New Prescribing Options in Metastatic Melanoma

Melanoma is currently the fifth-most common cancer diagnosis; however, the incidence of melanoma is increasing faster than that of any other form of cancer.^1,2 The rate of invasive melanoma in the United States is increasing by 4% to 6% every year, with a 1 in 30 lifetime risk of developing either invasive or in situ melanoma in 2010.¹ Surgical therapy for early-stage melanoma often yields long-term disease-free survival, but the prognosis is poor for patients with more advanced disease.

Until recently, there were few effective treatment options for patients diagnosed with unresectable stage III or IV melanoma.³ Dacarbazine was the only chemotherapy approved for treatment of metastatic melanoma, despite low overall response rates,⁴ while interleukin-2 (IL-2) was the only biologic therapy approved in this setting. Other chemotherapy agents including temozolomide, cisplatin, carboplatin, fotemustine, vindesine, and vinblastine have been evaluated as monotherapy or in association with IL-2 and/or interferon. These evaluations have not significantly improved upon overall survival (OS) or progression-free survival (PFS) associated with dacarbazine.^5-8 The utility of high-dose IL-2 is limited by toxicity concerns, reliance on specialized treatment centers, and lack of proven impact on long-term survival.^4,9

Advancements in understanding of the molecular pathways involved in the establishment and progression of melanoma have led to the development and recent approval of 2 new therapies with novel mechanisms of action for the treatment of melanoma. Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), was approved by the US Food and Drug Administration (FDA) in March 2011 for the treatment of patients with unresectable or metastatic melanoma; patients treated with this agent had improved OS compared with controls in 2 phase 3 trials of treatment-naive and previously treated patients with metastatic melanoma.^10-12 Vemurafenib, a small-molecule BRAF inhibitor, was approved in August 2011 by the FDA for patients with metastatic melanoma and documented V600E mutation in BRAF.¹³ Ipilimumab and vemurafenib are recommended in the current National Comprehensive Cancer Network guidelines for consideration in appropriate patients as per the approved indication for each agent.¹⁴

CLINICAL DEVELOPMENT OF IPILIMUMAB

Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4, an important component of immune signaling.⁴ CTLA-4 is upregulated by T cells following activation via antigen-specific stimulation and functions to downregulate the antigen-specific T-cell response. Ipilimumab, through blockade of the inhibitory CTLA-4 pathway, augments antitumor T-cell responses (

Figure 1

).

The efficacy and safety of ipilimumab monotherapy have been demonstrated in several phase 2 and 3 studies conducted in patients with unresectable stage III or stage IV disease (

Table 1

^13-17). In the first phase 2 study, patients with previously treated melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 cycles followed by maintenance therapy (every 3 months). A best overall response rate (BORR) of 5.8% was achieved, with a median OS of 10.2 months (7.6-16.3 months). Adverse events (AEs) were most frequently attributable to the agent’s immunebased mechanism of action and thus were termed immune-related AEs (irAEs). The most common irAEs were in the skin and gastrointestinal (GI) tract, with 19% grade 3 and 3.2% grade 4. The incidence of grade 3/4 irAEs was skin, 3.2%; GI, 8.4%; liver, 7.1%; and endocrine, 1.3%. Treatment was discontinued due to drug-related AEs in 18.1% of patients.18 In a second phase 2 study, 217 patients with previously treated melanoma were randomized to receive ipilimumab 10 mg/kg (n = 73), 3 mg/kg (n = 72), or 0.3 mg/kg (n = 72) induction and maintenance therapy. The BORR was 11.1% for 10 mg/kg, 4.2% for 3 mg/kg, and 0% for 0.3 mg/kg. Again, the most common grade 3 to 4 adverse events were GI irAEs, occurring in 15% and 3% of patients who received 10 mg/kg and 3 mg/kg ipilimumab, respectively. Adverse events leading to treatment discontinuation occurred in 15%, 7%, and 3% of patients receiving 10 mg/kg, 3 mg/kg, or 0.3 mg/kg ipilimumab, respectively.¹⁹

