Abstract: The last several years have seen a dramatic rise in the number of effective therapies that have been shown to improve survival outcomes for patients with advanced melanoma. Among these treatments are the immune checkpoint inhibitors, a new class of immunotherapy, that have demonstrated the ability to improve both response rates and survival outcomes. Pembrolizumab, an immune checkpoint inhibitor that blocks the negative regulatory PD-1 receptor on T-cell lymphocytes, has shown improved efficacy compared to standard therapies with an acceptable tolerability profile. Additionally, this agent is being evaluated in adjuvant and combination trial strategies that have great potential to further advance outcomes. This review focuses on the advances that pembrolizumab has made in melanoma and what studies are upcoming that could change the future of melanoma treatment yet again.
Keywords: keytruda, MK-3475, immune checkpoint inhibitor, PD-1 inhibitor, adjuvant therapy, combination therapies, immunotherapy
Malignant melanoma remains an important health concern with the incidence of melanoma rising faster than other malignancies with an estimated incidence of >87,000 new melanoma cases in the USA in 2017.1 It also remains a deadly disease with ~10,000 deaths annually associated with melanoma. Unlike the more common skin malignancies of squamous cell carcinoma and basal cell carcinoma, melanoma has far greater potential for distant spread, and when paired with poor sensitivity to conventional oncology treatments such as chemotherapy and radiation therapy, historically, clinical improvements in this disease have been quite challenging to see. For decades, only three therapies were US Food and Drug Administration (US FDA) approved for the disease, dacarbazine and interleukin-2 for unresectable metastatic disease and interferon for adjuvant treatment after surgery. Unfortunately, these drugs resulted in poor response rates (≤10%) and no improvement in average survival.2–4 The cytokines, interferon and interleukin-2, highlighted the potential for immunotherapy’s role in treating melanoma; however, these early immunotherapy treatments had high toxicity rates, low response rates, and no improvement in the average survival of patients.2
Fortunately, since 2011, there have been advances in the treatment of advanced melanoma.5 These therapies have primarily come in two forms, genetically targeted therapies and immune modulating therapies. From the genomics standpoint, the BRAF oncogene became a relevant treatment target after 2002 when it was found that 40–50% of melanoma tumors harbor BRAF V600 mutations.6Several late phase trials have shown significant improvement in response and survival outcomes with the use of BRAF and MEK inhibitors in patients with BRAF mutant metastatic melanoma.7–9 These new drugs include the BRAF inhibitors, vemurafenib and dabrafenib, as well as the MEK inhibitors, trametinib and cobimetinib. Recent studies have shown that blocking both the BRAF and MEK proteins in patients with BRAF mutant melanoma has resulted in superior outcomes compared to only BRAF blockade alone.10–12
In addition to genetically targeted therapies, immunotherapy has made a dramatic resurgence in the management of patients with advanced malignant melanoma. Previous work had shown that infiltration of tumor lymphocytes could be associated with improved outcomes; however, there were clear barriers to lymphocyte anticancer activities including lymphocyte regulation by tumors and other inflammatory cells.13 An important breakthrough was the identification and targeting of regulatory protein “switches” (called immune checkpoints) on the surface of T-cell lymphocytes.14 These immune checkpoints were found to have the ability to regulate lymphocyte function both in the early activation phase as well as inducing T-cell fatigue later during the immune process. The first immune checkpoint inhibitor that has been approved is ipilimumab, which is an antibody that targets the negative immune checkpoint cytotoxic lymphocyte antigen-4 (CTLA-4) on the T cells.15 Blocking CTLA-4 on the T cell promotes the activation and potentiation of these immune cells allowing them to have an immune cytotoxic effect on the cancer cells. Ipilimumab has been evaluated in two pivotal large Phase III trials, both of which have shown improvement in median overall survival (OS) in patients with metastatic melanoma, making it the first immunotherapy to ever do so.16,17 Although the improvement in average survival with ipilimumab was modest, there is a clear subset of patients, ~18%, who have prolonged survival benefit at the 8–10 years timepoint.18 Ipilimumab has also been demonstrated to have potential for significant autoimmune toxicities in some patients, requiring careful monitoring and prompt intervention when side effects are detected. Common side effects have included fatigue, colitis, dermatitis, and immune-related endocrinopathies. Approximately 10–15% of patients have experienced grade 3–4 immune-related toxicity in the standard 3 mg/kg dosing pivotal Phase III trial, and although most patients were able to achieve complete reversal of toxicity with steroid administration, a small percentage of patients required salvage infliximab for immune-related colitis and 1% of patients had immune-related toxicity resulting in death.