Systemic Therapy of Metastatic Melanoma: On the Road to Cure

Table: Treatment Characteristics and Endpoints to Consider in Tailoring Treatment for a Patient With Metastatic Melanoma

The 10-year survival rate for patients with metastatic melanoma has historically been less than 10%. However, recent successes with immunotherapy and BRAF-targeted therapy have ushered in a new era in systemic therapy of this disease. These therapies have been associated with significant improvements in patient outcomes in several randomized phase III trials. Not only have these breakthroughs increased the likelihood of long-term survival in patients with melanoma, but they have also spurred the investigation of a new generation of agents for treatment of melanoma. This article reviews both current options for systemic treatment of metastatic melanoma and promising investigational approaches. We also discuss important considerations in choosing among systemic therapy options, to match the unique goals of therapy for individual patients.

Introduction

Until recently, metastatic melanoma had historically been a challenging disease to treat, with a 10-year survival rate of less than 10%.[1] Dacarbazine was the benchmark systemic therapy for this disease for more than 3 decades after its initial approval by the US Food and Drug Administration (FDA) in 1975. Numerous attempts to improve upon the survival of patients with metastatic disease had met with failure in the past.[2] Over the last several years, however, phase III trials have reported significantly improved outcomes associated with several new therapies for advanced melanoma.[3,4] The availability of these new agents in the setting of metastatic disease marks the dawn of a new era of systemic therapy for this life-threatening malignancy. Our understanding of the biology of melanoma continues to increase steadily, and as a result, several other promising therapeutic approaches are on the horizon. In this article, we summarize the systemic therapies now available for melanoma, with a focus on the recently approved agents for cutaneous melanoma; discuss important considerations in selecting a treatment from the available options; and highlight some of the promising investigational approaches for this disease.

Therapeutic Options for Stage IV Melanoma

The mainstay of treatment for stage IV melanoma is systemic therapy to address both clinically detectable and subclinical sites of metastases. Systemic therapies commonly used for metastatic melanoma can be broadly classified into three groups: cytotoxic chemotherapy, molecular targeted therapy, and immunotherapy. The former two groups reflect drugs that work directly against the cancer cells, usually by interfering with cellular processes relevant to cancer cell proliferation.

Immunotherapeutic interventions usually work indirectly via modulation of the host immune responses against cancer cells. The various systemic therapies that were used prior to 2011 have been reviewed in detail elsewhere.[2] Historically, cytotoxic chemotherapeutic agents with modest antitumor efficacy in metastatic melanoma have included alkylating agents (dacarbazine, temozolomide, nitrosoureas), the microtubular toxins (eg, paclitaxel), and the platinum analogs. Combinations of cytotoxic agents yielded somewhat higher response rates than monotherapy, but were associated with greater toxicity and did not extend overall survival (OS) significantly.[2] High-dose interleukin-2 (HD IL-2) was associated with a durable complete response (CR) in some patients, but its utilization was limited by a low objective response rate (ORR), treatment-associated toxicities, and a paucity of predictive biomarkers. Historical attempts to combine cytotoxic chemotherapy with immunotherapy (the “biochemotherapy” regimens) were sometimes associated with a higher ORR, but these regimens did not result in reproducible, significant improvement in OS compared with chemotherapy alone.[5] Fortunately, there have recently been major advances on the fronts of molecular targeted therapy and immunotherapy, which are leading to significant improvements in patient outcomes, including OS.

Immunotherapy

Laboratory and clinical observations have long suggested that melanoma is susceptible to immune therapeutic approaches. T cells reactive to melanoma-associated antigens have been documented in the peripheral blood of patients with metastatic melanoma; responses have been noted both to melanocyte differentiation antigens (eg, tyrosinase or MART-1 [Melanoma Antigen Recognized by T cells 1]) and to cancer-testis antigens selectively expressed in melanoma cells (eg, MAGE [melanoma-associated antigens], NY-ESO-1).[6] Recent studies using whole-exome sequencing and tandem mini-genes have also identified patient-specific mutations encoding proteins that elicit T-cell responses in tumor-infiltrating lymphocytes.[7,8]

Complementing these laboratory observations, the clinical success of HD IL-2 in inducing durable CRs in some patients with metastatic melanoma provided “proof of concept” for the field of cancer immunotherapy, and fuelled the investigation of several immunotherapeutic approaches over the last few decades. These approaches have included efforts to amplify the number and/or function of tumor-reactive T cells (eg, through lymphokines similar to IL-2, vaccines, or adoptive T-cell therapy approaches), or to modulate signals that regulate T-cell function (eg, by use of immune checkpoint inhibitors or costimulatory agonists). The persistent efforts of both laboratory immunologists and clinical immunotherapists have paid off handsomely over the last few years with the striking success of cancer immune therapies, a select few of which are discussed below.