A third phase 2 study evaluated whether addition of budesonide to ipilimumab would decrease the incidence of immune-related diarrhea. Previously treated and treatment-naïve patients with melanoma received ipilimumab at 10 mg/kg with budesonide (n = 58) or placebo (n = 57). Addition of budesonide did not affect the rate of grade >2 diarrhea. The BORR was 12.1% for ipilimumab and budesonide and 15.8% for ipilimumab and placebo, with a median OS of 17.7 and 19.3 months, respectively.¹⁵

Other phase 2 studies evaluated ipilimumab with or without gp100 vaccine, according to HLA-A*0201 status.^16,17 The first study included previously treated and treatment-naïve metastatic melanoma patients (n = 139) and achieved a BORR of 17% and median PFS and OS of 2.9 and 15.7 months, respectively.¹⁶ The second study also included previously treated and treatment-naïve metastatic melanoma patients (n = 56) and achieved a BORR of 13%.¹⁷ Of note, response times exceeded 50 months for some patients achieving a partial response, and in patients achieving a complete response, some responseslasted more than 53 months.¹⁶ Results from phase 2 studies led to evaluation of ipilimumab safety and efficacy in phase 3 studies.

PHASE 3 REGISTRATION TRIALS

MDX10-20 was a phase 3 study to evaluate the safety and efficacy of ipilimumab administered at 3 mg/kg. Patients with unresectable stage III or IV melanoma (n = 676) were enrolled and randomized to receive ipilimumab alone (n = 137), gp100 alone (n = 136), or ipilimumab plus gp100 (n = 403). The gp100 vaccine was used as an active control because, based on previous studies, it wasbelieved to be at least as efficacious as placebo and had the potential for therapeutic synergy with ipilimumab.²⁰ Results showed a statistically significant increase in OS with ipilimumab alone (10.1 months vs 6.4 months; hazard ratio [HR] = .66; P = .003) or in combination with gp100 (10.0 months vs 6.4 months; HR = .68; P <.001) when compared with gp100 alone.¹⁰ The combination of ipilimumab and gp100 vaccine, while effective, did not demonstrate an increase in OS over ipilimumab alone. Rates of OS for the ipilimumab plus gp100 group, the ipilimumab alone group, and the gp100 alone group, respectively, were 43.6%, 45.6%, and 25.3% at 1 year, and 21.6%, 23.5%, and 13.7% at 2 years.¹⁰

As seen in phase 2 studies, the most common safety events were irAEs, which occurred in around 60% of the patients treated with ipilimumab and 32% of the patients treated with gp100. The frequency of grade 3 or 4 irAEs was 10% to 15% in the ipilimumab groups and 3% in the gp100 alone group. The most common irAEs were diarrhea and rash. Diarrhea occurred at any grade in 27% to 31% of the patients in the ipilimumab groups, but was grade 3 in 3.7% to 4.6% of patients with no grade 4 diarrhea observed. Rash occurred at any grade in 18% to 19% of the patients in the ipilimumab groups, but was grade 3 in 0.8% to 1.3% of patients with no grade 4 rash observed (

Table 2

^19,21). There were 14 deaths related to the study drugs (2.1%), of which 7 were associated with irAEs.¹⁰

Ipilimumab received approval in the United States as a monotherapy treatment for patients with unresectable or advanced melanoma, including fi rst-line or subsequent line of therapy. Ipilimumab is approved at 3 mg/ kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.²² Antitumor responses to ipilimumab often are delayed, and in some cases, may not be observed until week 12 of therapy or later. For this reason, ipilimumab therapy should be completed (as tolerated) despite the appearance of new lesions or growth of existing lesions. Formal assessments of tumor response should be conducted after completion of induction therapy.^23,24 Ipilimumab has since been approved in the European Union, Australia, and Canada. In the European Union and Canada, ipilimumab is approved for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy. In Australia, ipilimumab is also approved as monotherapy, but only for the treatment of patients with unresectable or metastatic melanoma who have failed or are intolerant to prior therapy.²⁵

Based on preclinical data showing synergy with anti-CTLA-4 blockade and chemotherapy and following promising phase 2 data, a second ipilimumab phase 3 study (CA184-024) in previously untreated patients with metastatic melanoma compared dacarbazine in combination with ipilimumab with dacarbazine plus placebo.^11,26

