Treating metastatic melanoma: Understanding a brave new world

By Kathryn Schwarzenberger, MD, April 2, 2018

In this month's Acta Eruditorum column, Physician Editor Kathryn Schwarzenberger, MD, talks with Jane Grant-Kels, MD, and Daniel Klufas, MD, about their recent Journal of the American Academy of Dermatology article, "The new paradigm of systemic therapies for metastatic melanoma." 

Dr. Schwarzenberger: The treatment of metastatic melanoma is undergoing a process of major change. Could you please explain the major differences between the two categories of systemic therapies: immune vs cellular?

Dr. Grant-Kels and Dr. Klufas: There are two major mechanisms now being employed to combat melanoma that have revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients. One involves immunomodulation or “immune checkpoint inhibition” and the other targets genetic mutations of the melanoma cell that fosters growth and proliferation.

Immune therapy capitalizes on the knowledge of mechanisms to enhance the immune response against tumors. A melanoma-specific immune response is generated when melanoma antigen [via antigen-presenting cells (APCs)] is presented to T-cell receptors on T cells — the antigen primed T cell becomes activated by engagement of its CD28 molecule with costimulatory molecules on APCs. A tight synapse forms between the T cell and APC leading to proliferation and survival of T cells that help eliminate tumor cells. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptors represent two inhibitory molecules expressed on activated T cells that regulate growth, proliferation, and survival of T cells. When ligands on tumor cells (e.g. PDL-1/2, B7) outcompete the CD28 molecule on T cells and bind to PD-1 and CTLA-4 receptors on T-cells, this results in abolition of T-cell antitumor activity. The goal of drugs like ipilumumab (an anti-CTLA-4 antibody) and pembolizumab or nivolumab (anti-PD-1 antibodies) is to block the inhibitory ligands on tumor cell surfaces thereby preventing tumor cells from ceasing the T-cell immune response. In summary, immune therapy aims to keep the T-cell mediated immune response “on” and reinvigorate the anti-tumor response, when a tumor’s major defense mechanism is to turn the immune system “off.”

Targeted, or cellular, therapy, on the other hand, has the primary goal of blocking cellular proliferation. Targeted therapy involves control of tumor growth with small molecules designed to block the aberrant proteins (i.e. mutated gene products) for cellular signaling pathways responsible for growth, proliferation, and cell death. Two of the most studied signaling systems are the RAS/MAPK and RAS/PI3K cascades. A mutation in certain proteins involved in these signaling pathways can lead to unregulated activity leading to tumor cell proliferation. In melanoma, the most common activation mutation is the BRAF mutation, which results in unregulated kinase activity leading to constitutive activation of the growth-promoting extracellular signal-regulated (ERK) pathway. It is important to note that activated BRAF phosphorylates and activates MEK 1/2 proteins, which leads to increased transcription of genes responsible for cellular growth and proliferation. As such, therapies have been developed to target these two key components of the signaling cascade. BRAF inhibitors, such as vemurafenib and dabrafenib, are potent kinase inhibitors of the mutant BRAF gene, whereas MEK inhibitors, such as trametinib, cobimetinib, binimetinib, and selumetinib, inactivate the downstream MEK protein. In patients with acral and mucosal melanomas, mutations in c-kit are sometimes present. KIT inhibitors are currently being investigated in clinical trials for this patient population.

In summary, immune therapy can be viewed as increased immune system-mediated destruction of cancer cells whereas targeted therapy is the destruction of tumor cells by disallowing further growth and proliferation.

Dr. Schwarzenberger: For cellular therapies, what combination gives the most favorable outcomes?

Dr. Grant-Kels and Dr. Klufas: The most robust data published about combination therapies surrounds combination BRAF and MEK inhibitors, particularly vemurafenib plus cobimetinib and dabrafenib plus trametinib.

In regards to vemurafenib plus cobimetinib, the coBRIM trial, a phase 3, double-blind, placebo-controlled, multi-center study featuring 495 patients with BRAF(V600)-mutant, stage IIIC or stage IV melanoma were randomly assigned to receive cobimetinib plus vemurafenib (combination group) or placebo plus vemurafenib (placebo group). The primary endpoint was progression-free survival (PFS), which was 12.3 months in the combination group as compared to 7.2 months for the placebo group (HR 0.58, 95% CI 0.46-0.72, p<0.0001). Median overall survival, a secondary endpoint, was 22.3 months for the combination group as compared to 17.4 months for the placebo group (HR 0.70, 95% CI 0.55-0.90; p=0.005). Of note, serious adverse events occurred in 37% of combination group patients as compared to 28% in the placebo group.