Immune Checkpoint Inhibitors

T-cell activation is triggered by engagement of the T-cell receptor (TCR) with antigen, presented in the context of major histocompatibility complex (MHC) antigen. Binding of the T cell’s CD-28 antigen to B7 expressed on the surface of the antigen-presenting cell (APC) delivers a costimulatory signal to the T cell. These activation events result in T-cell proliferation and the release of cytokines that facilitate antitumor immune response. However, after T-cell activation, the counter-regulatory processes ensue, including expression of cytotoxic T-lymphocyte antigen (CTLA)-4, an antigen that competes for binding to B7 and transmits an inhibitory signal to the T cell.[9-12] CTLA-4 is also constitutively expressed on regulatory T cells that inhibit excessive immune stimulation. CTLA-4 blockade was demonstrated in preclinical models to augment T-cell immune responses and induce major regressions and even cure of established tumors.[9,11,12] Another immune checkpoint axis under intense study is the programmed cell death protein (PD)-1:PD ligand (PDL)-1,2 axis. Engagement between PD-1 expressed on CD8+ T cells and its ligands (PD-L1 or PD-L2) expressed on cancer cells or APCs induces immune exhaustion; antibodies that bind to either PD-1 or its ligands interrupt this negative signal and result in enhanced T-cell number and function.[13-16] Monoclonal antibodies that bind CTLA-4 (eg, ipilimumab) or PD-1 (eg, pembrolizumab, nivolumab) have been associated with unprecedented clinical success in patients with metastatic melanoma and have also ushered in a therapeutic revolution in cancer immunotherapy in general.

CTLA-4 Blockade (Ipilimumab)

In two separate phase III trials, ipilimumab was associated with improved survival of patients with advanced melanoma.[3,17] The first pivotal phase III trial, which led to the FDA approval of ipilimumab for advanced melanoma in March 2011, demonstrated significantly improved OS with ipilimumab compared with gp100 vaccine therapy (median OS of 10 months vs 6.4 months, respectively) in patients who had received prior systemic therapy for unresectable stage III or IV melanoma.[3] Ipilimumab was administered intravenously (IV) at a dose of 3 mg/kg every 3 weeks for up to four doses (induction) without any maintenance dosing; however, patients were eligible for re-induction therapy (with four more doses) at the time of progressive disease after initial benefit. The best ORR in the ipilimumab monotherapy group was 11% (CR = 1.5%; partial response [PR] = 9.5%). The disease control rate (DCR), defined as the proportion of patients with objective response or stable disease (SD), was 28%. Although the ORRs and CR rates were low, responses were mostly durable, with 60% of the responders maintaining their response beyond 2 years. While 60% of patients on ipilimumab monotherapy experienced immune-related adverse events (irAEs), severe (grade 3 or higher) irAEs were seen in only 15% of patients and included diarrhea/colitis (8%), endocrinopathy (2%), dermatologic toxicity (< 2%), and hepatic toxicity (< 1%). Most irAEs resolved by 6 to 8 weeks with appropriate immunosuppressive treatment (mostly glucocorticoids), although residual symptoms (eg, vitiligo, endocrinopathy symptoms, rectal pain) were sometimes present in long-term survivors. A second randomized phase III trial that compared ipilimumab (at 10 mg/kg) plus dacarbazine vs dacarbazine alone in patients with previously untreated metastatic melanoma also showed longer median OS with ipilimumab plus dacarbazine (11.2 mo) vs dacarbazine alone (9.1 mo), and higher 3-year survival (21% vs 12%, respectively).[17]

A meta-analysis of pooled OS data from ipilimumab trials, which includes data from 1,861 melanoma patients, highlights the potential for long-term treatment-free survival in some patients.[18] This meta-analysis listed a 3-year OS rate of 22%, with a plateau in the pooled Kaplan-Meier curve beginning at approximately 3 years after initiation of therapy, and extending through follow-up of as long as 10 years.

