Drug Evaluation
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Ipilimumab in the treatment of advanced melanoma -- a clinical update 1.
Introduction
2.
Durable survival outcomes with ipilimumab
3.
Dosing issue
4.
Antitumor activity of ipilimumab in patients with active brain metastases
5.
Adjuvant ipilimumab therapy
6.
Biomarkers
7.
Current issue regarding ipilimumab sequencing with other therapeutic agents
8.
Current issues regarding ipilimumab in combination with other therapy
9. 10.
Conclusion Expert opinion
Dae Won Kim, Van Anh Trinh & Wen-Jen Hwu† †
The University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology, Houston, TX, USA
Introduction: Ipilimumab has become an important treatment option for patients with advanced melanoma; however, active research perseveres to resolve many clinical practice issues and to further improve the therapeutic index of this agent. Areas covered: This article aims to provide an update on long-term data, current challenge and recent progress relating to the clinical application of ipilimumab in the treatment of advanced melanoma. A literature search using PubMed database was conducted using search words ipilimumab, melanoma, treatment sequencing, adjuvant therapy, combination therapy, and biomarkers. Data were also obtained from meeting abstracts and clinical trial registries. Expert opinion: Signal of clinical activity as adjuvant therapy in patients with resected high-risk melanoma begins to emerge, but longer follow-up is required for confirmation. Many issues, such as optimal dosing schedules and therapeutic sequences, remain unraveled. At present, treatment should be individualized based on patient- and disease-specific factors. Immunotherapy like ipilimumab still represents the best treatment option for durable remission; however, targeted therapies are more appropriate for patients with BRAF V600-mutated tumor who are symptomatic or have rapidly growing disease. With novel therapeutic options in the pipeline, the role of ipilimumab continues to evolve in the rapidly changing treatment landscape of advanced melanoma. Most likely, this agent will be utilized in combinatorial or sequential approach. Keywords: adjuvant therapy, biomarkers, combination therapy, ipilimumab, melanoma, treatment sequencing Expert Opin. Biol. Ther. (2014) 14(11):1709-1718
1.
Introduction
Ipilimumab (Box 1) is a fully human mAb against cytotoxic T-lymphocyte antigen 4 (CTLA-4), an inhibitory immune checkpoint molecule that plays a critical role in regulating T cell-mediated antitumor immunity [1]. Since its approval by regulatory agencies worldwide [2,3], ipilimumab has become a standard treatment option for patients with unresectable or metastatic melanoma. Data of long-term follow-up are emerging to validate the durable survival benefit of this agent. Recently, three small-molecule kinase inhibitors targeting the MAPK signaling transduction pathway, vemurafenib, dabrafenib and trametinib, received marketing authorization for patients with BRAF V600-mutant advanced melanoma [4-6]. The rapid changes in the landscape of melanoma therapy have led to the debate regarding the optimal therapeutic sequence or combination for patients with advanced melanoma. Paralleling the effort to determine the optimal combinatorial or sequential therapy is the research endeavor to improve the safety and efficacy of ipilimumab. This review 10.1517/14712598.2014.963053 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name Phase Indication Pharmacology description Route of administration Chemical structure Pivotal trial(s)
Ipilimumab Launched Melanoma mAb, CTLA-4 inhibitor Intravenous Biological, protein, IgG1 mAb MDX010-20 CA184-024 EORTC 18071 E1609
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
aims to provide an update on long-term data, current challenge and recent progress relating to the clinical application of this immunologic agent in the treatment of advanced melanoma. 2. Durable survival outcomes with ipilimumab
Ipilimumab has demonstrated the ability to induce durable benefit with sustained disease control following completion of therapy. Long-term follow-up of the MDX010-20 and CA184-024 studies, the two randomized Phase III trials that gained ipilimumab regulatory approval for the treatment of advanced melanoma, revealed an overall survival (OS) duration of 2 years or longer in ~ 20% of patients [7-10]. At the 2013 European Cancer Congress, Schadendorf et al. presented pooled survival data of 1861 ipilimumab-treated patients in eight Phase II, two Phase III, and two retrospective observational studies [11]. The median OS was 11.4 months (95% CI: 10.7 -- 12.1), with a 3-year OS rate of 22% (95% CI: 20 -- 24). The plateau in the OS curve, evolving at 3 years and extending to 10 years, was independent of prior therapies or ipilimumab dosing schedules. When including the survival data from 2985 patients enrolled in the ipilimumab expanded access program (EAP), the median OS was 9.5 months and the 3-year OS rate was 21%. Notably, patients treated in the EAP were more likely to carry unfavorable prognostic factors, such as performance status (PS) of 2, brain metastases, multiple prior therapies or non-cutaneous melanomas [11]. 3.
Dosing issue
Optimal dosing schedules of ipilimumab The currently approved dosing schedule of ipilimumab is 3 mg/kg intravenously every 3 weeks for a total of four doses [2,3]. However, many questions remain unanswered regarding the optimal dosing schedules of ipilimumab. The randomized Phase III study comparing the safety and efficacy of the approved 3 mg/kg dose versus an investigational 10 mg/kg 3.1
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dose in patients with metastatic melanoma has completed accrual (NCT01515189), and its results are eagerly anticipated. Although a maintenance phase has been incorporated in a number of ipilimumab trials, its addition to standard induction schedule has not yet been systematically evaluated; therefore, it is not recommended at this time. Reinduction Reinduction ipilimumab, administered upon disease progression, has been used to restore disease control in patients who had attained stable disease (SD) or clinical response to previous ipilimumab. In the MDX010-20 study, 31 patients with confirmed objective response or SD lasting at least 3 months to prior ipilimumab were given reinduction therapy upon disease progression [7,12]. Each retreatment cycle, consisting of four doses, was delivered using the same schedule as the original treatment. Most patients were able to receive the full four doses of the first reinduction cycle; five of them completed the second retreatment cycle; and one concluded the whole third round. Approximately 70% of patients who received reinduction ipilimumab were able to regain disease control, with best overall response rate (ORR) approaching 40% [12]. The safety profile of reinduction therapy was similar to ipilimumab induction [12]. Additionally, the development of immune-related adverse events (irAEs) during the original treatment cycle did not increase the risk of toxicities of subsequent retreatment series. Reinduction ipilimumab is currently recognized as a viable therapeutic option for select patients who did not experience high grade irAEs from previous ipilimumab and had achieved initial clinical response or SD lasting at least 3 months [13]. 3.2
Antitumor activity of ipilimumab in patients with active brain metastases
4.
The development of brain metastases is a common and devastating event in patients with advanced melanoma. The prevalence of brain metastases is 20 -- 40% in clinical series and up to 75% in autopsy series [14,15]. In general, patients with advanced melanoma and active brain metastases have the worst prognosis, with a median OS of < 5 months [15,16]. Because of this, they are often excluded from clinical trials, and effective systemic treatment for this patient population remains an area of medically unmet need. Intracranial activity of ipilimumab has been demonstrated in a multicenter Phase II study by Margolin et al. [17]. Ipilimumab’s antitumor activity was similar in the brain and at extracranial sites. Out of 51 patients who were neurologically asymptomatic and were not receiving corticosteroid, 8 achieved partial response and 4 had SD in the brain according to the modified WHO criteria. However, the rate of disease control in the brain appeared lower in the steroid-dependent patients (n = 21), with one patient achieving a complete response (CR) and one SD. This encouraging result has led to the NIBIT-M1 trial, in which ipilimumab was combined
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Ipilimumab
with fotemustine, a nitrosourea able to cross the blood--brain barrier, to treat 20 patients with asymptomatic brain metastases [18]. The majority of those patients had 2 -- 3 intracranial lesions; a third of them had received prior local therapy including stereotactic radiosurgery or whole brain radiotherapy. Eight patients achieved an objective response and two of them had disease stabilization in the brain. The positive result of this trial is being confirmed in the ongoing Phase III NIBIT-M2 trial, in which the combination is compared with single-agent fotemustine in patients with stage IV melanoma with brain involvement. Additionally, ipilimumab is continued to be developed in combination with other modalities, such as radiotherapy, temozolomide, selective BRAF kinase inhibitors or other immunostimulatory agents, for the management of melanoma patients with brain metastases. 5.