More robust trial data exists for the combination of dabrafenib plus trametinib with two phase 3 trials having been conducted. In the phase 3 COMBI-d trial, 423 patients were treated with dabrafenib plus trametinib or to dabrafenib plus placebo. The primary endpoint was PFS, which at 3 years was 22% with the combination group versus 12% with the placebo/monotherapy group. As a secondary outcome, 3-year overall survival was 44% for combination group and 32% for the placebo group. It is important to note that the safety profile was similar to previous clinical trial reports. In the other phase 3 trial, 704 patients were treated with dabrafenib plus trametinib versus vemurafenib. The primary endpoint for this study was overall survival, which was 72% in the combination group and 65% in the vemurafenib group (HR for death 0.69, 95% CI 0.53-0.89). Secondary endpoints were 3-year overall survival, which was higher in the combination group (25%) than in the vemurafenib group (11%), and median PFS, which was 11.4 months in the combination group versus 7.3 months in the vemurafenib group.

Dr. Schwarzenberger: For immune checkpoint inhibitors, which combination gives the most favorable outcomes? Does single-agent PD-1 inhibition show similar outcomes as combined PD-1 plus CTLA-4 inhibition?

Dr. Grant-Kels and Dr. Klufas: As discussed in our manuscript, in a randomized, double-blind phase 3 study (CheckMate 067 trial) featuring 945 previously untreated patients with unresectable stage III and IV melanoma treated with combined ipilimumab (CTLA-4 inhibition) and nivolumab (PD-1 inhibition), patients showed significantly longer PFS and higher rates of objective response with nivolumab plus ipilimumab and with nivolumab alone than with ipilimumab alone.

Since the publication of our manuscript, the authors of the aforementioned study have reported on 3-year overall survival outcomes. The data show the survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab groups, as compared to 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The hazard ratio for death with combination therapy vs. ipilimumab monotherapy was 0.55 [p<0.001]; while for nivolumab vs. ipilimumab was 0.65 [p<0.001].

It is worth noting that the results of an open-label, phase 1b trial (KEYNOTE-029), featuring 153 patients with unresectable stage III or IV melanoma treated with standard-dosed pembrolizumab in combination with reduced-dose ipilimumab, show a manageable toxicity profile and robust anti-tumor activity (as measured by 1-year PFS and 1-year overall survival). These promising results prompted further assessment with a randomized phase 2 trial, which is currently underway.

Based on these findings, the best data supports combination treatment with nivolumab plus ipilimumab in patients with advanced melanoma as evidenced by increased longer overall survival. Further trials comparing other combination therapies head-to-head (i.e. pembrolizumab plus ipilimumab vs. nivolumab plus ipilimumab) would be necessary to appropriately determine the best combination therapy. Additionally, as seen in the CheckMate 067 follow-up publication, overall survival outcomes are superior with combined PD-1 plus CTLA-4 inhibition as compared to single-agent PD-1 inhibition (and both being superior to single-agent anti-CTLA-4 inhibition).

Dr. Schwarzenberger: Would there be any reason to use single-agent CTLA-4 inhibition anymore?

Dr. Grant-Kels and Dr. Klufas: As discussed above, for immune therapies, the most favorable outcomes occur with combination PD-1 and CTLA-4 inhibition or PD-1 inhibition alone as compared to CTLA-4 inhibition monotherapy. As such, single-agent CTLA-4 inhibition is falling increasingly out of favor. Furthermore, immune-related side effects are significantly less frequent and less severe with anti-PD-1 agents (i.e. nivolumab, pembrolizumab) than with anti-CTLA-1 antibody agents (i.e. ipilimumab). Given that anti-PD-1 agents are more active and present with less toxicities, there are no current recommendations that would support single-agent CTLA-4 inhibition at this time, though the role of these agents as combination therapies continues to be promising.

Dr. Schwarzenberger: Comparing cellular therapies to immune checkpoint inhibitors, which works better in the first 6 months? Which works better after the first 6 months?

Dr. Grant-Kels and Dr. Klufas: The data concerning this is sparse. Furthermore, the decision on which systemic treatments to initiate in a patient with a newly diagnosed metastatic melanoma are patient specific and need to be individualized depending on various factors. First, it needs to be determined if the patient has a targetable gene mutation, such as a BRAF, MEK, or KIT mutation. If the answer is “no,” then immunotherapy is the first line systemic treatment. If the answer is “yes,” it is more complicated as immunotherapy and/or cellular/targeted therapy can be the initial treatment of choice. Finally the potential side effect profile and patient co-morbidities need to be taken into consideration.

Additional DermWorld Resources