Treatment Strategies for BRAF Wild-Type Metastatic Melanoma

An estimated 76,380 new cases of melanoma will be diagnosed in 2016, with an estimated 10,130 dying of this disease. Incidence rates for melanoma have increased steadily over the past several decades. In fact, in the United States, melanoma now has the 5th and 7th highest incidence for all cancers among men and women, respectively.¹ If diagnosed at an early stage, the prognosis for melanoma is robust with a 98.4% relative 5-year survival rate if disease is localized. This number decreases dramatically if metastatic disease is diagnosed, with the 5-year survival decreasing to 17.9%.²

This dramatic decrease in survival with metastatic melanoma combined with its prevalence in the US population points to the need for proven therapeutics aimed at treating advanced disease.

In predicting the prognosis of those with metastatic melanoma, a few factors have been elucidated. A retrospective study examined over 1500 patients and determined the initial site of metastasis to have varying median survivals and estimated 5-year survival rates. Those patients with cutaneous or nodal metastasis had improved prognosis compared with those with metastasis to the lungs, who have a better prognosis than those with other visceral metastases.³ Additional factors associated with poor prognosis in melanoma include poor performance status, older age, male sex, and an increased number of sites of metastases. Some lab abnormalities are also associated with a poorer prognosis, including elevated serum lactate dehydrogenase levels and serum S100⁴ and hypoalbuminemia.⁵

In the past few years multiple agents have been used to treat metastatic melanoma, of which the treatment for BRAF wild-type patients will be discussed. The BRAF mutation is present in 40% to 50% of all melanomas, of which the most common is V600E, accounting for 70% to 80% of all BRAF mutations.^6,7 In this review we focus on BRAF wild-type melanoma patients, who represent a significant proportion of those patients presenting with advanced melanoma.

Melanoma as an Immunogenic Tumor

Immunotherapy has been at the forefront of treatment options for cancer for the past few years and yet has been markedly prolific of late. Immunotherapy, specifically anti–programmed death-1 (anti–PD-1) antibodies, have now achieved regulatory approval for a variety of cancers, including melanoma, non–small cell lung cancer, Hodgkin lymphoma, and renal cell carcinoma. Historically, however, melanoma has been considered as a relatively more immunogenic cancer. First, it has been suggested that primary, and rarely metastatic, melanomas can spontaneously regress, a phenomenon more frequently observed in melanoma than other cancers, the estimated incidence of which has been cited to be between 3% and 15%.⁸ The explanation has been linked to host immunity, triggering an immune mechanism capable of leading to regression, possibly supported by the presence of tumor-infiltrating lymphocytes (TILs) in primary melanomas associated with tumor regression.⁹ In fact, lymphoid infiltrates within melanoma have prognostic value. TIL density within primary melanoma and lymph node metastases have been shown to be prognostic of disease outcome.¹⁰ An additional factor is the elucidation of vitiligo as an independent prognostic factor in melanoma patients who are treated with immunotherapy, including interferon-alpha (IFN-α), interleukin-2 (IL-2), cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, and PD-1 blockade.¹¹ Vitiligo is the autoimmune destruction of melanocytes, and whereas it represents an independent factor for positive prognosis in melanoma patients, it has been noted to have increased incidence in those patients treated with immunotherapy. This association can be explained by shared melanocyte lineage antigens that are expressed both by melanoma cells and normal melanocytes, thus promoting autoimmunity.¹² And last, melanoma has been suggested to have a poorer prognosis in those individuals who are immunosuppressed, indirectly supporting a role for the immune response in melanoma in particular. Similarly, although all tumors have tumor-associated antigens (TAAs), melanoma has tissue-specific—or melanocyte lineage–specific—TAAs allowing for more potential immunotherapy targets through tumor vaccination strategies.¹³