In this study, patients were randomized to ipilimuma (10 mg/kg) plus dacarbazine (n = 250) or dacarbazine plus placebo (n = 252). Patients with stable disease or an objective response and no dose-limiting toxic effects then received ipilimumab or placebo every 12 weeks as maintenance therapy. The primary end point was OS. Compared with dacarbazine plus placebo, dacarbazine plus ipilimumab demonstrated a statistically signifi cant increase in patients’ OS (11.2 months vs 9.1 months; HR = .716; P = .0009). The survival benefit achieved with ipilimumab was observed across patient subgroups regardless of age,sex, Eastern Cooperative Oncology Group performance status, baseline serum lactate dehydrogenase level, and substage of metastatic disease. In addition, there was a 24% reduction in the risk of progression with ipilimumab plus dacarbazine versus dacarbazine plus placebo (HR = .76; P = .006). Among all randomly assigned patients with a complete response or partial response, the median duration of response was 19.3 months (95% confi dence interval [CI], 12.1-26.1 months) for ipilimumab plus dacarbazine compared with 8.1 months (95% CI, 5.19-19.8 months) for dacarbazine plus placebo (P = .03). Estimated OS rates in the ipilimumab-dacarbazine arm and the dacarbazine-placebo arm, respectively, were 47.3% and 36.3% at 1 year, 28.5% and 17.9% at 2 years, and 20.8% and 12.2% at 3 years (HR for death with ipilimumab-dacarbazine = .72; P <.001).¹¹

The most common safety events were irAEs, and these were consistent with the types of events observed in previous studies. However, the rates of specific events differed from those observed when ipilimumab was used as monotherapy. Adverse events observed more frequently with ipilimumab-dacarbazine than with dacarbazineplacebo included elevation of liver enzymes, diarrhea, pruritus, and rash. Grade 3 or 4 AEs occurred in 56.3% of patients receiving ipilimumab-dacarbazine and in 27.5%of patients receiving dacarbazine-placebo (P <.001). The most common grade 3/4 irAE was immune-mediated hepatitis (31.6% vs 2.4% for ipilimumab-dacarbazine vs dacarbazine-placebo). Grade 3 or 4 immune-mediated enterocolitis was seen in 4.9% of ipilimumab-dacarbazine patients and no patients in the dacarbazine group. During the maintenance phase, the most common AEs (all grades) for ipilimumab-dacarbazine versus dacarbazineplacebo were rash (25.6% vs 5.7%), pruritus (16.3% vs 3.8%), diarrhea (14.0% vs 5.7%), nausea (7.0% vs 5.7%), and fatigue (9.3% vs 3.8%).¹¹

Unlike the previous MDX010-20 study,¹⁰ the present study reported that there were no study drug—related deaths, cases of GI perforation, or hypophysitis. Reasons for this difference may include possible protective effects of the combination with dacarbazine; an alternative explanation is an improved recognition of ipilimumab toxicities and more effective management of irAEs as a result of the ongoing clinical development program. In contrast to earlier studies, the most frequently reported AE in the present study was abnormal blood tests of liver function, which had been observed previously but never as the most frequently reported irAE. This apparent shift in the safety profi le may be due to the addition of dacarbazine, which has been associated with hepatic events.^27-29

Immune-related AEs and their management have been characterized during the clinical development of ipilimumab.³⁰ Although most irAEs were of mild to moderate severity, they can arise and/or escalate rapidly in severity. The median time to onset for any irAE grade 2 to 4 is 7 weeks (95% CI, 4.1-8.4 weeks) after initiation of treatment.^10,30 While most irAEs occur during the induction phase of treatment, some irAEs arise months after therapy has been completed, although such late-onset irAEs are rare. In clinical studies, AEs were managed by close adherence to guidelines, which emphasize vigilance and early use of corticosteroids as appropriate.¹⁰ Importantly, the use of corticosteroids in the management of safety events does not appear to negatively impact ipilimumab efficacy.^15,31 Treatment guidelines have been developed to assist healthcare professionals in managing ipilimumab- related safety events. These guidelines emphasize that unless an alternative etiology has been identifi ed, signs or symptoms of infl ammation should be considered immune mediated and appropriate treatment should be initiated.³² The importance of patient education cannot be overstated, and tools such as a patient wallet card can be useful.³²