Adjuvant ipilimumab therapy
Expansion of ipilimumab utility into the adjuvant setting is underway. Adjuvant ipilimumab for patients with resected high-risk melanoma is being tested in two ongoing Phase III studies. In EORTC 18071, ipilimumab, administered at 10 mg/kg every 3 weeks for four doses plus subsequent maintenance dose every 12 weeks for up to 3 years, is compared against placebo in 951 patients with resected stage III melanoma [19]. The study population was at particularly high risk for disease relapse: 80% with stage IIIB or IIIC melanoma and 20% with stage IIIA disease with at least 1 nodal metastatic focus of greater than 1 mm in diameter. The primary endpoint was relapse-free survival (RFS). The preliminary safety and efficacy data have recently been presented at the 2014 ASCO Annual Meeting, demonstrating an RFS advantage favoring adjuvant ipilimumab, with median RFS of 17.1 and 26.1 months (hazard ratio [HR]: 0.75; 95% CI: 0.64 -- 0.90) in the placebo and ipilimumab groups, respectively. Although the manifestation of irAEs was similar to prior experience with ipilimumab, the severity of toxicities appeared more substantial, causing treatment discontinuation in 48.8% of patients and limiting the median number of doses per patient to 4. Most irAEs were manageable and reversible with the established treatment algorithms. Five patients (1.1%) died of treatment-related adverse events, three from colitis and one each from myocarditis and Guillain--Barre syndrome [19]. EORTC 18071 is ongoing, and data remain blinded for OS and distant metastasis-free survival. E1609 is the other Phase III adjuvant study examining the efficacy of postoperative ipilimumab at either 3 mg/kg or 10 mg/kg for four induction doses followed by four additional maintenance doses every 12 weeks versus standard adjuvant high-dose interferon for 1 year (NCT01274338). This study will supplement EORTC 18071 in defining the role of ipilimumab, especially at the dose recommended by regulatory agencies worldwide, in preventing disease recurrence in patients with resected high-risk melanoma.
6.
Biomarkers
Since only a small fraction of patients derive clinical benefit from ipilimumab and significant irAEs are associated with this agent, various biomarkers to predict clinical response and/or high-grade adverse events to ipilimumab, from the easily obtainable parameters such as lactate dehydrogenase (LDH) and absolute lymphocyte counts (ALC) to those requiring complex analytical methods like circulating antibody to the cancer-testis antigen NY-ESO-1 or frequency of monocytic myeloid-derived suppressor cells, have been studied extensively. LDH is a well-known prognostic indicator in melanoma. In subgroup analyses of the MDX010-20 and CA184-024 studies, clinical benefit of ipilimumab was primarily limited to the patients with non-elevated LDH at baseline [7,8]. More recently, multivariate analysis identified baseline LDH as the strongest predictive factor for OS in a retrospective multi-center study involving 166 patients with advanced melanoma treated in the ipilimumab EAP in the Netherlands [20]. At a median follow-up duration of ~ 18 months, median OS was 10 months in the group with baseline LDH less than twice upper limit normal (ULN) versus 2.9 months in those with LDH greater than twice ULN (p < 0.001). This finding was corroborated in an independent cohort of 64 patients treated with ipilimumab in the United Kingdom, with median OS of 5 months in the group with baseline LDH less than twice ULN versus 3.2 months in those with LDH greater than twice ULN (p = 0.004) [20]. ALC has also been examined as a predictive biomarker of tumor response to ipilimumab. In a single-institution evaluation of 51 patients treated with compassionate-use ipilimumab at 10 mg/kg, Ku et al. noted a statistically significant improvement in OS in the subgroup with high ALC (ALC ‡ 1000/µl) after the first or second ipilimumab dose [21]. Median OS was 7.9 months in patients with high ALC versus 1.8 months in those with low ALC at week 4 after treatment initiation (p < 0.01). A similar result was observed when OS was correlated with ALC at week 7, with median OS of 11.9 months versus 1.4 months in the subgroup with high and low ALC, respectively (p < 0.0001) [21]. This pattern persisted after adjusting for baseline LDH. The strong association between ALC, while measured at different time points, and OS has also been shown by other non-controlled singleinstitution studies of ipilimumab [22,23]. Many other biomarkers have been correlated with clinical benefit of ipilimumab, such as circulating VEGF-A [24], Creactive protein [22], elevation of inducible co-stimulator (ICOS) expressing CD4+ T cells [25], integrated NY-ESO-1specific antibody and CD8+ T-cell response [26], and frequency of monocytic myeloid-derived suppressor cells [27]. Despite the promising results of the aforementioned biomarkers, they must be validated in prospective clinical trials before being incorporated into routine clinical practice.
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Cut-off points and measurement timelines remain to be determined and justified. Some of these surrogate markers will not be evident until after the initiation of ipilimumab; thus they may not be useful for patient screening. In view of novel treatment options emerging in the pipeline, future ipilimumab biomarker studies must adapt to the rapidly evolving role of this agent.
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7. Current issue regarding ipilimumab sequencing with other therapeutic agents
The addition of four novel agents (ipilimumab and three targeted agents) to the therapeutic repertoire of advanced melanoma has undoubtedly made treatment decisions more complex, particularly for those patients with BRAF V600mutated melanoma.
Treatment sequencing with high dose IL-2 IL-2 is a T-cell growth factor necessary for CD8+ T-cell proliferation, survival and effector function [28]. High-dose IL-2 was approved by the US FDA for the treatment of advanced melanoma based on durable disease control observed in a small group of patients in Phase II studies [29]. It is not clear whether ipilimumab or high-dose IL-2 should be administered first. At present, the Society for Immunotherapy of Cancer recommends that high-dose IL-2 precede ipilimumab in the patients meeting high-dose IL-2 eligibility criteria for two important reasons [30]. First, high-dose IL-2 does not negatively impact subsequent administration of ipilimumab in terms of efficacy and safety, whereas there are limited data on the outcomes of the opposite sequence. In the MDX01020 study, 23% of patients had received prior high-dose IL-2 [7]. A retrospective evaluation by Joseph et al. of 48 patients treated with ipilimumab after progressing on highdose IL-2 demonstrated a response rate of 16.7% with a median OS of 12 months, similar to the result of the MDX010-20 [31]. Second, many clinicians are concerned about the feasibility of delivering high-dose IL-2 after ipilimumab. In contrast to the acute toxicities of high-dose IL-2, which resolve rapidly after treatment discontinuation, ipilimumab-associated irAEs, such as colitis and hepatitis, can take weeks to subside and may require prolonged corticosteroids or other immunosuppressive therapies [32], thus precluding subsequent high-dose IL-2. In addition, a retrospective review of 22 patients treated with high-dose IL-2 after ipilimumab at the National Cancer Institute revealed an incidence of bowel perforations of 13.6%, significantly higher than the reported rate of 0.45% in patients who received high-dose IL-2 alone [33,34]. PROCLIVITY 02, a randomized Phase IV study comparing the two sequences of high-dose IL-2 and ipilimumab in patients with metastatic melanoma, is being conducted to define the optimal sequence in delivering these two immunologic agents (NCT01856023). 7.1
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Treatment sequencing with BRAF inhibitors Whether ipilimumab or BRAF inhibitor represents the optimal frontline therapy for patients with BRAF V600-mutated advanced melanoma remains debatable. Proponents for ipilimumab first in the sequence underscore its durable benefit, a significant advantage when compared with the short-lived anti-tumor effect of targeted therapy. Despite the high response rate (the majority of tumor responses to BRAF inhibitors are partial), duration of response to BRAF inhibitors rarely lasts beyond a year. In the extended follow-up analysis of BRIM-3, the Phase III study establishing the survival benefit of the BRAF inhibitor vemurafenib, 14% of patients were progression free at 18 months [35]. With disease progression on BRAF inhibitors, ~ 50% of patients are rapid progressors and likely to die within 28 d of the last dose of BRAF inhibitors [36-38]. Thus, the likelihood of a timely response to salvage ipilimumab is low in this setting, considering the delayed onset of ipilimumab’s antitumor activity. These notions have prompted many retrospective analyses to discern the relative difference in survival outcomes of opposite treatment sequences. In a retrospective cohort of 274 patients treated with BRAF inhibitors at five different institutions, Ackerman et al. observed similar benefits to targeted therapy (vemurafenib, dabrafenib, or dabrafenib-trametinib combination), whether administered before or after immunotherapy (high-dose IL-2 or ipilimumab), with respect to the response rate (66 vs 57%; p = 0.31), progression-free survival (PFS) (5.6 vs 6.7 months; p = 0.43), and OS (13.4 vs 19.6 months; p = 0.4) [37]. However, in the subgroup of 40 patients treated with ipilimumab after BRAF inhibitor failure, no one achieved a clinical response to ipilimumab, with 6% having SD and 94% experiencing progressive disease [37]. Median OS was 5 months (95% CI: 3 -- 8.8), inferior to the results of MDX010-20 and CA184-024 trials. Notably, only 50% of these patients were able to complete all four doses of ipilimumab. Above data pose the hypothesis that immunotherapy administered before BRAF inhibitor may have a survival advantage when compared with the opposite sequence. This notion is corroborated by the data from 93 patients identified from the Italian cohort of the ipilimumab EAP to have sequentially received a BRAF inhibitor and ipilimumab [38]. Survival outcome evaluation of this patient subgroup demonstrated a statistically significant improvement in median OS when ipilimumab was administered before targeted therapy (14.5 vs 9.9 months; p = 0.04) [38]. Despite the intriguing results, the aforementioned retrospective studies are subjected to recall and patient selection biases. Since high probability and rapid onset of tumor response are two key advantages of BRAF inhibitors, these agents are particularly valuable to the patients with bulky tumor load, active brain metastases, elevated LDH, poor PS, and/or heavy symptom burden who urgently need a therapeutic response. Therefore, the patient- and/or disease-specific characteristics that steer treating physicians to select BRAF 7.2
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inhibitors upfront may signify a patient subset with a more aggressive tumor biology compared to those who started out with immunotherapy. Moreover, the practice of continuation of BRAF inhibitors post progression or resumption of targeted therapy subsequently is difficult to capture, further confounding the analyses [37,38]. Thus, there is an urgent need for randomized controlled trials to determine the optimal sequence of therapies; nevertheless, the rapidly changing treatment options for immuneand targeted therapy make the design of these sequencing trials a moving target. Until data are available from randomized controlled trials to settle the therapy sequencing dilemma, most clinicians agree that immunotherapy, such as ipilimumab or high-dose IL-2, should be considered first in asymptomatic patients with low or moderate disease burden since immunotherapy offers the best chance for long-term disease control [13]. BRAF inhibitors should be used upfront only in patients with BRAF V600-mutated advanced melanoma with symptomatic bulky disease, active brain metastases, markedly elevated LDH, and/or poor PS who urgently need a rapid therapeutic response [13].