With the improvement in understanding of tumor biology and the immune resistance mechanisms involved in evading the host tumor response, a multitude of new molecular targets have been identified, most importantly immune checkpoints. Whereas under physiologic conditions immune checkpoints serve a critical function in controlling and balancing the immune response and preventing autoimmunity, in the presence of a tumor they have been implicated in mediating immune tolerance. Learning to modulate these immune targets has had massive implications in successfully treating a multitude of cancers. The history of immunotherapy in melanoma dates back to the first regulatory approval of IFN-α in the mid-1990s for the adjuvant treatment of stage IIB/III melanoma, which was followed by high-dose bolus IL-2 approval in 1998 for the treatment of metastatic melanoma.¹⁴ However, since then major strides have been made in further upregulating the host’s antitumor immune response via the elucidation of immune checkpoint modulators, most notably CTLA-4– and PD-1–blocking antibodies.

Chemotherapy

For years, chemotherapy with dacarbazine (DTIC) as either a single agent or in combination, and more recently temozolomide (TMZ), fotemustine (not available in the United States),¹⁵ or the combination of carboplatin/pac­litaxel^16,17 was an essential part of the standard of care of metastatic melanoma, although little was shown to support an overall survival benefit with these regimens. Single-agent DTIC is the only chemotherapeutic agent approved by the FDA for metastatic melanoma based on limited clinical activity observed in early trials almost 4 decades ago. A review of 48 randomized controlled trials assessing for the efficacy of DTIC alone and in combination with other agents in unresectable stage III and stage IV melanoma patients found generally poor outcomes.¹⁸ In a randomized trial comparing DTIC with TMZ, response rates were less than 10% with both agents.¹⁹ The combination of carboplatin/paclitaxel demonstrated a response rate that approached 20% as first-line therapy in a randomized phase 3 trial.¹⁷ Combinations of chemotherapy and cytokine (IFN, IL-2) therapy, termed biochemotherapy, was extensively tested in melanoma, and whereas initial phase 2 studies demonstrated promising results, definitive testing in randomized phase 3 trials failed to demonstrate a survival benefit over chemotherapy alone.²⁰ Chemotherapy is now used only as salvage therapy in patients with BRAF wild-type disease in whom initial immunotherapy fails and in the absence of adequate clinical trial options.

High-Dose Bolus IL-2

Although approved for renal cell carcinoma in 1992, it was not until 1998 that high-dose (HD) IL-2 was approved by the FDA for the treatment of metastatic melanoma.^4,21 The premise of HD IL-2 is durable responses in a small group of patients (~5%) who were free of melanoma relapse for over 10 years, which was the first clue that metastatic melanoma can be cured through immunotherapy.²² Further, HD IL-2 has the advantage of a relatively short course of therapy with no need for long-term maintenance. Its toxicities, however, are severe, requiring inpatient administration, and the offering of HD IL-2 remains limited to expert institutions. Such toxicities include a sepsis-like syndrome inclusive of hypotension, fever, pulmonary edema, and capillary leak syndrome. In an update on the long-term survival of a series of 270 melanoma patients treated with HD IL-2 as part of 8 clinical trials, the overall response rate was 16%, but the majority of these responders had a durable response, with an average median survival of at least 59 months.²³ HD IL-2 continues to be part of the systemic immunotherapy options for patients with metastatic melanoma, and several combination studies, including with vascular endothelial growth factor inhibitors and checkpoint inhibitors, are ongoing.

