.9 months (95% CI, 2.8-3.4) with ipilimumab alone. Both patients in the nivolumab-plus-ipilimumab group and the nivolumab group experienced significantly longer PFS versus those receiving ipilimumab alone (nivolumab plus ipilimumab: HR, 0.42; 99.5% CI, 0.31-0.57; nivolumab: HR, 0.57; 99.5% CI, 0.43-0.76; P <.001 for both). The ORR for nivolumab plus ipilimumab was 57.6% (95% CI, 52.0%-63.2%) compared with 43.7% (95% CI, 38.1%-49.3%) with nivolumab alone and 19.0% (95% CI, 14.9%-23.8%) with ipilimumab alone.39

In the same study, in patients whose tumor was PD-L1 positive, the median PFS was 14.0 months (95% CI, 9.7-not reached) with nivolumab plus ipilimumab, 14.0 months (95% CI, 9.1-not reached) with nivolumab alone, and 3.9 months (95% CI, 2.8-4.2) with ipilimumab alone. In patients who were negative for tumor PD-L1, the median PFS was 11.2 months (95% CI, 8.0-not reached), 5.3 months (95% CI, 2.8-7.1), and 2.8 months (95% CI, 2.8-3.1), respectively.39 A higher incidence of grade 3 or 4 treatment-related AEs were observed in patients receiving nivolumab plus ipilimumab (55.0%) compared with nivolumab alone (16.3%) and ipilimumab alone (27.3%). 

The most common AEs in patients receiving nivolumab plus ipilimumab were diarrhea, pruritus, and fatigue. The percentage of patients who discontinued the study drug due to AEs (any grade) were 36.4% for nivolumab plus ipilimumab, 14.8% for ipilimumab alone, and 7.7% for nivolumab alone.39

Recently, data were presented from a post hoc analysis of 3 phase 3 clinical studies evaluating combination therapy with nivolumab plus ipilimumab (N = 409) versus each agent alone (nivolumab, N = 526; ipilimumab, N = 362). In this pooled analysis, the ORR was 58.9% in patients receiving combination therapy versus 43.9% with nivolumab alone and 18% with ipilimumab alone; CRs were observed in 18%, 16%, and 4% of patients, respectively. Of patients in the combination therapy cohort experiencing a CR, 77% are no longer receiving treatment, and 2-year PFS and OS are 86% and 92%, respectively. Of patients in the combination therapy cohort, 60% of patients who had a CR experienced grade 3 to 4 treatment-related AEs and 31% of those patients discontinued. In the same combination therapy cohort, 65% of patients who achieved a partial response and 60% of patients who had stable disease experienced grade 3 to 4 treatment-related AEs, with 36% and 35% of patients discontinuing treatment respectively. No treatment-related deaths were reported.40

IDO Inhibitors

New agents in development for advanced melanoma target indoleamine-2,3-dioxygenase (IDO), an intracellular enzyme that is induced by an immune response. IDO initiates tryptophan degradation along the kynurenine metabolic pathway and aids tumor progression by supporting an immunosuppressive tumor microenvironment. Tumor cells use the IDO pathway to build tolerance to tumor antigens, and antigen-presenting cells expressing IDO can directly suppress a T-cell response, allowing tumor cells to escape  detection by the immune system. Inhibiting IDO can restore the proliferation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, and T cells, as well as boost interferon (IFN) production, and reduce the numbers of tumor-associated regulatory T cells.41-43 

Epacadostat is a hydroxyamidine small-molecule IDO1 inhibitor currently being evaluated in early clinical trials. A phase 1/2 study is exploring the safety, tolerability, and efficacy of epacadostat in combination with pembrolizumab in patients with melanoma and other solid tumors (estimated N = 508).41,44 Updated phase 1 results were recently presented. Responses were observed in all groups receiving epacadostat at a dose of 50 mg or higher twice a day. The median PFS was not reached at the time of this report; however, responses were observed in patients previously treated for advanced melanoma and other cancers. A maximum tolerated dose was not established. Most common treatment-related AEs (≥15%, any grade) were fatigue, joint pain, rash, diarrhea, pruritus, and nausea. Grade 3 treatment-related AEs occurred in 18% of patients, and there were no treatment-related deaths. This study is expected to be completed in February 2020. Based on the interim results of this study, investigators recommended a phase 2 dose of 100 mg twice daily, and a phase 3 study in treatment-naïve patients with advanced melanoma was initiated (NCT02752074).45