Current issues regarding ipilimumab in combination with other therapy
8.
In an effort to improve the response rate of ipilimumab, various combinations of ipilimumab with other therapeutic agents are being investigated. Below are select combinations with sound rationales and/or encouraging preliminary results.
the discontinuation of the trial. Investigators are now assessing the toxicity profile of sequential administration of vemurafenib and ipilimumab in a Phase II study (NCT01673854). Ipilimumab in combination with dabrafenib with or without trametinib
8.1.2
The low incidence of hepatic adverse events with dabrafenib [5], the other commercially available BRAF inhibitor, makes it an ideal candidate for combination therapy with ipilimumab. Ipilimumab with dabrafenib plus or minus trametinib, a MEK inhibitor, has been investigated in a Phase I dose finding study in patients with BRAF V600-mutant advanced melanoma (NCT01767454). Preliminary safety data have recently been presented at the 2014 ASCO Annual Meeting [42]. The doublet regimen, in which both ipilimumab and dabrafenib were administered at full dose, was well tolerated (n = 8). Common adverse events, primarily of grade 1 or 2, were chills, fatigue, hand-foot syndrome, pyrexia and maculopapular rash. Transient grade 3 transaminitis was documented in one out of eight patients after the second dose of ipilimumab and resolved after a week of high-dose steroid. The doublet arm is now entering the expansion phase. The triplet regimen began with ipilimumab at full dose in combination with dabrafenib 100 mg twice daily and trametinib 1 mg daily (n = 7). Early-onset high grade colitis and intestinal perforation were seen in two out of seven patients receiving the three drug combination, leading to the discontinuation of the triplet arm [42]. Ipilimumab in combination with other biologics Ipilimumab has also been combined with other biologics such as vaccines, cytokines or other immune checkpoint-targeted antibodies. 8.2
8.1
Ipilimumab in combination with targeted therapy
Theoretically, rapid tumor antigens released by MAPK inhibitor-induced tumor apoptosis can effectively stimulate antigen-specific cytotoxic T-lymphocyte responses, of which activation and proliferation are augmented by concurrent ipilimumab. In addition, preclinical data have shown that tumor response to BRAF inhibitor therapy is associated with an increase in melanoma antigen expression and CD8+ T-cell infiltration in tumor microenvironment [39,40]. Combination with vemurafenib A Phase I dose finding study was conducted to explore the safety of concurrent ipilimumab and vemurafenib, a selective BRAF inhibitor [41]. After 1-month vemurafenib 960 mg orally twice daily lead-in, the first 6-patient cohort received both drugs concomitantly, ipilimumab 3 mg/kg intravenously every 3 weeks for four doses and vemurafenib 960 mg orally twice daily. Within 5 weeks after the first dose of ipilimumab, four out of six patients developed grade 3 transaminitis. A reduced dose of vemurafenib, 720 mg twice a day, was used for the second cohort. Despite this modification, grade 2 or 3 elevation in liver function tests was again observed in three out of four patients within 3 weeks from the first ipilimumab administration. The additive hepatotoxicity seen with concurrent administration of these two agents led to 8.1.1
Ipilimumab in combination with high-dose IL-2 High-dose IL-2 and ipilimumab are two immunotherapeutic options currently available for the management of advanced melanoma. IL-2 has been shown to induce not only effector T-cell stimulation but also regulatory T-cell (Treg) expansion [28]. Since CTLA4 is constitutively expressed on Tregs and contributes to their immunosuppressive function [43], concurrent ipilimumab and high-dose IL-2 administration may have an additive or synergistic effect. This concept has been explored clinically in a Phase I/II study by Prieto et al. [44]. In this study, three patients each received ipilimumab at 0.1, 0.3, 1, and 2 mg/kg/dose; 24 patients had ipilimumab at 3 mg/kg/dose. The first dose of ipilimumab was given without IL-2. All subsequent doses of ipilimumab were followed by high-dose IL-2 within 24 h. Patients received up to six cycles of the combination. At a median follow-up duration of 84 months, the ORR was 25%, with unprecedented CR rate of 17%. All CRs are durable, lasting 76 -- 89+ months. The median OS was 16 months, with a 5-year OS rate of 25%. The incidence of grade 3 or 4 irAEs was 17%, with gastrointestinal (GI) irAEs (gastritis, duodenitis, enteritis, and 8.2.1
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colitis) being the most common [44]. The combination of ipilimumab and IL-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial. Ipilimumab in combination with nivolumab Programmed cell death-1 (PD-1) receptor, expressed on activated T- and B-cells, natural killer cells and monocytes, is another important negative regulator of the immune system. Engagement of PD-1 to its primary ligand, PD-1 ligand 1 (PD-L1 or B7-H1), inhibits T-cell effector function, ultimately inducing T-cell exhaustion and deletion [45,46]. Upregulation of PD-L1 expression has been demonstrated in the tumor microenvironment of many human tumor systems, including melanoma. MAbs targeting the PD-1/PDL1 pathway are actively investigated as immunotherapeutic strategies for various human cancers. Nivolumab (BMS 936558, MDX-1106), a fully human anti-PD1 antibody, has been shown to generate robust and durable clinical response in patients with advanced melanoma [47]. Since CTLA-4 and PD-1 are non-overlapping regulators of the activation and effector phases of T-cell immunity, respectively, ipilimumab and nivolumab have been explored either as sequential or concurrent administration in a Phase I study [48]. From December 2009 to February 2013, 53 and 33 patients with advanced melanoma were treated with the concurrent and sequenced regimen, respectively. Patients on the sequential treatment must have already received at least three ipilimumab doses, with the last dose within 4 -- 12 weeks prior to the first nivolumab administration. Nivolumab, either at 1 or 3 mg/kg/dose, was repeated every 2 weeks for up to 48 doses in the sequenced regimen. Patients treated in the concurrent arm received escalating doses of both mAbs every 3 weeks for four cycles followed by a maintenance phase, with nivolumab preceding ipilimumab administration in each cycle [48]. Safety and efficacy data of the sequential regimen were similar to the Phase I experience of single-agent nivolumab, with grade 3 or 4 therapy-related toxicities of 18% and ORR of 31% [48,49]. A post-hoc analysis was performed to assess the effect of residual ipilimumab plasma concentration on response to subsequent nivolumab treatment. Plasma ipilimumab levels ranged from 0.881 to 33.90 mcg/ml, with a median exposure of 7.255 mcg/ml. Interestingly, those with residual ipilimumab exposure ‡ 7.255 mcg/ml attained a higher ORR to nivolumab than those with residual ipilimumab level below the median (57.1 vs 14.3%) [49], supporting the notion of additive or synergistic activity of the two agents. More remarkable is the efficacy of the concurrent regimen. The maximum tolerated dose (MTD) of the concurrent regimen was established at 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab [48]. The overall confirmed response rate was 42%. Even more unprecedented was the depth of the response, with tumor reduction of 80% or more at 36 weeks observed in 42% of patients. Median duration of response has not been reached, and the majority of clinical responses are ongoing, even after treatment discontinuation. Survival