CTLA-4 Blockade with Ipilimumab

The survival benefits of ipilimumab, a monoclonal antibody that blocks CTLA-4, were first reported in 2010 as tested in the MDX10-20 randomized phase 3 trial. Ipilimumab was the first immune checkpoint–blocking antibody utilized for the treatment of metastatic melanoma shown to have an effect on overall survival.²⁴ This trial enrolled 750 study patients with stage III/IV unresectable melanoma who had previously undergone treatment with either chemotherapy or HD IL-2. The trial looked to compare treatment with induction ipilimumab (3 mg/kg) plus gp100 peptide vaccine with ipilimumab plus a vaccine placebo and with gp100 peptide vaccine plus an ipilimumab placebo. It demonstrated a median overall survival of 10 months in the ipilimumab plus gp100 group versus 6.4 months in the gp100 vaccine group (P <.001).²⁴ A phase 2 multicenter trial first demonstrated an improved overall survival with ipilimumab monotherapy in a dose-varying trial comparing ipilimumab at an induction dose of either 0.3 mg/kg, 3 mg/kg, or 10 mg/kg in stage III/IV unresectable, previously treated melanoma patients.²⁵ The primary end point of overall survival varied by dose, suggesting improved overall survival with increased dose. Further, the overall response rate was higher at 10 mg/kg (11.1%; 95% CI, 4.9-20.7) compared with the 3-mg/kg (4.2%; 95% CI, 0.9-11.7) or 0.3-mg/kg (0%; 95% CI, 0.0-4.9) dose. The outcomes of the dose-varying phase 2 study and related pharmacokinetic analyses supported further development of the 10-mg/kg dose level. This led to a phase 3 study that tested the combination of ipi­limumab at 10 mg/kg plus dacarbazine compared with dacarbazine plus placebo as a control.²⁶ It is worth noting that subjects in this study were previously untreated. Unlike the prior study that planned only 4 doses of ipilimumab, this study included maintenance therapy of ipilimumab given every 3 months following the initial 4 induction cycles. Overall survival was greater in the combination arm of ipilimumab (10 mg/kg) plus dacarbazine than with dacarbazine alone (11.2 months vs 9.1 months). Also impressive was the durability of the responses observed in the ipilimumab arm. The overall response was 19.3 months versus 8.1 months in favor of ipilimumab.²⁶

The outcomes of these studies led to the regulatory approval of ipilimumab in the United States at the dose level of 3 mg/kg every 3 weeks for 4 doses total. One question continues to be open and relates to the superiority of the 10-mg/kg dose level over 3 mg/kg. A phase 3 trial, CA184-169, recently presented at the 2016 European Society for Medical Oncology, suggested that there is an overall survival advantage for ipilimumab at 10 mg/kg (hazard ratio [HR], 0.84; 95% CI, 0.70-0.99; P = .04). There was no significant difference in progression-free survival, and, as expected, toxicity was greater with the higher dose.²⁷

Treatment with ipilimumab is associated with the development of immune-related adverse events that are related to its mechanism of action. These may include rash, diarrhea and colitis, hepatitis, endocrinopathies, and neuropathies, among others. Toxicity management guidelines have been developed and must be followed closely in the management of these patients.²⁸

PD-1 and PD-L1 Inhibitors

The PD-1–blocking monoclonal antibodies nivolu­mab and pembrolizumab are now the first-line treatment options for patients with metastatic melanoma. Since the initial FDA approval of pembrolizumab and nivolu­mab for the treatment of melanoma in 2014, monoclonal antibodies that target the PD-1/PD-L1 (PD-1 ligand 1) pathway have now achieved regulatory approval in multiple malignancies, including renal cell cancer, squamous and nonsquamous non–small cell lung cancer, Hodgkin lymphoma, and urothelial cell carcinoma.

PD-1 is an immune-regulating transmembrane receptor expressed on the surface of activated T- and B-cell lymphocytes and myeloid cells. Its ligands, PD-L1 and PD-L2, are members of the B7 protein family and play an important role in maintaining immune homeostasis through their interaction with PD-1. PD-L1 is expressed in multiple tissue types, including hematopoietic, endothelial, and epithelial cells, and it is also expressed by tumor cells. The interaction of PD-L1 on the tumor with PD-1 on the cytotoxic T cells promotes downregulation of cytotoxic T-cell activity leading to tumor immune tolerance evasion of the host’s immune response.²⁹ Monoclonal antibodies that inhibit PD-1/PD-L1 interaction promote cytotoxic T-cell–enhanced antitumor activity.

