The immune checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have dramatically improved outcomes for patients with metastatic melanoma; however, not all patients benefit from monotherapy with these agents. To address this issue, complementary combinations of immunotherapy are increasingly being explored as a strategy to improve outcomes. However, combinatorial approaches come with heightened risk of toxicity. In this review, we highlight combinations for which there are prospective data from clinical trials. The combinations discussed include ipilimumab plus anti–programmed death 1 agents, ipilimumab plus granulocyte-macrophage colony-stimulating factor, checkpoint inhibitor plus talimogene laherparepvec, ipilimumab plus chemotherapy, checkpoint inhibitor plus BRAF/MEK targeted therapy, and checkpoint inhibition plus radiation therapy. We discuss data regarding the efficacy and toxicity of combination therapy, and we identify clinical scenarios that may favor treatment with combination therapy.
The immune system can eliminate cancer, so strategies to increase antitumor immunity have emerged as a primary therapeutic approach for the treatment of melanoma. While the immune system is complex and multifaceted, therapeutic approaches to antitumor immunity have largely focused on T cells. T-cell immunity is controlled by immune checkpoints. These are physiologic on/off switches that enable immune responses to potentially threatening antigens, while protecting the host from overzealous immune responses and autoimmunity.[1,2] For the treatment of melanoma, there are currently three checkpoint inhibitors that have been approved by the US Food and Drug Administration (FDA): ipilimumab, nivolumab, and pembrolizumab. These have two main targets: cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which is targeted by ipilimumab, and programmed death receptor 1 (PD-1), which is targeted by nivolumab and pembrolizumab. All three of the approved checkpoint inhibitors are widely used in clinical practice.
Single-agent immune checkpoint inhibition has proved to be a successful strategy for the treatment of metastatic melanoma. Ipilimumab is also approved as adjuvant therapy for resected stage III disease. More recently, nivolumab was approved for adjuvant therapy based on an improvement in recurrence-free survival compared with ipilimumab in patients with resected stage IIIB, IIIC, or IV melanoma.
Despite the known efficacy of these agents, not all patients benefit from single-agent immune checkpoint inhibitor therapy, prompting further investigation into whether combining immune checkpoint inhibitors, either with each other or with other anticancer treatments, could improve outcomes. Combinations ideally should have complementary and not overlapping mechanisms of immune activation to maximize benefit and minimize toxicity.[3,4]
While combinatorial approaches hold considerable promise, it is important that the potential added risk of toxicity with a proposed combination therapy not outweigh the added benefit. In this article, we take a practical approach to understanding the role of combination strategies for checkpoint inhibition in melanoma by examining data on the superiority of combinations vs single agents, and thereby trying to answer controversial questions of “which is better.” We focus on clinically relevant therapeutic strategies for which clinical trial data are available. A number of other combinations are being actively investigated—such as those that involve indoleamine 2,3-dioxygenase inhibitors or lymphocyte-activation gene 3—but these are not yet ready for the clinic due to the paucity of randomized data. The Figure shows the mechanisms of action of the various approaches we discuss. The Table lists ongoing phase III clinical trials of combinations of immune checkpoint inhibition with other approaches. In the many areas where much remains unknown, we highlight key questions in the field and propose strategies for remedying deficiencies in available knowledge.
Ipilimumab Plus Anti–PD-1 vs Ipilimumab Alone vs Anti–PD-1 Alone
CTLA-4 was the first immune checkpoint targeted for clinical intervention. CTLA-4 is expressed on the surface of T cells and regulates early activation, known as priming, of naive T cells during their first encounter with a tumor peptide, which is presented as part of the major histocompatibility complex by antigen-presenting cells in the draining lymph node. Binding of CTLA-4 to its ligands on antigen-presenting cells inhibits T cells, so preventing this binding is one mechanism by which CTLA-4 blockade increases T-cell responses against tumors. Ultimately, the anti–CTLA-4 monoclonal antibody ipilimumab was shown to improve overall survival (OS) in patients with advanced melanoma, and ipilimumab was approved by the FDA for the treatment of metastatic melanoma in March 2011.
While CTLA-4 blockade functions primarily, though not exclusively, in lymph nodes, PD-1 is thought to operate primarily within the tumor microenvironment, where it decreases the activity of peripheral T cells. Therefore, anti–PD-1 therapy has a mechanism of therapeutic checkpoint inhibition that complements rather than overlaps that of CTLA-4 blockade. In a phase I clinical trial of the combination of ipilimumab and nivolumab at escalating doses in patients with melanoma, response rates were favorable compared with each agent as monotherapy. However, an increase in immune-related adverse events (irAEs) with the combination compared with each agent as monotherapy was also reported.[9,10]
The phase II CheckMate 069 study of 142 patients with advanced untreated melanoma, which compared ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) vs ipilimumab alone, demonstrated an objective response rate (ORR) of 61% for combination therapy vs 11% for ipilimumab alone in patients with BRAF wild-type melanoma. The risk of progression or death was reduced by 60% with combination therapy compared with ipilimumab alone (hazard ratio [HR], 0.40; 95% CI, 0.22–0.71; P < .002). In a subsequent exploratory OS analysis after a median of 24.5 months of follow-up, the 2-year OS rate in the ipilimumab + nivolumab arm was 63.8% (95% CI, 53.3%–72.6%) vs 53.6% in the ipilimumab-alone arm (95% CI, 38.1%–66.8%), and median OS was not yet reached in either arm. Grade 3/4 toxicity was observed in 54% of patients treated with combination therapy and in 24% of patients treated with ipilimumab alone.