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outcomes are also promising for patients treated with the combination, with 79% of patients alive at 2 years and a median OS of 40 months [49]. The concurrent regimen was more toxic. Serious treatmentrelated adverse events were documented in 49% of patients, with common grade 3 or 4 adverse events including elevated serum pancreatic enzymes (25%), hepatic toxicities (15%), GI manifestations (9%) and renal disorders (6%) [48]. Cases of pneumonitis or uveitis were also reported. Most toxicities were manageable and reversible with standard irAE management guidelines. Although there was no treatment-related death, 21% of patients discontinued therapy due to treatment-related adverse events [48]. The extraordinary antitumor activity of nivolumab-ipilimumab combination provides evidence of synergistic activity of the combined immune checkpoint blockades, which is being prospectively validated in CheckMate 069, a randomized Phase II study comparing the ORR of nivolumab combined with ipilimumab versus ipilimumab monotherapy, and CheckMate 067, a randomized, double-blind Phase III trial comparing the survival outcomes of nivolumab and/or nivolumab plus ipilimumab to ipilimumab alone, in patients with newly diagnosed advanced disease (NCT01844505). Ipilimumab in combination with GM-CSF Based on the synergistic activity of ipilimumab and GM-CSFtransduced allogeneic tumor cell vaccine in preclinical animal models [50], E1608, a randomized Phase II study, was conducted to explore the efficacy and safety of the combination of ipilimumab and GM-CSF [51]. A total of 245 previously treated patients with advanced melanoma were randomized to ipilimumab, 10 mg/kg intravenously for four doses followed by a maintenance phase, with or without GM-CSF 250 mcg subcutaneously for 14 d of a 21-d cycle. At a median follow up duration of 13.3 months, no statistically significant difference was noted in ORR or PFS between the two treatment arms. However, there was an OS benefit favoring the combination, 17.5 months versus 12.7 months (HR: 0.64; p = 0.014) [51]. Notably, the combination seemed better tolerated than single-agent ipilimumab, with high-grade irAEs of 44.9 and 58.3% (p = 0.038), respectively. Specifically, the addition of GM-CSF appeared protective against grade 3 -- 5 pulmonary (0 vs 7.5%; p = 0.030) and GI (16.1 vs 26.7%; p = 0.047) irAEs [51]. This organ-specific protective effect was attributed to the role of GM-CSF in maintaining pulmonary homeostasis and accelerating GI mucosal repair. GM-CSF, the first agent shown to ameliorate ipilimumabinduced irAEs without compromising its clinical activity, is worthy of further investigation. 8.2.3
Ipilimumab in combination with bevacizumab Pre-treatment circulating VEGF-A levels have been correlated with clinical response and OS of patients with advanced melanoma treated with ipilimumab [24]. VEGF has been shown to elicit negative impact on anti-tumor immunity through 8.2.4
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inhibiting dendritic cell maturation and antigen presentation. In addition, VEGF influences lymphocyte trafficking into tumor deposits. These suggest a potential synergy between ipilimumab and bevacizumab, an antagonist mAb against VEGF-A. A Phase I study has been conducted to investigate the above concept in four cohorts of patients with advanced melanoma [52]. Cohorts 1 and 2 received ipilimumab, 10 mg/kg every 3 weeks for four doses followed by a maintenance phase, in combination with bevacizumab 7.5 or 15 mg/kg every 3 weeks, respectively. Similar bevacizumab dosing schemas, combined with ipilimumab 3 mg/kg, were used for cohorts 3 and 4. Five patients were enrolled in each cohort. An additional 12 patients were evaluated at the MTD. No dose-limiting toxicities were observed in any of the cohorts. The MTD was declared at the dose level of ipilimumab 10 mg/kg with bevacizumab 15 mg/kg (cohort 2). At a median follow-up of 17.3 months, best ORR, median PFS and OS were 19.6% (95% CI: 9 -- 34%), 9 months (95% CI: 5.5 -- 14.5) and 25.1 months (95% CI: 12.7--not reached), respectively, for the entire study population. Best results were achieved in cohort 2; however, there were no statistically significant differences in the aforementioned endpoints among the cohorts. Correlative pharmacodynamic investigations demonstrated increased immune infiltrates of CD8+ T cells and CD162+ dendritic macrophages in tumor microenvironment, expanded circulating memory immune cells and enhanced antibody response to galactins [52]. Ipilimumab in combination with radiotherapy Rapid antigen release from radiation-induced tumor cell apoptosis can also prime antigen-specific cytotoxic T lymphocytes. Supporting this hypothesis is the observation of abscopal effect, an event in which local radiotherapy causes tumor regression at a distant site [53]. Therefore, there is a strong interest in combining ipilimumab with radiotherapy [54]. Several trials are ongoing to examine the combination of ipilimumab with concomitant radiotherapy in patients with metastatic melanoma with or without brain metastases (NCT01565837, NCT0170350). 8.3
9.
Conclusion
immune-related toxicity, as well as define optimal treatment sequence or combination with other therapies. Early Phase I/ II studies of various combinations have suggested synergistic antitumor activity with an acceptable safety profile. The role of this agent continues to evolve with the rapidly changing treatment landscape of advanced melanoma. 10.
Expert opinion
Currently, ipilimumab and reinduction have been wellintegrated into the treatment schema of advanced melanoma. It is also a viable option for patients with brain metastases who are neurologically asymptomatic and not receiving corticosteroid. The signal of clinical activity as an adjuvant therapy in preventing disease relapse in patients with resected high-risk melanoma has begun to emerge, but still awaits maturation of EORTC 18071 survival data and confirmation from the E1609 study, especially at the currently approved dose level. Many issues with ipilimumab therapy remain unresolved, such as optimal dosing schedules and therapeutic sequences or combinations. Until data from randomized controlled trials become available, treatment should be individualized based on patient- and disease-specific factors. Immunotherapy, such as ipilimumab and high-dose IL-2, remains the best treatment option for durable remission, and high-dose IL-2 should precede ipilimumab in the patients meeting high-dose IL-2 eligibility criteria. Targeted therapies are more appropriate frontline therapy for patients with BRAF V600-mutated advanced melanoma who are symptomatic with rapidly growing tumors. With the emerging PD-1:PD-L1 pathwaytargeted mAbs and the rapidly changing landscape of melanoma treatment, the role of ipilimumab continues to evolve and will most likely be integrated into a combinatorial approach. Intensive research effort has focused on identifying biomarkers to predict clinical response and/or high-grade adverse events to ipilimumab. However, none of these surrogate parameters have been validated in prospective clinical trials, and thus cannot be incorporated into current clinical practice.
Declaration of interest
Ipilimumab, the first immune checkpoint-targeted immunotherapy, has opened a new era in the management of patients with advanced melanoma. Breaking immune tolerance mediated by CTLA-4, ipilimumab has led to durable tumor regression. Active clinical research of ipilimumab is ongoing to maximize its antitumor activity, minimize associated serious
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
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Presented at: ASCO Annual Meeting 2014; 30 May -- 3 June 2014; Chicago, Illinois. Available from: http:// meetinglibrary.asco.org/content/94818? media=vm This presentation provides preliminary safety data of the concurrent administration of ipilimumab and dabrafenib with or without trametinib.
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Expert Opin. Biol. Ther. (2014) 14(11)
Affiliation Dae Won Kim1 MD, Van Anh Trinh2 PharmD & Wen-Jen Hwu†1 MD PhD † Author for correspondence 1 The University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology, 1515 Holcombe Boulevard, Box 430, Houston, TX 77030, USA E-mail: [email protected] 2 Clinical Pharmacy Specialist, The University of Texas MD Anderson Cancer Center, Pharmacy Clinical Programs, Houston, TX, USA
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Ipilimumab in the treatment of advanced melanoma -- a clinical update 1.