PD-1 Blockade (Pembrolizumab, Nivolumab)

Several drugs blocking the interaction of PD-1 with PD-L1 are in various phases of clinical development in multiple cancer types. Pembrolizumab (MK-3475) and nivolumab (BMS-936558) are both monoclonal antibodies binding to PD-1 and are under extensive investigation in patients with melanoma. In September 2014, the FDA approved pembrolizumab for patients with metastatic melanoma who had previously been treated with ipilimumab (and if BRAF-mutated, with BRAF inhibitors). This approval was based on the results of a randomized open-label trial (KEYNOTE-001) comparing the efficacy and safety of two doses of pembrolizumab (2 mg/kg and 10 mg/kg administered IV every 3 weeks) in melanoma patients who were considered refractory to ipilimumab treatment.[19] Treatment with pembrolizumab (2 mg/kg dose) in this trial was associated with an ORR of 26%, an estimated progression-free survival (PFS) at 24 weeks of 45%, and an estimated 1-year OS of 58%. The majority of responders (88%) were alive and progression-free at the time of analysis, with at least 6 months of follow-up. Treatment was well tolerated, with drug-related grade 3 or 4 AEs in only 12% of patients. Only 3% of patients discontinued treatment due to AEs. Safety data were consistent with results from other reported trials of PD-1 blockade,[20-22] although this trial report did not comment on the safety of pembrolizumab in patients who may have had prior irAEs with ipilimumab. There were no significant differences in safety and efficacy endpoints between the two dose levels. Similar to the KEYNOTE-001 trial, preliminary results from a phase III trial comparing nivolumab to chemotherapy (either dacarbazine or carboplatin plus paclitaxel) in ipilimumab-treated melanoma patients suggest nivolumab has antitumor activity in this patient population; specifically, nivolumab was associated with a higher ORR (32% vs 11%) and a lower rate of grade 3/4 AEs (9% vs 31%) compared with chemotherapy.[23] Overall, the results of these two trials confirm that blockades of PD-1 and CTLA-4 represent two distinct therapeutic approaches with unique mechanisms of action. The lack of durable benefit from ipilimumab does not appear to preclude benefit from subsequent PD-1-blockade, which highlights the non–cross-resistant potential of these immune therapies for advancing outcomes in metastatic melanoma.

PD-1 blockade is being studied extensively in the first-line treatment setting as well. A phase III trial that compared nivolumab to dacarbazine in previously untreated patients with metastatic melanoma without a BRAF mutation was reported recently. Nivolumab was associated with a significantly better 1-year OS rate (73% vs 42%), median PFS (5.1 mo vs 2.2 mo), and ORR (40% vs 14%) than dacarbazine.[24] Randomized trials comparing PD-1 blockade with CTLA-4 blockade for first-line therapy of metastatic melanoma include a trial of pembrolizumab at two schedules of administration (every 2 weeks vs every 3 weeks) vs ipilimumab (National Cancer Institute ClinicalTrials.gov identifier NCT01866319) and another trial that compares nivolumab alone vs nivolumab plus ipilimumab vs ipilimumab alone (NCT01704287); both trials have completed accrual and results are eagerly awaited.

Combination CTLA-4 + PD-1 Blockade

The distinct sites of action and the complementary roles of CTLA-4 and PD-1 in the regulation of adaptive immune responses suggest that combination blockade may be synergistic. While CTLA-4 blockade may lead to enhanced activation of naive T cells being primed by the APCs in the lymphoid tissue draining the tumors, PD-1 blockade may reverse exhaustion of the previously activated T cells in the peripheral tissues. Based on this rationale and on promising preclinical data, a phase I study tested the combination of ipilimumab plus nivolumab at several dose levels.[25] The results showed striking efficacy for this regimen, with near-CRs (defined as > 80% tumor regression) in the majority of patients (53%) treated with 4 cycles of ipilimumab (3 mg/kg every 3 weeks) plus nivolumab (1 mg/kg every 3 weeks) followed by nivolumab monotherapy (1 mg/kg every 2 weeks). The 2-year OS rate in patients treated with concurrent ipilimumab plus nivolumab in this phase I trial was recently reported to be 75%.[26] However, the combination was associated with considerable toxicity in this trial, with a 53% rate of grade 3 or higher treatment-related AEs.[25] The phase III trial comparing nivolumab plus ipilimumab vs nivolumab alone vs ipilimumab alone (NCT01704287) has completed accrual and results are awaited.

Important Considerations in the Use of Immune Checkpoint–Blocking Agents

Optimal dose

The optimal dose of ipilimumab (3 or 10 mg/kg) remains undefined. In a randomized phase II trial, 217 patients with advanced melanoma were randomly assigned to ipilimumab at either 10 mg/kg, 3 mg/kg, or 0.3 mg/kg every 3 weeks for 4 cycles (induction) followed by maintenance therapy every 3 months.[27] The results of this trial suggested that both the antitumor efficacy and toxicity were dose-dependent; however, the small number of patients in each group precluded a definite conclusion regarding the optimal dose of ipilimumab. Results of a prospective phase III trial (NCT01515189) that compares the 3 mg/kg vs 10 mg/kg doses are awaited.