In comparison with the former standard-of-care chemotherapy (prior to ipilimumab), nivolumab, a PD-1 antibody, was found to have durable responses in patients who had progressed on the CTLA-4 antibody ipi­limumab. Although ipilimumab had surpassed chemotherapy as standard of care, it is worth noting in this study patients had progressed on ipilimumab. The superiority of nivolumab was illustrated in a randomized, controlled, open-label, multicenter trial across 14 countries in the phase 3 setting. Patients were randomly assigned to receive an IV infusion of nivolumab 3 mg/kg every 2 weeks, chemotherapy with dacarbazine 1000 mg/m² every 3 weeks, or paclitaxel 175 mg/m² combined with carboplatin until disease progression or toxic adverse effects of therapy. The efficacy, objective response, and safety/toxicity profile of nivolumab were shown to be superior in comparison with chemotherapy.^30,31 Similarly, when nivolumab plus ipilimumab was compared with ipilimumab alone, there was a noted improvement in the nivolumab combination arm. In the CheckMate 069 trial, objective responses approached 60% (95% CI, 49-72) in the combination arm versus 11% (95% CI, 3-25) in the ipilimumab-only arm.³² Similar results were reported in a later phase 3 trial testing the combination of ipi­limumab-nivolumab or nivolumab alone versus ipilimumab, with objective responses seen in 57.6% of treated patients in the combination arm.³³ However, this unprecedented level of clinical activity comes at a major cost in terms of toxicity, with over 50% of patients experiencing grade 3/4 treatment-related adverse events.³³ PD-L1 expression was shown to correlate with response to nivolumab monotherapy; however, the cutoff value for positivity has yet to be concretely defined, and further studies are needed to define the therapeutic predictive value of PD-L1 expression.

Pembrolizumab was approved in September 2014 for the treatment of metastatic melanoma based on significant clinical activity seen in the phase 1 trial KEYNOTE-001 (ipilimumab-naive and-treated patients).³⁴ Pembrolizumab has also been compared with chemotherapy in the KEYNOTE-002 trial (ipilimumab-treated patients) and with ipilimumab in KEYNOTE-006 (ipi­limumab-naive patients) and has consistently shown improved response rates, progression-free survival, and overall survival. In the KEYNOTE-006 phase 3, randomized controlled trial with 834 patients assigned to either a pembrolizumab arm with treatment either every 2 or 3 weeks or to an ipilimumab arm, the progression-free survival at 6 months was shown to be 47.3%, 46.4%, and 26.5%, respectively (HR for disease progression, 0.58%; P <.001 for both pembrolizumab regimens, 95% CI, 0.46-0.72 and 0.47-0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (HR, 0.63; 95% CI, 0.47-0.83; P = .0005; and HR 0.69; 95% CI, 0.52-0.90; P = .0036). Also notable were significantly lower rates of treatment-related adverse events of grade 3 to 5 severity in the pembroliz­umab arms versus the ipilimumab arm.³⁵

Intralesional Immunotherapy

Talimogene laherparepvec (T-VEC) is an oncolytic genetically engineered herpes simplex virus type 1 that contains the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF). Genetic modifications of the virus result in selective replication in tumor cells. In a phase 3 trial that compared T-VEC with GM-CSF in patients with stage IIIB-IV melanoma,³⁶ the durable response rate was 16.3% with T-VEC, and the overall response rate was 26.4%. The median survival was 23.3 months and 18.9 months in the T-VEC and GM-CSF groups, respectively (P = .051).³⁶ The benefits with T-VEC were primarily seen in patients with earlier stages (IIIB, IIIC, and IV M1a). The results from this study led to the regulatory approval of T-VEC in the United States. Studies combining T-VEC with other forms of immunotherapy, including anti–PD-1, are ongoing.

Adoptive Cell Therapy

Adoptive cell therapy (ACT) takes advantage of the host’s antitumor immune response by harvesting existing TILs from the surgically resected tumor. TILs are cultured, expanded, and selected for subsequent infusion back into the patient from which the initial biopsy was taken. Reinfusion is preceded by a conditioning regimen for lymphocyte depletion and is followed by HD IL-2 or other cytokines.^37,38 ACT with TILs has been reported to have high response rates close to 50% in patients with metastatic melanoma who eventually are treated successfully.^39-41 Similar to immune checkpoint inhibitor therapy and HD IL-2, most of these responses are durable. However, several limitations may affect eligibility for TIL therapy, including successful TIL generation, and access, as ACT is limited to select institutions.⁴¹