Introduction
2.
Durable survival outcomes with ipilimumab
3.
Dosing issue
4.
Antitumor activity of ipilimumab in patients with active brain metastases
5.
Adjuvant ipilimumab therapy
6.
Biomarkers
7.
Current issue regarding ipilimumab sequencing with other therapeutic agents
8.
Current issues regarding ipilimumab in combination with other therapy
9. 10.
Conclusion Expert opinion
Dae Won Kim, Van Anh Trinh & Wen-Jen Hwu† †
The University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology, Houston, TX, USA
Introduction: Ipilimumab has become an important treatment option for patients with advanced melanoma; however, active research perseveres to resolve many clinical practice issues and to further improve the therapeutic index of this agent. Areas covered: This article aims to provide an update on long-term data, current challenge and recent progress relating to the clinical application of ipilimumab in the treatment of advanced melanoma. A literature search using PubMed database was conducted using search words ipilimumab, melanoma, treatment sequencing, adjuvant therapy, combination therapy, and biomarkers. Data were also obtained from meeting abstracts and clinical trial registries. Expert opinion: Signal of clinical activity as adjuvant therapy in patients with resected high-risk melanoma begins to emerge, but longer follow-up is required for confirmation. Many issues, such as optimal dosing schedules and therapeutic sequences, remain unraveled. At present, treatment should be individualized based on patient- and disease-specific factors. Immunotherapy like ipilimumab still represents the best treatment option for durable remission; however, targeted therapies are more appropriate for patients with BRAF V600-mutated tumor who are symptomatic or have rapidly growing disease. With novel therapeutic options in the pipeline, the role of ipilimumab continues to evolve in the rapidly changing treatment landscape of advanced melanoma. Most likely, this agent will be utilized in combinatorial or sequential approach. Keywords: adjuvant therapy, biomarkers, combination therapy, ipilimumab, melanoma, treatment sequencing Expert Opin. Biol. Ther. (2014) 14(11):1709-1718
1.
Introduction
Ipilimumab (Box 1) is a fully human mAb against cytotoxic T-lymphocyte antigen 4 (CTLA-4), an inhibitory immune checkpoint molecule that plays a critical role in regulating T cell-mediated antitumor immunity [1]. Since its approval by regulatory agencies worldwide [2,3], ipilimumab has become a standard treatment option for patients with unresectable or metastatic melanoma. Data of long-term follow-up are emerging to validate the durable survival benefit of this agent. Recently, three small-molecule kinase inhibitors targeting the MAPK signaling transduction pathway, vemurafenib, dabrafenib and trametinib, received marketing authorization for patients with BRAF V600-mutant advanced melanoma [4-6]. The rapid changes in the landscape of melanoma therapy have led to the debate regarding the optimal therapeutic sequence or combination for patients with advanced melanoma. Paralleling the effort to determine the optimal combinatorial or sequential therapy is the research endeavor to improve the safety and efficacy of ipilimumab. This review 10.1517/14712598.2014.963053 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name Phase Indication Pharmacology description Route of administration Chemical structure Pivotal trial(s)
Ipilimumab Launched Melanoma mAb, CTLA-4 inhibitor Intravenous Biological, protein, IgG1 mAb MDX010-20 CA184-024 EORTC 18071 E1609
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
aims to provide an update on long-term data, current challenge and recent progress relating to the clinical application of this immunologic agent in the treatment of advanced melanoma. 2. Durable survival outcomes with ipilimumab
Ipilimumab has demonstrated the ability to induce durable benefit with sustained disease control following completion of therapy. Long-term follow-up of the MDX010-20 and CA184-024 studies, the two randomized Phase III trials that gained ipilimumab regulatory approval for the treatment of advanced melanoma, revealed an overall survival (OS) duration of 2 years or longer in ~ 20% of patients [7-10]. At the 2013 European Cancer Congress, Schadendorf et al. presented pooled survival data of 1861 ipilimumab-treated patients in eight Phase II, two Phase III, and two retrospective observational studies [11]. The median OS was 11.4 months (95% CI: 10.7 -- 12.1), with a 3-year OS rate of 22% (95% CI: 20 -- 24). The plateau in the OS curve, evolving at 3 years and extending to 10 years, was independent of prior therapies or ipilimumab dosing schedules. When including the survival data from 2985 patients enrolled in the ipilimumab expanded access program (EAP), the median OS was 9.5 months and the 3-year OS rate was 21%. Notably, patients treated in the EAP were more likely to carry unfavorable prognostic factors, such as performance status (PS) of 2, brain metastases, multiple prior therapies or non-cutaneous melanomas [11]. 3.
Dosing issue
Optimal dosing schedules of ipilimumab The currently approved dosing schedule of ipilimumab is 3 mg/kg intravenously every 3 weeks for a total of four doses [2,3]. However, many questions remain unanswered regarding the optimal dosing schedules of ipilimumab. The randomized Phase III study comparing the safety and efficacy of the approved 3 mg/kg dose versus an investigational 10 mg/kg 3.1
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dose in patients with metastatic melanoma has completed accrual (NCT01515189), and its results are eagerly anticipated. Although a maintenance phase has been incorporated in a number of ipilimumab trials, its addition to standard induction schedule has not yet been systematically evaluated; therefore, it is not recommended at this time. Reinduction Reinduction ipilimumab, administered upon disease progression, has been used to restore disease control in patients who had attained stable disease (SD) or clinical response to previous ipilimumab. In the MDX010-20 study, 31 patients with confirmed objective response or SD lasting at least 3 months to prior ipilimumab were given reinduction therapy upon disease progression [7,12]. Each retreatment cycle, consisting of four doses, was delivered using the same schedule as the original treatment. Most patients were able to receive the full four doses of the first reinduction cycle; five of them completed the second retreatment cycle; and one concluded the whole third round. Approximately 70% of patients who received reinduction ipilimumab were able to regain disease control, with best overall response rate (ORR) approaching 40% [12]. The safety profile of reinduction therapy was similar to ipilimumab induction [12]. Additionally, the development of immune-related adverse events (irAEs) during the original treatment cycle did not increase the risk of toxicities of subsequent retreatment series. Reinduction ipilimumab is currently recognized as a viable therapeutic option for select patients who did not experience high grade irAEs from previous ipilimumab and had achieved initial clinical response or SD lasting at least 3 months [13]. 3.2
Antitumor activity of ipilimumab in patients with active brain metastases
4.
The development of brain metastases is a common and devastating event in patients with advanced melanoma. The prevalence of brain metastases is 20 -- 40% in clinical series and up to 75% in autopsy series [14,15]. In general, patients with advanced melanoma and active brain metastases have the worst prognosis, with a median OS of < 5 months [15,16]. Because of this, they are often excluded from clinical trials, and effective systemic treatment for this patient population remains an area of medically unmet need. Intracranial activity of ipilimumab has been demonstrated in a multicenter Phase II study by Margolin et al. [17]. Ipilimumab’s antitumor activity was similar in the brain and at extracranial sites. Out of 51 patients who were neurologically asymptomatic and were not receiving corticosteroid, 8 achieved partial response and 4 had SD in the brain according to the modified WHO criteria. However, the rate of disease control in the brain appeared lower in the steroid-dependent patients (n = 21), with one patient achieving a complete response (CR) and one SD. This encouraging result has led to the NIBIT-M1 trial, in which ipilimumab was combined
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Ipilimumab
with fotemustine, a nitrosourea able to cross the blood--brain barrier, to treat 20 patients with asymptomatic brain metastases [18]. The majority of those patients had 2 -- 3 intracranial lesions; a third of them had received prior local therapy including stereotactic radiosurgery or whole brain radiotherapy. Eight patients achieved an objective response and two of them had disease stabilization in the brain. The positive result of this trial is being confirmed in the ongoing Phase III NIBIT-M2 trial, in which the combination is compared with single-agent fotemustine in patients with stage IV melanoma with brain involvement. Additionally, ipilimumab is continued to be developed in combination with other modalities, such as radiotherapy, temozolomide, selective BRAF kinase inhibitors or other immunostimulatory agents, for the management of melanoma patients with brain metastases. 5.