Pembrolizumab is also being studied at different dose levels and schedules of administration. The KEYNOTE-001 trial included two dose cohorts of pembrolizumab administered at 2 mg/kg or 10 mg/kg every 3 weeks.[19] There were no major differences in efficacy or safety outcomes between the two cohorts, and the FDA-approved dose is 2 mg/kg every 3 weeks. Other trials are looking at administration schedules of every 2 weeks vs every 3 weeks (NCT01866319).

Optimal duration (maintenance or re-induction dosing)

Patients who appear to derive clinical benefit from the induction phase of immune checkpoint blockade (eg, ipilimumab administered every 3 weeks for a total of 4 doses) may potentially benefit from continuation of checkpoint blockade as maintenance therapy[17] or from re-induction dosing at the time of disease progression.[3,28] Such strategies may potentially assist the host immune system in continually adapting to the tumor immune-evasion mechanisms (such as altered antigen expression, production of immunosuppressive cytokines, T-cell exhaustion, etc) that lead to acquired refractoriness to immunotherapy. In the phase III ipilimumab monotherapy trial, 6% of patients in the ipilimumab groups received re-induction therapy at the time of progressive disease after experiencing initial clinical benefit (PR/CR/SD), and approximately two-thirds of these patients re-experienced an objective response or stabilization of disease.[3] Compared with the potential advantage of the re-induction strategy in some patients, the relative benefits of using maintenance dosing of ipilimumab have been more challenging to ascertain. On the other hand, most trials using PD-1 blockade have used continuous administration schedules (every 2 or 3 weeks) until disease progression, or in some trials up to 2 years maximum. Given the variety of response patterns seen with immune checkpoint blockade,[29,30] the optimal duration of therapy will likely need to be tailored to the unique disease course of the individual patient.

Response kinetics and patterns

Responses to ipilimumab may not be apparent until 12 to 16 weeks into the therapy.[3,17,29] This late-onset tumor regression with ipilimumab may be especially problematic in patients who are symptomatic or are at risk of impending symptoms from tumors that are bulky or in critical locations (such as the central nervous system). Infiltration of such tumors by immune cells may also result in transient inflammatory tumor swelling, further predisposing to symptoms. This inflammatory swelling of tumors may also be mistaken for disease progression by conventional antitumor response assessment criteria, for example Response Evaluation Criteria in Solid Tumors (RECIST)[31] or World Health Organization (WHO) criteria,[32] and may lead to inappropriate discontinuation of an effective immunotherapy.[29] These observations led to the development of modified criteria for evaluation of antitumor responses to immune therapy of solid tumors.[33] These modified criteria allow for continuation of immune therapy despite mild progression of existing lesions or the emergence of isolated new lesions, as long as the total tumor burden is not significantly increased. Tumor regression in patients treated with pembrolizumab, as well as ipilimumab plus nivolumab, appears to have an earlier onset than in those treated with ipilimumab, with most responses identified at 9 to 12 weeks.[19,21,25]

Immune-related adverse events

In addition to the more common irAEs seen with CTLA-4 and PD-1 blockade (such as diarrhea/colitis, pneumonitis, dermatitis, hepatitis, and hypophysitis), other immune toxicities have been observed in clinical trials, including episcleritis/uveitis, secondary sarcoidosis, neuropathies (such as enteric neuropathy and myasthenia gravis–type syndromes), and pancreatitis.[34,35] Algorithms have been developed for management of the more common irAEs and usually include the use of immunosuppressive treatments such as glucocorticoids or infliximab in severe cases.[34] The severity and onset of irAEs may be different for various drugs and dose levels; the reported rate of grade 3 or higher irAEs has varied from 9%–12% (pembrolizumab,[19] nivolumab[24]), to 15% (ipilimumab at 3 mg/kg[36]) and 18%–22% (ipilimumab at 10 mg/kg[17,37]), to as high as 53% (ipilimumab plus nivolumab[25]). Close vigilance, prompt identification, and aggressive treatment of irAEs are essential to prevent potentially life-threatening complications and long-term morbidity.

Other Immunotherapy Approaches

Buoyed by the success of immune checkpoint blockade, several other immunotherapeutic approaches for melanoma are in development. These include intratumoral immunotherapies (eg, talimogene laherparepvec[38]), novel cytokines (interleukin-15, interleukin-21[39]), cancer vaccines, and T-cell costimulatory agonists (CD40, OX40, CD137/4-1BB, etc). One such approach that deserves special mention is adoptive cellular therapy (ACT) using autologous tumor-specific immune cells, as this has been extensively investigated for metastatic melanoma.