NRAS and KIT Mutant Melanoma

Major advances in our understanding of the molecular biology of melanoma have supported the testing of molecularly targeted agents such as c-KIT inhibitors in KIT mutant melanoma and MEK inhibitors in NRAS mutant melanoma. Preliminary data are promising, including studies of imatinib and dasatinib in metastatic melanoma harboring somatic alterations of KIT⁴² and MEK inhibitors in advanced melanoma harboring NRAS mutations, leading to randomized trials.⁴³

Radiation Therapy

Although melanoma traditionally has been considered a cancer not sensitive to radiation therapy, there are certain scenarios in which, despite systemic treatment, radiation therapy still plays a role. Stereotactic radiosurgery continues to be a key treatment strategy for patients presenting with brain metastases.⁴⁴ A recent series reported that among patients presenting with stage III/IV melanoma at 1 institution, 44% developed brain metastases.⁴⁴ It has also been shown that among melanoma patients with brain metastases, it is the contributing factor leading to death in up to 54% of these cases.⁴⁵ The potential radiologic treatment strategies for brain metastases also include whole brain radiation, often reserved for multiple brain metastases. External beam radiation therapy has a role in the local management of symptomatic bony, soft tissue, or lymphatic metastases not responding to systemic therapy. Although our focus in this review is on cutaneous melanomas, uveal melanomas are a distinct subset in which radiation therapy is a fundamental part of local therapy. Plaque brachytherapy has shown improved long-term visual outcomes with overall survival equivalent to surgical enucleation.⁴⁵

Future Directions

Combination studies of immune checkpoint–modulating agents are ongoing with the ultimate goals of improving clinical efficacy and reducing toxicity. Agents targeting novel immune checkpoints such as CD40, OX40, CD137, TIM3, LAG3, among others, have made it to the clinic.¹⁴ Preliminary data are very encouraging, such as the combination of indoleamine 2,3-dioxygenase inhibition and PD-1 blockade that has now made it into phase 3 trial testing and the combination of IFN and CTLA-4 blockade leading to randomized trials.^46,47 In addition, major efforts are ongoing focused on the testing of biomarkers that may predict therapeutic benefits from immunotherapy. Preliminary studies are very encouraging in relation to immune-related gene expression signatures,^48,49 exome sequencing studies,⁵⁰ and CD8 TIL infiltration of the tumor microenvironment.⁵¹

Conclusion

Compared with earlier-stage melanomas, stage III (unresectable) and stage IV melanomas carry a much poorer prognosis. However, the recent advancements in the treatment of these cancers have shown significant promise. For advanced-stage unresectable melanomas with wild-type BRAF status, immunotherapy with anti–PD-1 antibodies is considered first-line therapy in patients without contraindications. Ipilimumab has mostly moved into the second-line setting, or first-line in combination with nivolumab. The use of HD IL-2 is still a valid option, but it has mostly become salvage therapy for patients in whom checkpoint inhibitor immunotherapy has failed. ACT is an option for select patients at limited institutions. Patients with KIT- or NRAS-mutant melanoma may benefit from targeted therapeutic agents. Chemotherapy as salvage therapy is often the last resort. Clinical trials should continue to be considered a priority in the management of these patients.

Conflicts of Interest

AT has contracted research support from Merck, Bristol-Myers Squibb, Amgen, Prometheus, and Novartis. AT acted as consultant (advisory board) for Merck and Bristol-Myers Squibb.

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Zahra Rahman is a third-year Graduate Medical Resident in Internal Medicine at the University of Pittsburgh, PA.
Ahmad Tarhini, MD, PhD, is an Associate Professor of Medicine and Translational Science at the University of Pittsburgh School of Medicine, Division of Hematology-Oncology, and the University of Pittsburgh’s Clinical and Translational Science Institute. He specializes in melanoma and other skin cancers. He received his master of science degree in clinical research and doctorate degree in clinical and translational science from the University of Pittsburgh School of Medicine.