Adjuvant ipilimumab therapy
Expansion of ipilimumab utility into the adjuvant setting is underway. Adjuvant ipilimumab for patients with resected high-risk melanoma is being tested in two ongoing Phase III studies. In EORTC 18071, ipilimumab, administered at 10 mg/kg every 3 weeks for four doses plus subsequent maintenance dose every 12 weeks for up to 3 years, is compared against placebo in 951 patients with resected stage III melanoma [19]. The study population was at particularly high risk for disease relapse: 80% with stage IIIB or IIIC melanoma and 20% with stage IIIA disease with at least 1 nodal metastatic focus of greater than 1 mm in diameter. The primary endpoint was relapse-free survival (RFS). The preliminary safety and efficacy data have recently been presented at the 2014 ASCO Annual Meeting, demonstrating an RFS advantage favoring adjuvant ipilimumab, with median RFS of 17.1 and 26.1 months (hazard ratio [HR]: 0.75; 95% CI: 0.64 -- 0.90) in the placebo and ipilimumab groups, respectively. Although the manifestation of irAEs was similar to prior experience with ipilimumab, the severity of toxicities appeared more substantial, causing treatment discontinuation in 48.8% of patients and limiting the median number of doses per patient to 4. Most irAEs were manageable and reversible with the established treatment algorithms. Five patients (1.1%) died of treatment-related adverse events, three from colitis and one each from myocarditis and Guillain--Barre syndrome [19]. EORTC 18071 is ongoing, and data remain blinded for OS and distant metastasis-free survival. E1609 is the other Phase III adjuvant study examining the efficacy of postoperative ipilimumab at either 3 mg/kg or 10 mg/kg for four induction doses followed by four additional maintenance doses every 12 weeks versus standard adjuvant high-dose interferon for 1 year (NCT01274338). This study will supplement EORTC 18071 in defining the role of ipilimumab, especially at the dose recommended by regulatory agencies worldwide, in preventing disease recurrence in patients with resected high-risk melanoma.
6.
Biomarkers
Since only a small fraction of patients derive clinical benefit from ipilimumab and significant irAEs are associated with this agent, various biomarkers to predict clinical response and/or high-grade adverse events to ipilimumab, from the easily obtainable parameters such as lactate dehydrogenase (LDH) and absolute lymphocyte counts (ALC) to those requiring complex analytical methods like circulating antibody to the cancer-testis antigen NY-ESO-1 or frequency of monocytic myeloid-derived suppressor cells, have been studied extensively. LDH is a well-known prognostic indicator in melanoma. In subgroup analyses of the MDX010-20 and CA184-024 studies, clinical benefit of ipilimumab was primarily limited to the patients with non-elevated LDH at baseline [7,8]. More recently, multivariate analysis identified baseline LDH as the strongest predictive factor for OS in a retrospective multi-center study involving 166 patients with advanced melanoma treated in the ipilimumab EAP in the Netherlands [20]. At a median follow-up duration of ~ 18 months, median OS was 10 months in the group with baseline LDH less than twice upper limit normal (ULN) versus 2.9 months in those with LDH greater than twice ULN (p < 0.001). This finding was corroborated in an independent cohort of 64 patients treated with ipilimumab in the United Kingdom, with median OS of 5 months in the group with baseline LDH less than twice ULN versus 3.2 months in those with LDH greater than twice ULN (p = 0.004) [20]. ALC has also been examined as a predictive biomarker of tumor response to ipilimumab. In a single-institution evaluation of 51 patients treated with compassionate-use ipilimumab at 10 mg/kg, Ku et al. noted a statistically significant improvement in OS in the subgroup with high ALC (ALC ‡ 1000/µl) after the first or second ipilimumab dose [21]. Median OS was 7.9 months in patients with high ALC versus 1.8 months in those with low ALC at week 4 after treatment initiation (p < 0.01). A similar result was observed when OS was correlated with ALC at week 7, with median OS of 11.9 months versus 1.4 months in the subgroup with high and low ALC, respectively (p < 0.0001) [21]. This pattern persisted after adjusting for baseline LDH. The strong association between ALC, while measured at different time points, and OS has also been shown by other non-controlled singleinstitution studies of ipilimumab [22,23]. Many other biomarkers have been correlated with clinical benefit of ipilimumab, such as circulating VEGF-A [24], Creactive protein [22], elevation of inducible co-stimulator (ICOS) expressing CD4+ T cells [25], integrated NY-ESO-1specific antibody and CD8+ T-cell response [26], and frequency of monocytic myeloid-derived suppressor cells [27]. Despite the promising results of the aforementioned biomarkers, they must be validated in prospective clinical trials before being incorporated into routine clinical practice.
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Cut-off points and measurement timelines remain to be determined and justified. Some of these surrogate markers will not be evident until after the initiation of ipilimumab; thus they may not be useful for patient screening. In view of novel treatment options emerging in the pipeline, future ipilimumab biomarker studies must adapt to the rapidly evolving role of this agent.
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7. Current issue regarding ipilimumab sequencing with other therapeutic agents
The addition of four novel agents (ipilimumab and three targeted agents) to the therapeutic repertoire of advanced melanoma has undoubtedly made treatment decisions more complex, particularly for those patients with BRAF V600mutated melanoma.
Treatment sequencing with high dose IL-2 IL-2 is a T-cell growth factor necessary for CD8+ T-cell proliferation, survival and effector function [28]. High-dose IL-2 was approved by the US FDA for the treatment of advanced melanoma based on durable disease control observed in a small group of patients in Phase II studies [29]. It is not clear whether ipilimumab or high-dose IL-2 should be administered first. At present, the Society for Immunotherapy of Cancer recommends that high-dose IL-2 precede ipilimumab in the patients meeting high-dose IL-2 eligibility criteria for two important reasons [30]. First, high-dose IL-2 does not negatively impact subsequent administration of ipilimumab in terms of efficacy and safety, whereas there are limited data on the outcomes of the opposite sequence. In the MDX01020 study, 23% of patients had received prior high-dose IL-2 [7]. A retrospective evaluation by Joseph et al. of 48 patients treated with ipilimumab after progressing on highdose IL-2 demonstrated a response rate of 16.7% with a median OS of 12 months, similar to the result of the MDX010-20 [31]. Second, many clinicians are concerned about the feasibility of delivering high-dose IL-2 after ipilimumab. In contrast to the acute toxicities of high-dose IL-2, which resolve rapidly after treatment discontinuation, ipilimumab-associated irAEs, such as colitis and hepatitis, can take weeks to subside and may require prolonged corticosteroids or other immunosuppressive therapies [32], thus precluding subsequent high-dose IL-2. In addition, a retrospective review of 22 patients treated with high-dose IL-2 after ipilimumab at the National Cancer Institute revealed an incidence of bowel perforations of 13.6%, significantly higher than the reported rate of 0.45% in patients who received high-dose IL-2 alone [33,34]. PROCLIVITY 02, a randomized Phase IV study comparing the two sequences of high-dose IL-2 and ipilimumab in patients with metastatic melanoma, is being conducted to define the optimal sequence in delivering these two immunologic agents (NCT01856023). 7.1
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Treatment sequencing with BRAF inhibitors Whether ipilimumab or BRAF inhibitor represents the optimal frontline therapy for patients with BRAF V600-mutated advanced melanoma remains debatable. Proponents for ipilimumab first in the sequence underscore its durable benefit, a significant advantage when compared with the short-lived anti-tumor effect of targeted therapy. Despite the high response rate (the majority of tumor responses to BRAF inhibitors are partial), duration of response to BRAF inhibitors rarely lasts beyond a year. In the extended follow-up analysis of BRIM-3, the Phase III study establishing the survival benefit of the BRAF inhibitor vemurafenib, 14% of patients were progression free at 18 months [35]. With disease progression on BRAF inhibitors, ~ 50% of patients are rapid progressors and likely to die within 28 d of the last dose of BRAF inhibitors [36-38]. Thus, the likelihood of a timely response to salvage ipilimumab is low in this setting, considering the delayed onset of ipilimumab’s antitumor activity. These notions have prompted many retrospective analyses to discern the relative difference in survival outcomes of opposite treatment sequences. In a retrospective cohort of 274 patients treated with BRAF inhibitors at five different institutions, Ackerman et al. observed similar benefits to targeted therapy (vemurafenib, dabrafenib, or dabrafenib-trametinib combination), whether administered before or after immunotherapy (high-dose IL-2 or ipilimumab), with respect to the response rate (66 vs 57%; p = 0.31), progression-free survival (PFS) (5.6 vs 6.7 months; p = 0.43), and OS (13.4 vs 19.6 months; p = 0.4) [37]. However, in the subgroup of 40 patients treated with ipilimumab after BRAF inhibitor failure, no one achieved a clinical response to ipilimumab, with 6% having SD and 94% experiencing progressive disease [37]. Median OS was 5 months (95% CI: 3 -- 8.8), inferior to the results of MDX010-20 and CA184-024 trials. Notably, only 50% of these patients were able to complete all four doses of ipilimumab. Above data pose the hypothesis that immunotherapy administered before BRAF inhibitor may have a survival advantage when compared with the opposite sequence. This notion is corroborated by the data from 93 patients identified from the Italian cohort of the ipilimumab EAP to have sequentially received a BRAF inhibitor and ipilimumab [38]. Survival outcome evaluation of this patient subgroup demonstrated a statistically significant improvement in median OS when ipilimumab was administered before targeted therapy (14.5 vs 9.9 months; p = 0.04) [38]. Despite the intriguing results, the aforementioned retrospective studies are subjected to recall and patient selection biases. Since high probability and rapid onset of tumor response are two key advantages of BRAF inhibitors, these agents are particularly valuable to the patients with bulky tumor load, active brain metastases, elevated LDH, poor PS, and/or heavy symptom burden who urgently need a therapeutic response. Therefore, the patient- and/or disease-specific characteristics that steer treating physicians to select BRAF 7.2
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inhibitors upfront may signify a patient subset with a more aggressive tumor biology compared to those who started out with immunotherapy. Moreover, the practice of continuation of BRAF inhibitors post progression or resumption of targeted therapy subsequently is difficult to capture, further confounding the analyses [37,38]. Thus, there is an urgent need for randomized controlled trials to determine the optimal sequence of therapies; nevertheless, the rapidly changing treatment options for immuneand targeted therapy make the design of these sequencing trials a moving target. Until data are available from randomized controlled trials to settle the therapy sequencing dilemma, most clinicians agree that immunotherapy, such as ipilimumab or high-dose IL-2, should be considered first in asymptomatic patients with low or moderate disease burden since immunotherapy offers the best chance for long-term disease control [13]. BRAF inhibitors should be used upfront only in patients with BRAF V600-mutated advanced melanoma with symptomatic bulky disease, active brain metastases, markedly elevated LDH, and/or poor PS who urgently need a rapid therapeutic response [13].