ACT using tumor-infiltrating lymphocytes (TIL) has been associated with promising results in melanoma patients. TILs are isolated from the patient’s resected tumor; expanded and selected in the laboratory; and then infused back into the patient, usually preceded by administration of a lymphocyte-depleting conditioning regimen and followed by T-cell growth factors (such as HD IL-2).[40] TIL therapy has been associated with a high ORR of ~50% (CR rate, 7% to 22%) in treated patients with metastatic melanoma in several trials across multiple institutions.[41-43] However, these response rates should be interpreted with caution, as they do not account for patient selection bias and are not based on intention-to-treat (since many potential TIL patients do not have successful TIL generation or become ineligible due to progression of disease before TIL culture is completed). Nonetheless, the responses to TIL therapy have been durable, with 95% of CRs ongoing beyond 3 years[43]; even the majority of partial responses were ongoing for 13+ to 31+ months.[42]

To improve the efficacy further, promising combinations of TIL therapy and checkpoint blockade are being explored. The use of genetically engineered T cells is also being investigated in small pilot studies. T-cell receptors with high avidity for melanoma antigens such as MART-1 and NY-ESO-1 can be transduced into lymphocytes and induce tumor regression in melanoma patients; however, early data suggest that there may be a higher risk for “on-target/off-tumor” toxicity from genetically engineered T cells attacking healthy tissue, depending on the tumor antigen that is targeted.[8,44]

Despite the promising results, there are numerous challenges to widespread utilization of the ACT approach. These challenges stem from the need for specialized expertise in cell processing, the potential problems in cell product generation, the need for aggressive conditioning regimens, and the use of HD IL-2 in current protocols.

Molecular Targeted Therapy

Concurrent with the advances on the immunotherapy front, rapid progress has also been made in our understanding of the pathogenesis of melanoma, specifically in regard to the identification of somatic mutations occurring in melanoma tumors. Commonly mutated genes linked to the malignant phenotype have presented compelling targets for potential therapeutic intervention. The gene that encodes the intracellular kinase BRAF represents the most frequently mutated gene in melanoma, and this observation has focused attention on aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling pathway in melanoma, which transmits growth and survival signals via the RAS/RAF/MEK/ERK cascade.[45] The BRAF gene codes for one of the three serine/threonine kinases of the Raf kinase family, which is regulated by the (upstream) Ras protein. Somatic missense mutations in the BRAF gene that result in constitutive activation of the BRAF kinase have been reported in 60% of cutaneous malignant melanomas.[46,47] Approximately 80% to 90% of these mutations result in the substitution of glutamic acid for valine at codon 600 (BRAF V600E), although other activating mutations have been found (such as BRAF V600K and BRAF V600R).[48] The absolute and relative frequencies of the different mutations of BRAF are age-dependent, with an inverse relationship between age and BRAF mutation rate and a higher proportion of BRAF V600K mutations in older patients.[49] Small-molecule inhibitors of the BRAF V600 and MEK kinases have been successfully investigated in patients with BRAF-mutated metastatic melanoma. Similar efforts (outside the scope of this review) are underway in BRAF wild-type melanoma.

BRAF V600 inhibitors (vemurafenib, dabrafenib)

Earlier attempts to target BRAF kinase in melanoma with sorafenib, a weak inhibitor of the mutant BRAF kinase, were not successful.[50] In contrast to sorafenib, however, vemurafenib and dabrafenib are far more potent and selective, with marked antitumor effects against melanoma cells with the BRAF mutation but not against cells with wild-type BRAF.[51,52] Both of these drugs have been associated with improved outcomes in phase III trials in patients with BRAF-mutated metastatic melanoma.[4,53] Vemurafenib was compared with dacarbazine in 675 patients with untreated metastatic melanoma with the BRAF V600E mutation (the BRIM-3 trial).[4,54] Outcomes favored vemurafenib over dacarbazine for ORR (57% vs 9%; P < .0001), PFS (median PFS, 6.9 mo vs 1.6 mo; hazard ratio [HR] = 0.38; P < .001), and median OS (13.6 mo vs 9.7 mo; HR = 0.70; P = .0008).[54] Adverse events (AEs) led to dose interruption or modification in 38% of vemurafenib-treated patients, with skin symptoms (photosensitivity, rash, pruritis), arthralgias, and fatigue being the most common toxicities. Cutaneous squamous cell carcinoma (SCC), keratoacanthoma (KA), or both developed in 18% of vemurafenib-treated patients. These data led to FDA approval in August 2011 of vemurafenib for the treatment of patients with metastatic melanoma with BRAF V600 mutation.