After the superiority of the combination over ipilimumab in short-term endpoints (response rates and progression-free survival [PFS]) had been demonstrated in CheckMate 069, the phase III trial (CheckMate 067) randomized 945 patients with advanced untreated melanoma to ipilimumab alone, nivolumab alone, or concurrent ipilimumab and nivolumab. ORRs for the ipilimumab, nivolumab, and combination arms were 19%, 44%, and 58%, respectively. An updated survival analysis was recently published, with a minimum of 36 months of follow-up; this showed that the median OS was 19.9 months for ipilimumab, 37.6 months for nivolumab, and not yet reached for the ipilimumab + nivolumab arm (HR for death with ipilimumab plus nivolumab vs ipilimumab alone, 0.55; P < .001). Three-year OS rates for ipilimumab, nivolumab, and combination therapy were 34%, 52%, and 59%, respectively. The study was not powered sufficiently to compare nivolumab alone against ipilimumab plus nivolumab.
Again, this study demonstrated that improved efficacy with combination therapy compared with ipilimumab alone comes with the detriment of higher toxicity. Grade 3/4 toxicity rates were 28.3% for ipilimumab, 16.3% for nivolumab, and 55% for combination therapy. While 31% of patients receiving ipilimumab plus nivolumab stopped therapy because of adverse events (compared with 14.1% in the ipilimumab arm and 7.7% in the nivolumab arm), the ORR was 70% among those who discontinued therapy and median OS was not yet reached, raising questions about the optimal duration of combination immunotherapy.
Given the impressive efficacy yet ongoing concerns about increased toxicity with the combination of checkpoint inhibitors targeting CTLA-4 and PD-1, there is considerable interest in altering schedules and/or dosing of CTLA-4 blockade to try to minimize irAEs while maintaining efficacy.[16,17] Specifically, altering the administration of ipilimumab by lowering the dose to 1 mg/kg in combination with anti–PD-1 therapy, or administering ipilimumab less frequently (ie, every 6 or 12 weeks), have been appealing strategies. In one single-arm nonrandomized study of reduced-dose ipilimumab (1 mg/kg) with standard-dose pembrolizumab, the response rate appeared similar to that seen with standard-dose ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg). However, ipilimumab is known to have dose-dependent effects on OS that are not necessarily dependent on response rates, given that 10 mg/kg of ipilimumab was recently shown to improve OS compared with 3 mg/kg, without an apparent difference in response rate or PFS. Thus, clinicians must be cautious when considering reduced dosing of ipilimumab in combination with an anti–PD-1 agent based on response rate endpoints alone. Randomized trials with longer-term follow-up are needed to assess the true efficacy of these modifications.
In summary, ipilimumab plus nivolumab is clearly superior to ipilimumab alone, but the question of whether combination ipilimumab plus nivolumab is superior to nivolumab alone remains a difficult dilemma for clinicians who must decide between these treatments for their patients. The exploratory data that demonstrate the highest efficacy for the combination are intriguing, but this advantage comes at the cost of higher toxicity, requiring appropriate patient selection and counseling.
- Ideal combinations should have complementary—not overlapping— mechanisms of immune activation to maximize benefit and minimize toxicity.
- Ipilimumab + nivolumab is clearly superior to ipilimumab alone, but the superiority of the combination compared with nivolumab alone is not clearly established. The risk of toxicity is significantly higher with combination therapy. We favor using ipilimumab + nivolumab in patients with multiple brain metastases who are not candidates for stereotactic radiosurgery, patients with mucosal melanoma, and those patients who are well enough.
- At this time, there are insufficient data to recommend the combination of checkpoint inhibitors + BRAF/MEK inhibition.
- While there is not clear evidence for improved efficacy with radiation therapy + checkpoint blockade, data suggest that the combination is safe, so concurrent treatment is reasonable to pursue when both modalities are independently indicated.
Unfortunately, no biomarker has been shown to be specifically predictive of treatment benefit from nivolumab plus ipilimumab compared with nivolumab (or pembrolizumab) alone. Nonetheless, testing for tumor programmed death ligand 1 (PD-L1) expression and mutational burden have been explored as potential predictive indicators of response to immunotherapy—with PD-L1 positivity and high mutational burdens being favorable for better outcomes. Despite some exploratory signals that the relative benefits of nivolumab plus ipilimumab compared with nivolumab alone were greatest in patients who were defined as PD-L1–negative, a statistical test for interaction was not positive, suggesting that PD-L1 negativity is not statistically predictive of treatment benefit from combination immunotherapy compared with single-agent anti–PD-1 therapy. Data for tumor mutational burden have not yet been reported in the setting of nivolumab plus ipilimumab. Therefore, while the hypotheses are provocative that perhaps patients with PD-L1–negative tumors or those with low mutational burden may derive greater benefit from nivolumab plus ipilimumab compared with single-agent anti–PD-1 therapy, the data are not strong enough to recommend using these markers to guide clinical practice.