Current issues regarding ipilimumab in combination with other therapy
8.
In an effort to improve the response rate of ipilimumab, various combinations of ipilimumab with other therapeutic agents are being investigated. Below are select combinations with sound rationales and/or encouraging preliminary results.
the discontinuation of the trial. Investigators are now assessing the toxicity profile of sequential administration of vemurafenib and ipilimumab in a Phase II study (NCT01673854). Ipilimumab in combination with dabrafenib with or without trametinib
8.1.2
The low incidence of hepatic adverse events with dabrafenib [5], the other commercially available BRAF inhibitor, makes it an ideal candidate for combination therapy with ipilimumab. Ipilimumab with dabrafenib plus or minus trametinib, a MEK inhibitor, has been investigated in a Phase I dose finding study in patients with BRAF V600-mutant advanced melanoma (NCT01767454). Preliminary safety data have recently been presented at the 2014 ASCO Annual Meeting [42]. The doublet regimen, in which both ipilimumab and dabrafenib were administered at full dose, was well tolerated (n = 8). Common adverse events, primarily of grade 1 or 2, were chills, fatigue, hand-foot syndrome, pyrexia and maculopapular rash. Transient grade 3 transaminitis was documented in one out of eight patients after the second dose of ipilimumab and resolved after a week of high-dose steroid. The doublet arm is now entering the expansion phase. The triplet regimen began with ipilimumab at full dose in combination with dabrafenib 100 mg twice daily and trametinib 1 mg daily (n = 7). Early-onset high grade colitis and intestinal perforation were seen in two out of seven patients receiving the three drug combination, leading to the discontinuation of the triplet arm [42]. Ipilimumab in combination with other biologics Ipilimumab has also been combined with other biologics such as vaccines, cytokines or other immune checkpoint-targeted antibodies. 8.2
8.1
Ipilimumab in combination with targeted therapy
Theoretically, rapid tumor antigens released by MAPK inhibitor-induced tumor apoptosis can effectively stimulate antigen-specific cytotoxic T-lymphocyte responses, of which activation and proliferation are augmented by concurrent ipilimumab. In addition, preclinical data have shown that tumor response to BRAF inhibitor therapy is associated with an increase in melanoma antigen expression and CD8+ T-cell infiltration in tumor microenvironment [39,40]. Combination with vemurafenib A Phase I dose finding study was conducted to explore the safety of concurrent ipilimumab and vemurafenib, a selective BRAF inhibitor [41]. After 1-month vemurafenib 960 mg orally twice daily lead-in, the first 6-patient cohort received both drugs concomitantly, ipilimumab 3 mg/kg intravenously every 3 weeks for four doses and vemurafenib 960 mg orally twice daily. Within 5 weeks after the first dose of ipilimumab, four out of six patients developed grade 3 transaminitis. A reduced dose of vemurafenib, 720 mg twice a day, was used for the second cohort. Despite this modification, grade 2 or 3 elevation in liver function tests was again observed in three out of four patients within 3 weeks from the first ipilimumab administration. The additive hepatotoxicity seen with concurrent administration of these two agents led to 8.1.1
Ipilimumab in combination with high-dose IL-2 High-dose IL-2 and ipilimumab are two immunotherapeutic options currently available for the management of advanced melanoma. IL-2 has been shown to induce not only effector T-cell stimulation but also regulatory T-cell (Treg) expansion [28]. Since CTLA4 is constitutively expressed on Tregs and contributes to their immunosuppressive function [43], concurrent ipilimumab and high-dose IL-2 administration may have an additive or synergistic effect. This concept has been explored clinically in a Phase I/II study by Prieto et al. [44]. In this study, three patients each received ipilimumab at 0.1, 0.3, 1, and 2 mg/kg/dose; 24 patients had ipilimumab at 3 mg/kg/dose. The first dose of ipilimumab was given without IL-2. All subsequent doses of ipilimumab were followed by high-dose IL-2 within 24 h. Patients received up to six cycles of the combination. At a median follow-up duration of 84 months, the ORR was 25%, with unprecedented CR rate of 17%. All CRs are durable, lasting 76 -- 89+ months. The median OS was 16 months, with a 5-year OS rate of 25%. The incidence of grade 3 or 4 irAEs was 17%, with gastrointestinal (GI) irAEs (gastritis, duodenitis, enteritis, and 8.2.1
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colitis) being the most common [44]. The combination of ipilimumab and IL-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial. Ipilimumab in combination with nivolumab Programmed cell death-1 (PD-1) receptor, expressed on activated T- and B-cells, natural killer cells and monocytes, is another important negative regulator of the immune system. Engagement of PD-1 to its primary ligand, PD-1 ligand 1 (PD-L1 or B7-H1), inhibits T-cell effector function, ultimately inducing T-cell exhaustion and deletion [45,46]. Upregulation of PD-L1 expression has been demonstrated in the tumor microenvironment of many human tumor systems, including melanoma. MAbs targeting the PD-1/PDL1 pathway are actively investigated as immunotherapeutic strategies for various human cancers. Nivolumab (BMS 936558, MDX-1106), a fully human anti-PD1 antibody, has been shown to generate robust and durable clinical response in patients with advanced melanoma [47]. Since CTLA-4 and PD-1 are non-overlapping regulators of the activation and effector phases of T-cell immunity, respectively, ipilimumab and nivolumab have been explored either as sequential or concurrent administration in a Phase I study [48]. From December 2009 to February 2013, 53 and 33 patients with advanced melanoma were treated with the concurrent and sequenced regimen, respectively. Patients on the sequential treatment must have already received at least three ipilimumab doses, with the last dose within 4 -- 12 weeks prior to the first nivolumab administration. Nivolumab, either at 1 or 3 mg/kg/dose, was repeated every 2 weeks for up to 48 doses in the sequenced regimen. Patients treated in the concurrent arm received escalating doses of both mAbs every 3 weeks for four cycles followed by a maintenance phase, with nivolumab preceding ipilimumab administration in each cycle [48]. Safety and efficacy data of the sequential regimen were similar to the Phase I experience of single-agent nivolumab, with grade 3 or 4 therapy-related toxicities of 18% and ORR of 31% [48,49]. A post-hoc analysis was performed to assess the effect of residual ipilimumab plasma concentration on response to subsequent nivolumab treatment. Plasma ipilimumab levels ranged from 0.881 to 33.90 mcg/ml, with a median exposure of 7.255 mcg/ml. Interestingly, those with residual ipilimumab exposure ‡ 7.255 mcg/ml attained a higher ORR to nivolumab than those with residual ipilimumab level below the median (57.1 vs 14.3%) [49], supporting the notion of additive or synergistic activity of the two agents. More remarkable is the efficacy of the concurrent regimen. The maximum tolerated dose (MTD) of the concurrent regimen was established at 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab [48]. The overall confirmed response rate was 42%. Even more unprecedented was the depth of the response, with tumor reduction of 80% or more at 36 weeks observed in 42% of patients. Median duration of response has not been reached, and the majority of clinical responses are ongoing, even after treatment discontinuation. Survival