The phase III trial of dabrafenib enrolled 250 untreated patients with unresectable stage III or stage IV melanoma with the BRAF V600E mutation, and randomized them to treatment with dabrafenib vs dacarbazine.[53] Outcomes favored dabrafenib over dacarbazine for ORR (50% vs 6%), PFS (median PFS, 5.1 mo vs 2.7 mo; HR = 0.30; P < .0001), and OS (HR = 0.61). AEs that required discontinuation or dose reduction occurred in 31% of dabrafenib-treated patients. The most common AEs were cutaneous toxicity, pyrexia, fatigue, headache, and arthralgias. Cutaneous SCC/KA developed in 6% of dabrafenib-treated patients. When compared with vemurafenib across trials, dabrafenib appears to be associated with somewhat lower incidences of phototoxicity and SCC or KA, but a higher incidence of pyrexia. These data led to FDA approval in May 2013 of dabrafenib for treatment of patients with metastatic melanoma with BRAF V600 mutation.

MEK inhibitors (trametinib)

MEK is a constituent of the MAPK pathway that functions downstream of BRAF and therefore represents a rational target for inhibition in BRAF-mutated melanoma tumors. Trametinib is an orally available, selective inhibitor of MEK1 and MEK2 and was tested in a randomized phase III trial vs cytotoxic chemotherapy (dacarbazine or paclitaxel) in patients with BRAF V600E– or BRAF V600K–mutated unresectable or metastatic melanoma.[55] Outcomes favored trametinib over chemotherapy, including ORR (22% vs 8%), PFS (median PFS, 4.8 mo vs 1.5 mo; HR = 0.45; P < .001), and 6-month OS (81% vs 67%; HR = 0.54; P = .01). HRs for progression within BRAF V600E– vs BRAF V600K–mutation subgroups were comparable. The most common AEs in the trametinib cohort were rash, diarrhea, and peripheral edema. Ocular symptoms occurred in 9% and decreased cardiac ejection fraction was reported in 7% of trametinib-treated patients. Unlike with BRAF inhibitors, secondary skin neoplasms were not observed in patients treated with trametinib. Dose interruptions (35%) and dose reductions (27%) were required because of AEs in trametinib-treated patients. These data led to the FDA approval in May 2013 of trametinib for the treatment of patients with metastatic melanoma with BRAF V600E or V600K mutation.

Combination BRAF + MEK inhibition (such as dabrafenib plus trametinib)

Despite the high rate of initial tumor regression associated with BRAF or MEK inhibitor monotherapy, disease progression eventually ensues in most patients. The most prevalent mechanisms (discussed below) of acquired resistance to BRAF inhibitors involve reactivation of the MAPK pathway and suggest a strong rationale for investigating dual inhibition of this pathway using BRAF inhibitors plus MEK inhibitors together.

Several randomized phase III trials comparing dual MAPK inhibition vs BRAF inhibition alone have been completed. In the first such trial, 423 patients with previously untreated metastatic melanoma with a BRAF V600E or V600K mutation received either the combination of dabrafenib plus trametinib or dabrafenib plus placebo.[56] Outcomes favored the combination arm over dabrafenib alone by ORR (67% vs 51%, respectively; P = .002), PFS (median PFS, 9.3 vs 8.8 months; HR = 0.75; P = .03), and 6-month OS (93% vs 85%; HR = 0.63; P = .02). Overall rates of AEs were similar between arms. Combination therapy, compared with dabrafenib alone, was associated with lower rates of cutaneous SCC/KA (2% vs 9%, respectively), skin papilloma (1% vs 21%), hyperkeratosis (3% vs 32%), and hand-foot syndrome (5% vs 27%), but with a higher rate of pyrexia (51% vs 28%) and higher rates of dose discontinuation (9% vs 5%), dose modifications (25% vs 13%), and treatment interruptions (49% vs 33%).

Another phase III trial comparing the dabrafenib plus trametinib combination vs the other BRAF inhibitor, vemurafenib, has shown similarly improved efficacy with the combination in terms of ORR (64% vs 51%, respectively; P < .001), PFS (median PFS of 11.4 mo vs 7.3 mo; HR = 0.56; P < .001), and 12-month OS (72% vs 65%; HR = 0.69; P = .005).[57] Similar results have been noted in yet another phase III trial of dual inhibition of BRAF and MEK, where treatment with vemurafenib plus the MEK inhibitor cobimetinib is compared with use of vemurafenib alone.[58]

Taken together, these observations have defined dual BRAF-and-MEK inhibition as the new standard of care for appropriately selected patients with advanced melanoma and tumors that harbor a BRAF V600-mutation. The combination of dabrafenib plus trametinib was approved by the FDA in January 2014 for treatment of patients with metastatic melanoma with BRAF V600 mutation.

