Update on Immunotherapeutics in the Management of Metastatic Melanoma

David Bulir, MD, PhD; Steven Liang, BHSc, PhD (Candidate); Maureen O'Malley, MD, FRCPC; Elaine McWhirter, MD, MSc


Skin Therapy Letter. 2019;24(1) 

In This Article

Inhibition of CTLA-4 and PD-1

Presently, two main classes of immunotherapeutics, also known as immunotherapy or checkpoint inhibitors, exist for metastatic melanoma: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptor antagonists.[13–16] CTLA-4, also known as CD152, is a receptor found on the surface of both regulatory T cells, and activated T cells.[13–16] Activation or inhibition of the T cell depends on a sequence of events involving antigen-presenting cells (APCs). The T cell receptor (TCR) interacts with the APC via an epitope in the major histocompatibility complex (MHC).[13–16] In addition to the MHC, co-receptors CD80 or CD86 interact with the T cell through CTLA-4 or CD28, providing an inhibitory or activating signal, respectively. CTLA-4 binds CD80 and CD86 with higher affinity and avidity compared to CD28, leading to inhibition of T cell activation, thereby reducing the chance of T cells spontaneously reacting to self-antigens.[13–16] The fine balance between activating and inhibitory signals provided by CD28 and CTLA-4, respectively, is exploited in melanoma immunotherapy to non-specifically activate the immune system in attempts to destroy cancerous cells.

Programmed cell death protein 1 (PD-1), known as CD279, like CTLA-4, is a surface receptor on immune cells that also plays an important role in down-regulating the adaptive immune system at the effector phase and promoting tolerance in tissues.[13–16] Endogenous ligands for PD-1 are programmed cell death protein ligand 1 and 2 (PD-L1 and PD-L2).[13–16] In the absence of PDL1 or PD-L2 binding to PD-1, the immune system remains activated, leading to CD4+ and CD8+ T cell proliferation, and subsequent effector function through cytokine production and direct cytotoxic effect, respectively.[13–16] Although tumor cells can present antigens on MHC, which can signal to the immune system to respond and clear the cancerous cell, these aberrant cells are capable of immune evasion through a number of mechanisms, including upregulation of PD-L1 and subsequent downregulation of T cell effector function.[13–16] Like CTLA-4 receptor antagonists, the development of immunotherapeutics blocking the inhibitory nature of PD-1 following activation has also revolutionized the treatment of metastatic melanoma by harnessing the natural ability of the immune system to clear these cancerous cells. See Figures 1 and 2 for a brief overview of CTLA-4 and PD-1 in T cell regulation.

Figure 1.

CTLA-4 in T cell regulation

Figure 2.

PD-1 in T cell regulation


The first immunotherapeutic for metastatic melanoma approved by Health Canada was ipilimumab in 2012, a monoclonal antibody targeting the CTLA-4 receptor.[17] Approval for ipilimumab followed a trial demonstrating a significant overall survival of 10.1 months in the ipilimumab group compared to 6.4 months in the control arm of glycoprotein 100 (gp100) vaccine alone in patients who had previously treated, unresectable advanced melanoma.[17–19] Furthermore, 24-month overall survival rates were significantly higher in the ipilimumab group at 23.5%, compared to 13.7% in the gp100 vaccine group.[17–19] However, the unregulated proliferation and activity of immune cells induced by ipilimumab led to significant adverse reactions, including immune-mediated enterocolitis, dermatitis, hepatitis, endocrinopathies, and neuropathy among a significant number of patients.[17–19] It has been over a decade since the first clinical trial was conducted involving ipilimumab. In follow-up studies, patients who received ipilimumab and dacarbazine (DTIC) as part of a phase III trial have had an overall survival rate of 18.2%, compared to 8.8% among patients who received DTIC alone. The survival curve for patients receiving ipilimumab began to plateau 3 years after starting therapy, with minimal change thereafter.[20]


The first antibody targeting the PD-1 receptor was pembrolizumab, approved by Health Canada in June 2015 based on data from the KEYNOTE-001 trial.[21] Patients with metastatic melanoma and disease progression after receiving at least two doses of ipilimumab were randomized to different doses of pembrolizumab. Patients receiving either 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks had a similar overall response rate at 26% and median follow-up of approximately 8 months.[21] Follow-up of the phase Ib KEYNOTE-001 trial has demonstrated a 3-year overall survival rate of 40% in patients who received pembrolizumab, regardless of previous treatment.[22] The randomized, phase III KEYNOTE-006 trial compared two doses of pembrolizumab to ipilimumab in patients with unresectable or metastatic melanoma. Interim analysis during the study shows significant improvements in progression-free survival (47.3% and 46.4% pembrolizumab vs. 26.5% ipilimumab), 1-year overall survival (74.1% and 68.4% pembrolizumab vs. 58.2% ipilimumab), and overall response rate (33.7% and 32.9% pembrolizumab vs. 11.9% ipilimumab).[23] Recent updated results demonstrate a median overall survival of 16 months on the ipilimumab arm, which was not reached in either of the pembrolizumab groups. The 24-month overall survival rate was identical on the pembrolizumab arms at 55%, compared to 43% for ipilimumab.[24]


Shortly after approval of pembrolizumab, nivolumab, also an anti-PD-1 antibody, was approved for the treatment of melanoma. Interim analysis of 120 patients who received nivolumab in the CheckMate-037 trial provided the basis for nivolumab's approval. Patients whose disease progressed while on ipilimumab or a BRAF inhibitor were randomized to investigator's choice chemotherapy (ICC) or nivolumab. Patients receiving nivolumab demonstrated an overall response rate of 32%.[25,26] Long-term data published this year from the original CheckMate-037 trial demonstrated more durable responses among patients receiving nivolumab than ICC, but no difference was noted in overall survival (15.7 vs. 14.4, respectively). However, the absence of a difference in overall survival may be accounted for by a higher incidence of brain metastases, elevated LDH, and lower incidence of crossover treatments among patients receiving nivolumab vs. ICC.[27] These two classes of immunotherapeutics have revolutionized the treatment of metastatic melanoma and led to a significant number of clinical trials, regulatory approvals, and basic science research around immunotherapeutics.