CLINICAL DEVELOPMENT OF VEMURAFENIB (PLX4032)

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is an intracellular signaling cascade involved in the regulation of cell proliferation, differentiation, and survival.³³ In normal cells with unmutated BRAF, response to extracellular stimuli is achieved through binding of ligand to a relevant cell surface kinase receptor, which triggers phosphorylation and activation of Ras, a GTPase. Ras activation then induces dimerization and phosphorylation of RAF kinases—ARAF, BRAF and CRAF. These activated dimers drive phosphorylation of MAP-ERK-kinase (MEK), which in turn phosphorylates and activates ERK. Activated ERK is then able to enter the nucleus, where it acts as a transcription factor to activate genes involved in cell proliferation and survival (

Figure 2A

).^34,35

BRAF mutations involving the valine residue at position 600 (V600) have been described in approximately 8% of all solid tumors, including 50% of melanomas, 30% to 70% of papillary thyroid carcinomas, and 5% to 8% of colorectal adenocarcinomas.³⁶ The most common BRAF mutation in melanoma is a mutation in which V600 is replaced with glutamic acid (BRAFV600E). When this mutation is present, the MAPK pathway is inappropriately activated (approximately 500-fold) and becomes independent of upstream signaling.^{13,33,34,37,38} Of note, cells carrying the BRAFV600E mutation lack activated Ras; therefore, RAF kinases remain in the monomeric rather than the dimeric form; this hasimportance in the specifi city of BRAF inhibitors.³⁹

These observations provided a strong rationale for development of therapies targeting the MAPK pathway for cancer treatment. Vemurafenib binds to BRAFV600E and inhibits ERK phosphorylation in BRAFV600E-bearing cells but not in cells with wild-type unmutated BRAF (

Figure 2B

). In BRAFV600E-dependent tumor xenograft models, vemurafenib caused tumor regression or growth delay, without evidence of signifi cant cellular toxicity.³⁵

In a phase 1 dose-escalation trial in patients with metastatic melanoma, objective responses were seen in 11 of 16 patients (69%), while in an extension phase evaluating the maximum dose that could be administered without adverse effects, 26 of 32 patients (81%) achieved an objective response.⁴⁰ In a phase 2 study of vemurafenib in 132 patients with previously treated BRAFV600E-mutant metastatic melanoma (BRIM-2), 53% of patients achieved objective responses, 29% experienced stable disease, and 14% had disease progression. At a median followup of 12.9 months, median duration of response was 6.7 months, median PFS was 6.8 months, and median OS was 15.9 months.⁴¹ In this study, AEs observed in >25% of patients were arthralgia, rash, photosensitivity, fatigue, alopecia, pruritus, and skin papilloma, mostly grade 1 to 2. However, 26% of patients developed cutaneous squamous cell carcinoma (grade 3), the majority being keratoacanthoma type (Table 2).^42,43

A 6-month interim analysis of a large phase 3 study (BRIM-3) of vemurafenib in previously untreated patients with BRAFV600E-positive metastatic melanoma has been reported.¹³ A total of 2107 patients were screened, and 675 were randomized to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 intravenously every 3 weeks). Overall survival at 6 months was 84% (95% CI, 78%-89%) with vemurafenib compared with 64% (95% CI, 56%-73%) with dacarbazine; the corresponding median PFS was 5.3 months compared with 1.6 months. Patients receiving vemurafenib had a 63% relativereduction in the risk of death compared with patients receiving dacarbazine and a 74% relative reduction in the risk of either death or disease progression compared with patients receiving dacarbazine (P <.001 for both comparisons). In addition, response rates were significantly higher with vemurafenib compared with dacarbazine (48% vs 5%; P <.001) (Table 1). The OS benefit of vemurafenib over dacarbazine was observed across all patient subgroups regardless of age, sex, performance status, tumor stage, and lactate dehydrogenase level, although the study did not include patients with brain metastases.¹³