Important considerations in the use of BRAF inhibitors and MEK inhibitors

BRAF mutation testing. Accurate determination of BRAF mutation status in melanoma tumor samples is critical, as the efficacy of BRAF inhibitors is restricted to patients whose tumors harbor activating BRAF mutations.[59] Also, the use of BRAF inhibitors in wild-type BRAF cells may lead to the paradoxical activation of the downstream MEK-ERK pathway, especially if there is a pre-existing upstream activator (such as RAS mutation) in the cells.[60] The earlier trials of vemurafenib had included only patients with melanoma tumors harboring BRAF V600E mutations, as detected by the Cobas 4800 BRAF V600 Mutation Test using a real-time polymerase chain reaction (RT PCR) assay.[4,59]

However, a sizable portion (~10%–30%) of BRAF V600–mutant melanoma tumors have activating mutations in BRAF other than V600E, including most commonly V600K and less commonly, V600D or V600R.[48] Importantly, the efficacy of BRAF and MEK inhibitors appears to be preserved in melanoma patients with BRAF V600K mutations.[4,48,54-58] Key considerations in accurate molecular diagnosis in melanoma patients also include adequate sampling of tumor tissue, specimen processing, tumor heterogeneity, and characteristics of the diagnostic assay.

Cutaneous neoplasms. The clinical use of BRAF inhibitors has been associated with rapid development of cutaneous neoplasms, such as SCC and KA; the median time to onset of SCC is approximately 8 to 10 weeks.[59,61] This rapid proliferation of SCC/KA after initiation of BRAF inhibitors is most likely related to the aforementioned paradoxical activation of the downstream ERK signaling by BRAF inhibitors in cells with wild-type BRAF mutations,[60,61] which is further supported by the finding of RAS mutations in the majority of these neoplasms.[47] As predicted by the preclinical models, dual BRAF-and-MEK inhibition suppresses this paradoxical activation, and the rate of SCC has been significantly lower with combination BRAF-plus-MEK inhibition.[56-58] Luckily, these neoplasms can usually be managed with surgery and have a low likelihood of invasive or metastatic potential.[62]

Resistance to therapy. A small proportion of patients with BRAF-mutated melanoma do not experience any regression of tumors following treatment with inhibitors of BRAF and MEK. The mechanisms of this intrinsic (or primary) resistance are not yet completely understood, although amplification of the cell cycle–regulator cyclin D1, loss of the tumor suppressor gene PTEN, and stromal production of hepatocyte growth factor have been implicated.[63-65] Also, despite the high rate of initial tumor regressions with BRAF inhibitors and MEK inhibitors (administered alone or in combination) in BRAF-mutated melanoma, the eventual progression of disease in most patients has been sobering. The mechanisms of acquired (or secondary) resistance continue to be elucidated at a rapid pace[66,67] and may include:

(1) reactivation of the ERK–MAP kinase signaling due to flexible switching between RAF isoforms,[68] dimerization of aberrantly spliced variants of BRAF V600E,[69] amplification of BRAF V600E,[70] upstream activating mutations in NRAS,[71] increased expression of COT as an alternative activator of MEK[72] or downstream activating mutations in MEK[73]; and/or

(2) activation of alternative signaling pathways, such as increased platelet-derived growth factor receptor (PDGFR)-β signaling[71] or activation of phosphoinositide 3-kinase (PI3K)/AKT signaling via increased levels of insulin-like growth factor receptor 1 (IGFR1).[68]

Thorough understanding of these diverse resistance mechanisms will be critical to the further development of rational combinatorial strategies and to the individualization of therapy in patients with BRAF-mutated melanoma.

How to Choose Among Systemic Therapy Options?

The availability of several immune checkpoint–blocking agents and MAPK inhibitors raises several questions about optimal timing and sequencing for the various systemic therapies available for treatment of melanoma. In the absence of clinical trial data that directly address these important questions, the unique characteristics of the various therapies-such as mechanism of action, treatment-associated toxicity, and durability and kinetics of response-may help in customizing therapy to match the unique goals of care for an individual patient, beyond just improving survival (Table).

General guidelines

We propose the following general guidelines for matching therapy to the primary goal of care.

“Cure.” Stage IV melanoma is usually fatal in most patients. However, there have been long-term survivors with durable CRs, suggesting that some patients may be cured. Durable CRs have mostly been observed in the context of immunotherapeutic interventions. HD IL-2 has been associated with durable CRs in a small subset (~6%) of patients with good performance status and adequate organ function, although this agent has limited utility due to the high rate of serious associated toxicities.[74] Immune checkpoint blockade with ipilimumab and anti–PD-1 antibodies has also been associated with long-term responses, and the toxicity profiles with these approaches are favorable compared with that of HD IL-2.