TNF Receptor Family Antibodies

Members of the tumor necrosis factor (TNF)/TNF receptor (TNFR) family are responsible for many components of an effective immune response, including cellular activation, proliferation, and effector function, and cell survival and memory. More than 40 TNF/TNFR members have been identified thus far. Three TNFR members, OX40, CD27, and 4-1BB, have been shown to activate numerous signaling cascades and regulate the expression and survival of CD4+ and CD8+ cells, among other immune-stimulating mechanisms.46-48

Varlilumab is a fully human, igG1κ anti-CD27 mAb that was shown to be well tolerated and clinically active in a phase 1, open-label, dose-escalation and expansion study (N = 25). The study was open to patients with metastatic melanoma and other cancers whose disease had progressed and who had no remaining approved therapy options. Varlilumab demonstrated a transient increase in IP-10 (a key cytokine that is upregulated by CD27 co-stimulation in CD8+ cells) and an increase in effector T cells, circulating T cells with an active phenotype, and fewer naïve T cells. Treatment-related AEs were fatigue, rash, nausea, and diarrhea, and were generally grade 1 to 2. There was 1 case each of grade 3 hyponatremia, decreased appetite, and decreased lymphocyte count.49

Utomilumab is a fully human igG2 agonist of 4-1BB currently being evaluated in combination with pembrolizumab. An open-label, multicenter, phase 1b dose-escalation study was conducted in patients with advanced cancers, including melanoma, who had progressed on therapy or for whom no standard therapy was available (N = 23). All patients received utomilumab and pembrolizumab and were assessed for safety and tumor response. The ORR was 26% (95% CI, 10.2%-48.4%); 5 of the 6 patients who responded to treatment maintained a response for longer than 6 months. The best overall response of stable disease was achieved by 43.5% of patients across tumor types. No dose-limiting toxicities were observed and AEs were generally mild. The most common treatment-related AEs were fatigue, rash, pruritus, fever, decreased appetite, dry mouth, dry skin, and nausea. There was 1 instance each of grade 3 adrenal insufficiency and hypokalemia.50

An OX40 agonist, PF04518600, is being studied in early clinical trials for various cancers, including melanoma. An open-label, dose-escalation, phase 1/2 study in patients with locally advanced or metastatic cancer will evaluate the safety and tolerability of PF04518600 alone or in combination with utomilumab (estimated N = 210). This study is expected to be completed by December 2020.47,51

Advancements in Immuno-Oncology

Oncolytic Viral Therapies

An encouraging new field within immuno-oncology (IO) is that of virus-based therapies to induce systemic tumor-specific immunity. Although gene therapy uses viruses to simply carry and deliver information, in oncolytic viral therapy, the virus itself is active against the tumor. Viruses used in IO are genetically engineered to be noninfectious and are typically DNA based. T-VEC is a double-mutated herpes simplex virus-1 with gene deletions that render it unable to replicate in normal cells, but allow it to enter cancer cells due to their impaired regulatory functions. Also, T-VEC is augmented with the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene, intended to help induce antitumor immunity.52

T-VEC, a first-in-class intralesional oncolytic viral therapy, was administered in combination with ipilimumab in an open-label phase 1b/2 study in patients with unresectable stage IIIB-IVM1c melanoma, with no systemic therapy except adjuvant therapy in the preceding 6 months (N = 19).

The ORR was 50% (95% CI, 26.0%-74.0%). All but 1 patient who achieved CRs (22%) had a response lasting 6 months or longer. No dose-limiting toxicities were reported and no new emerging toxicities were observed. Grade 3 or higher treatment-related AEs were reported in 26.3% of patients; nausea was the only grade 3 or higher event reported in more than 1 patient.53

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