The most common AEs associated with vemurafenib therapy were cutaneous events, arthralgia, and fatigue. Keratoacanthoma, cutaneous squamous cell carcinomas, or both developed in 18% of patients who received vemurafenib, with all lesions treated by excision. Photosensitivity skin reactions of grade 2 or 3 were seen in 12% of the patients. In total, 38% of patients receiving vemurafenib and 16% of patients receiving dacarbazine required dose modifi cations or interruptions (Table 1). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended.¹³ The approved dose of vemurafenib is 960 mg (four 240-mg tablets) twice daily.²¹ For patients experiencing grade 2 to 3 AEs, interruption and/or dose modifi cations may be required and, in the case of grade 4 events, permanent discontinuation may be required.

The high response rates of vemurafenib are tempered with the development of resistance to the agent.^41,44 Varying mechanisms of resistance have been postulated, including bypass of the oncogenic pathway (eg, through activation of alternative pathways) or activation of a downstream target kinase (via secondary mutation and/or amplifi cation), both of which allow for continued signaling through the pathway with resultant disease progression.^44,45 Recent data suggest that resistance to RAF inhibitors may be mediated by the expression of splicing isoforms of BRAFV600E that dimerize in a RAS-independent manner.⁴⁶ Other data suggest that reactivation of the RAS/ RAF pathway and activation of an alternative pathway may be key mechanisms of disease relapse while on vemurafenib treatment, and these results support furtherclinical studies in which an inhibitor of downstream kinases such as MEK is added to vemurafenib treatment to overcome resistance.⁴⁷ Recent data have suggested that the heat shock protein-90 inhibitor XL888 is able to overcome vemurafenib resistance through a number of mechanisms.⁴⁸ Future studies will need to focus on mechanisms of overcoming acquired resistance.

EFFICACY IN PATIENTS WITH BRAIN METASTASES AND POTENTIAL COMBINATION THERAPY

Ipilimumab has been tested in clinical trials involving highly selected subjects with melanoma that has metastasized to the brain, and in this carefully monitored environment, there appear to be cases of antitumor activity in the brain metastases.⁴⁹ The safety profile of ipilimumab in patients with advanced melanoma and brain metastases was similar to that in patients without brain lesions, with no increase in central nervous system—related toxicities and no unique toxicities observed, provided patientsmet the inclusion criteria and there was adherence to the clinical protocol. The most common irAEs in this subset of patients included diarrhea, rash, and pruritus.^50,51

A phase 1 study of patients with incurable solid tumors with brain metastases, of whom 156 had metastatic melanoma, evaluated the safety of and response to treatment with dabrafenib, an inhibitor of BRAF kinase activity.⁵² The most common treatment-related AEs were cutaneous squamous cell carcinoma (20 patients, 11%), fatigue (14 patients, 8%), and pyrexia (11 patients, 6%). Responses were reported in patients at the dose of 150 mg twice daily, and of the patients with melanoma and untreated brain metastases, 9 of 10 had reductions in the size of brain lesions.⁵²

Preliminary data from an open-label pilot study of vemurafenib in previously treated, BRAFV600E-mutant metastatic melanoma patients with brain metastases indicates that this agent may also have activity against brain metastases.⁵³ A single-arm, phase 2 study specifically looking at use of vemurafenib in patients with brain metastases is ongoing.⁵⁴

Preclinical studies indicate that vemurafenib, at concentrations equivalent to those achieved in patients receiving standard doses, does not inhibit activation of T cells. Lymphocytes exposed to high concentrations of vemurafenib maintained their viability and function.⁵⁵ Furthermore, vemurafenib was able to enhance T-cell recognition of melanoma, again without negatively impacting lymphocyte function.⁵⁶ These data indicate the potential for the combination of immunotherapy and BRAF inhibition for the treatment of patients with BRAFV600E-mutant melanoma, and clinical trials are under development that will investigate the use of vemurafenib in combination with ipilimumab in patients with BRAFmutant metastatic melanoma. How best to combine or sequence these therapies remains unknown, but studies are ongoing.⁵⁷

EMERGING TREATMENT OPTION: MEK INHIBITION

Preclinical data suggest that that possession of a BRAF mutation may sensitize tumors to MEK inhibition; moreover, because MEK lies downstream of BRAF in the MAPK signaling pathway, inhibition of MEK may reverse resistance to BRAF inhibition.⁵⁸ As such, various agents targeted to MEK are currently in the early stages of clinical development.