However, the CR rate has been low (0–7%) in most monotherapy trials.[3,17,19,24,27] While the initial data on duration of these CRs are promising, long-term durability remains unproven at this time. The preliminary observation of dramatic near-complete responses (> 80% tumor regression) in the majority (53%) of patients treated with ipilimumab plus nivolumab raises hope for improving the frequency of durable CRs in patients with stage IV melanoma.[25] Although less accessible, ACT with TIL therapy has also been associated with durable CRs in small clinical trials.[41-43]

Non-immunotherapeutic interventions have generally not been associated with durable CRs, although several recent phase III trials have reported high CR rates with BRAF inhibitors (4%–9%) and with BRAF-plus-MEK inhibition (10%–13%).[56-58] The durability of these CRs remains unproven.

Palliation of symptoms. In patients who have ongoing (or impending) symptoms due to bulky metastases or tumors in critical locations, it may be desirable to start therapy with an agent associated with a high ORR and rapid onset of response. Tumor “debulking” from such a therapy may not only facilitate quick palliation of symptoms, but it may also improve the patient’s suitability for subsequent immunotherapy, with the possibility of a durable CR.

BRAF inhibitors and MEK inhibitors, given alone or in combination, have been associated with high ORR in patients with BRAF-mutated melanoma and may provide rapid palliation of symptoms in this population. However, since most patients eventually develop resistance to these agents, close surveillance is necessary to identify disease progression early, to allow for timely intervention with an alternative systemic therapy. Anti–PD-1 agents (administered alone or in combination with ipilimumab) also appear to yield a high ORR and may be a reasonable choice for achieving this goal, especially in patients with BRAF wild-type melanoma tumors, in whom the ORR following cytotoxic chemotherapy has historically been low (~10%–30%).[2,24]

When considering an immunotherapeutic option for the goal of symptom palliation, the low ORR with some agents (such as HD IL-2 or ipilimumab) and the potential for delayed responses should be kept in mind, especially in treating patients with symptomatic or bulky metastases; such patients may experience worsening of symptoms and/or decline in their performance status due to the immune-mediated inflammatory swelling of tumors or, more commonly, disease progression.

Toxicity/quality of life (QoL). The toxicity profiles of various available therapies are quite distinct and should be considered when choosing therapy to match the efficacy goal. The risk of serious toxicity is more acceptable if the treatment goal (eg, durable CR) necessitates aggressive therapy (eg, HD IL-2, or maybe ipilimumab plus nivolumab in the future). When the goal is improving survival, discussion of the impact of treatment-related AEs on QoL is important.

Formal QoL studies are warranted in future trials comparing various therapies to allow the clinician to discuss the pros and cons of various options. Also, close vigilance for unexpected toxicities is warranted with sequential use of various therapies, as the safety of sequential administration of certain drugs is not known at this time. For example, use of HD IL-2 administered sequentially after ipilimumab was reported as potentially resulting in severe gastrointestinal toxicities such as bowel perforation.[75] Novel combinations of available agents should only be used in the context of a clinical trial, as serious toxicities could occur, such as the observation of severe hepatotoxicity in a trial combining vemurafenib plus ipilimumab.[76]

Cost. With the rapidly rising costs of healthcare in the US, patients and their oncologists will increasingly be obligated to weigh the costs of treatment against the desired goals. The costs of the recently FDA-approved therapies are fairly high in the US: ipilimumab (~$120,000 for the full induction course of four doses), pembrolizumab (~$150,000 per year), vemurafenib (~$12,000 per month), and dabrafenib plus trametinib (~$20,000 per month). The high cost of these drugs underscores the importance of identifying predictive biomarkers for appropriate selection of patients. Further research into the cost and cost-effectiveness of these expensive therapies is warranted to allow an informed discussion with our patients.

Conclusion

A new era in the systemic therapy of metastatic melanoma has begun, with the recent successes of immune checkpoint blockade and MAPK-targeted therapies. However, several questions remain regarding the optimal timing and sequence of currently available therapies, the mechanisms of resistance to various agents, and the identification of predictive biomarkers. Promising approaches utilizing new immunotherapies and molecular targeted therapies are in development. The possibility of further improvement in patient outcomes is exciting, and the dream of curing selected patients with advanced melanoma is poised to become a reality.

Financial Disclosure:Dr. Bhatia’s institution has received research support from Bristol-Myers Squibb and Merck. Dr. Tykodi has received clinical trial funding on behalf of his institution from Bristol-Myers Squibb and GlaxoSmithKline, and he is a consultant to Prometheus. The other authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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