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outcomes are also promising for patients treated with the combination, with 79% of patients alive at 2 years and a median OS of 40 months [49]. The concurrent regimen was more toxic. Serious treatmentrelated adverse events were documented in 49% of patients, with common grade 3 or 4 adverse events including elevated serum pancreatic enzymes (25%), hepatic toxicities (15%), GI manifestations (9%) and renal disorders (6%) [48]. Cases of pneumonitis or uveitis were also reported. Most toxicities were manageable and reversible with standard irAE management guidelines. Although there was no treatment-related death, 21% of patients discontinued therapy due to treatment-related adverse events [48]. The extraordinary antitumor activity of nivolumab-ipilimumab combination provides evidence of synergistic activity of the combined immune checkpoint blockades, which is being prospectively validated in CheckMate 069, a randomized Phase II study comparing the ORR of nivolumab combined with ipilimumab versus ipilimumab monotherapy, and CheckMate 067, a randomized, double-blind Phase III trial comparing the survival outcomes of nivolumab and/or nivolumab plus ipilimumab to ipilimumab alone, in patients with newly diagnosed advanced disease (NCT01844505). Ipilimumab in combination with GM-CSF Based on the synergistic activity of ipilimumab and GM-CSFtransduced allogeneic tumor cell vaccine in preclinical animal models [50], E1608, a randomized Phase II study, was conducted to explore the efficacy and safety of the combination of ipilimumab and GM-CSF [51]. A total of 245 previously treated patients with advanced melanoma were randomized to ipilimumab, 10 mg/kg intravenously for four doses followed by a maintenance phase, with or without GM-CSF 250 mcg subcutaneously for 14 d of a 21-d cycle. At a median follow up duration of 13.3 months, no statistically significant difference was noted in ORR or PFS between the two treatment arms. However, there was an OS benefit favoring the combination, 17.5 months versus 12.7 months (HR: 0.64; p = 0.014) [51]. Notably, the combination seemed better tolerated than single-agent ipilimumab, with high-grade irAEs of 44.9 and 58.3% (p = 0.038), respectively. Specifically, the addition of GM-CSF appeared protective against grade 3 -- 5 pulmonary (0 vs 7.5%; p = 0.030) and GI (16.1 vs 26.7%; p = 0.047) irAEs [51]. This organ-specific protective effect was attributed to the role of GM-CSF in maintaining pulmonary homeostasis and accelerating GI mucosal repair. GM-CSF, the first agent shown to ameliorate ipilimumabinduced irAEs without compromising its clinical activity, is worthy of further investigation. 8.2.3
Ipilimumab in combination with bevacizumab Pre-treatment circulating VEGF-A levels have been correlated with clinical response and OS of patients with advanced melanoma treated with ipilimumab [24]. VEGF has been shown to elicit negative impact on anti-tumor immunity through 8.2.4
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inhibiting dendritic cell maturation and antigen presentation. In addition, VEGF influences lymphocyte trafficking into tumor deposits. These suggest a potential synergy between ipilimumab and bevacizumab, an antagonist mAb against VEGF-A. A Phase I study has been conducted to investigate the above concept in four cohorts of patients with advanced melanoma [52]. Cohorts 1 and 2 received ipilimumab, 10 mg/kg every 3 weeks for four doses followed by a maintenance phase, in combination with bevacizumab 7.5 or 15 mg/kg every 3 weeks, respectively. Similar bevacizumab dosing schemas, combined with ipilimumab 3 mg/kg, were used for cohorts 3 and 4. Five patients were enrolled in each cohort. An additional 12 patients were evaluated at the MTD. No dose-limiting toxicities were observed in any of the cohorts. The MTD was declared at the dose level of ipilimumab 10 mg/kg with bevacizumab 15 mg/kg (cohort 2). At a median follow-up of 17.3 months, best ORR, median PFS and OS were 19.6% (95% CI: 9 -- 34%), 9 months (95% CI: 5.5 -- 14.5) and 25.1 months (95% CI: 12.7--not reached), respectively, for the entire study population. Best results were achieved in cohort 2; however, there were no statistically significant differences in the aforementioned endpoints among the cohorts. Correlative pharmacodynamic investigations demonstrated increased immune infiltrates of CD8+ T cells and CD162+ dendritic macrophages in tumor microenvironment, expanded circulating memory immune cells and enhanced antibody response to galactins [52]. Ipilimumab in combination with radiotherapy Rapid antigen release from radiation-induced tumor cell apoptosis can also prime antigen-specific cytotoxic T lymphocytes. Supporting this hypothesis is the observation of abscopal effect, an event in which local radiotherapy causes tumor regression at a distant site [53]. Therefore, there is a strong interest in combining ipilimumab with radiotherapy [54]. Several trials are ongoing to examine the combination of ipilimumab with concomitant radiotherapy in patients with metastatic melanoma with or without brain metastases (NCT01565837, NCT0170350). 8.3
9.
Conclusion
immune-related toxicity, as well as define optimal treatment sequence or combination with other therapies. Early Phase I/ II studies of various combinations have suggested synergistic antitumor activity with an acceptable safety profile. The role of this agent continues to evolve with the rapidly changing treatment landscape of advanced melanoma. 10.
Expert opinion
Currently, ipilimumab and reinduction have been wellintegrated into the treatment schema of advanced melanoma. It is also a viable option for patients with brain metastases who are neurologically asymptomatic and not receiving corticosteroid. The signal of clinical activity as an adjuvant therapy in preventing disease relapse in patients with resected high-risk melanoma has begun to emerge, but still awaits maturation of EORTC 18071 survival data and confirmation from the E1609 study, especially at the currently approved dose level. Many issues with ipilimumab therapy remain unresolved, such as optimal dosing schedules and therapeutic sequences or combinations. Until data from randomized controlled trials become available, treatment should be individualized based on patient- and disease-specific factors. Immunotherapy, such as ipilimumab and high-dose IL-2, remains the best treatment option for durable remission, and high-dose IL-2 should precede ipilimumab in the patients meeting high-dose IL-2 eligibility criteria. Targeted therapies are more appropriate frontline therapy for patients with BRAF V600-mutated advanced melanoma who are symptomatic with rapidly growing tumors. With the emerging PD-1:PD-L1 pathwaytargeted mAbs and the rapidly changing landscape of melanoma treatment, the role of ipilimumab continues to evolve and will most likely be integrated into a combinatorial approach. Intensive research effort has focused on identifying biomarkers to predict clinical response and/or high-grade adverse events to ipilimumab. However, none of these surrogate parameters have been validated in prospective clinical trials, and thus cannot be incorporated into current clinical practice.
Declaration of interest
Ipilimumab, the first immune checkpoint-targeted immunotherapy, has opened a new era in the management of patients with advanced melanoma. Breaking immune tolerance mediated by CTLA-4, ipilimumab has led to durable tumor regression. Active clinical research of ipilimumab is ongoing to maximize its antitumor activity, minimize associated serious
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
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Affiliation Dae Won Kim1 MD, Van Anh Trinh2 PharmD & Wen-Jen Hwu†1 MD PhD † Author for correspondence 1 The University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology, 1515 Holcombe Boulevard, Box 430, Houston, TX 77030, USA E-mail: [email protected] 2 Clinical Pharmacy Specialist, The University of Texas MD Anderson Cancer Center, Pharmacy Clinical Programs, Houston, TX, USA