The dual MEK1 and MEK2 inhibitor GSK1120212 is currently in phase 2/3 clinical development with an allied predictive biomarker analysis program.⁵⁹ At the recommended phase 2 dose of 2 mg orally once daily (n = 46), the most common AEs were rash (85% all grades; 2% grade ≥3) and diarrhea (48% all grades; 2% grade ≥3). GSK1120212 produced objective responses in phase 1/2 studies, with a response rate of 40% in patients with BRAF mutations (n = 20; this included 2 complete responses) and 9% in BRAF wild-type patients (n = 22; all were partial responses).60,61 In addition, 2 patients who had previously received vemurafenib experienced stable disease after GSK1120212. An ongoing trial is investigating the effectiveness of this MEK inhibitor in patients who have previously received treatment with a BRAF inhibitor.⁶²

CONCLUSION

For decades, patients with advanced or metastatic melanoma had limited treatment options. Now, oncologists and patients have therapeutic options that have demonstrated clinical benefi ts in large, randomized studies. Ipilimumab has demonstrated long-term effi cacy in 2 phase trials, and is approved in the United States at a dose of 3 mg/kg for use in fi rst- and second-line advanced or metastatic melanoma. Vemurafenib, approved in the United States for use in patients that harbor the BRAFv600E mutation, is associated with high response rates in that patient subpopulation. More information is needed to fully address the question of how to best sequence the newer agents, and how or whether to incorporate existing agents, into the treatment paradigm for advanced melanoma.

The choice of therapy for patients with advanced, unresectable melanoma may be based on the patient’s molecular characteristics (eg, presence or absence of oncogenic mutations), the presence or absence of tumorrelated symptoms, and the tempo of disease. For subjects whose tumors express BRAF that is wild type, the choice of therapy will emphasize ipilimumab, IL-2 (for patients able to tolerate the toxicities of high-dose IL-2), or a clinical trial (if available). For BRAF wild-type patients with symptomatic, rapidly progressing disease, cytotoxic chemotherapy such as dacarbazine- or taxane-based therapymay be used in an effort to cytoreduce the tumor.

For patients whose melanoma expresses mutation of BRAF by a Clinical Laboratory Improvement Amendments— approved laboratory assay, vemurafenib is added to the choices listed above, though the questions of ideal timing and sequencing have yet to be answered. Within the population with BRAF-mutant tumors, it might sometimes be appropriate to initiate systemic therapy with an immunotherapeutic agent (eg, ipilimumab, IL- 2) to potentially induce a long-term antitumor response. If progression of disease is documented and the timing of progression suggests that a delayed response to immunotherapy is unlikely (eg, continued progression of disease at 16 weeks after initiation of ipilimumab), immunotherapy can be discontinued and vemurafenib therapy started. In patients who present initially with symptomatic metastatic melanoma, who have a high bulk of metastatic disease and/or a rapid tempo of progression, there may not be enough time for induction of an effective immune response. In this situation, use of an agent specifically targeted at mutant BRAF (for example, vemurafenib) is clearly indicated because of the rapid onset of antitumor effect and the high response rate associated with BRAF inhibitors.

Although great progress has been made, most patients still experience disease progression despite therapy with the aforementioned newer agents, indicating a continued need for additional options. Clinical trials in melanoma include studies of cellular therapy with adoptive transfer of autologous, antigen-specific T cells; novel immune “check-point inhibitors” such as anti-PD-1 or anti-PDL1; lymphokines such as IL-15 or IL-21; antiangiogenic agents such as bevacizumab or anti-integrins; molecularly targeted agents such as inhibitors of MEK, RAS, or PI3 kinase; or combinations of the above. With new therapies

and new combinations being explored, the future is promising for treatment of patients with advanced or metastatic melanoma.