Special considerations may be warranted for certain subgroups of patients. One example is patients with mucosal melanoma, who are generally believed to have a poor prognosis. A pooled analysis of patients with mucosal melanoma (N = 86) who received ipilimumab plus nivolumab or nivolumab alone in a clinical trial was recently published. Of these patients, the median PFS was 2.7 months in the ipilimumab arm, 3.0 months in the nivolumab arm, and 5.9 months in the combination arm. Combination immunotherapy response rates appeared lower in patients with mucosal melanoma (37%) than in patients with cutaneous melanoma (60%). Patients with mucosal melanoma had a response rate of 37% for combination immunotherapy vs a response rate of 23% for therapy with nivolumab alone. Notably, this absolute difference of 14 percentage points approximates the absolute difference in response rate between combination immunotherapy and nivolumab monotherapy seen in cutaneous melanoma. These data suggest that the choice of the combination of nivolumab plus ipilimumab for a patient with cutaneous melanoma should be largely based on the higher response rate and cannot simply be made based on the histology of the underlying melanoma subtype.
Similarly, particular attention has been paid to the efficacy of nivolumab plus ipilimumab in patients with brain metastases. At the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting, data were presented from two phase II trials. One study consisted of 50 patients with asymptomatic melanoma brain metastases who had not received prior local brain therapy or immune checkpoint blockade. Patients were randomized to ipilimumab plus nivolumab vs nivolumab alone. While not powered for a statistical comparison of OS, the 6-month OS rate was 59% for nivolumab alone vs 76% for ipilimumab plus nivolumab, suggesting an advantage to combination therapy for patients with intracranial metastases. Data from the CheckMate 204 study were also presented at the 2017 ASCO Annual Meeting; these demonstrated an intracranial ORR of 56% with the combination of ipilimumab plus nivolumab. Although these are small studies, and longer-term follow-up with more patients is needed, these data suggest impressive efficacy for the combination of ipilimumab plus nivolumab in patients with brain metastases. In our practice, we generally prefer combination immunotherapy over single-agent anti–PD-1 therapy for patients with multiple brain metastases who are not candidates for stereotactic radiosurgery (SRS).
Most important to the choice of combination immunotherapy in any setting, however, is that patients are perceived to be capable of handling the possibility of irAEs and consequent treatment with corticosteroids. Patients who do not have supportive caregivers or who are perceived as having difficulty communicating with the care team may not be good candidates for combination immunotherapy, since management requires close communication and may necessitate adherence to immunosuppressive treatment regimens in the event of significant toxicity. Because the 3-year OS rates of nivolumab plus ipilimumab and nivolumab alone are similar, single-agent anti–PD-1 therapy remains an appropriate choice for many patients and is the standard control arm of most randomized clinical trials.
GM-CSF Plus Ipilimumab vs Ipilimumab Alone
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine naturally secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and fibroblasts to stimulate stem cells to produce granulocytes and monocytes. The monocytes subsequently mature into macrophages and dendritic cells. From an oncologic perspective, GM-CSF augments the ability of dendritic cells to present antigen to lymphocytes, thereby boosting the antitumor activity of T- and B-lymphocytes.[25,26] Hodi and colleagues conducted a phase II randomized clinical trial in 245 patients who had advanced melanoma that had progressed on at least one prior therapy. Patients were randomized to receive either ipilimumab (10 mg/kg) plus sargramostim (GM-CSF; 250 µg subcutaneously on days 1–4 of a 21-day cycle) or ipilimumab (10 mg/kg) alone. At a median follow-up of 13.3 months, median OS in the ipilimumab + sargramostim group was 17.5 months (95% CI, 14.9 months–not reached) vs 12.7 months in the ipilimumab-alone arm (95% CI, 10.0 months–not reached; P = .01). Grade 3–5 toxicity was significantly lower in the ipilimumab + sargramostim arm than in the ipilimumab-alone arm (P = .04). Although follow-up time was short, this study provided the first evidence of an OS advantage with combination immunotherapy. The toxicity data are also reassuring. Despite the positive findings from incorporating GM-CSF into treatment with high-dose ipilimumab, this trial’s findings have not led to significant clinical use of GM-CSF with CTLA-4 blockade. Reasons for the limited uptake may be related to the difficulty of GM-CSF administration and the increase in use of the ipilimumab + anti–PD-1 combination at around the same time that the GM-CSF + ipilimumab combination data became available. Clearly, additional larger studies are needed with longer follow-up before conclusive recommendations can be made about the use of GM-CSF in addition to checkpoint blockade.
Checkpoint Inhibition Plus Talimogene Laherparepvec vs Checkpoint Inhibition Alone
Talimogene laherparepvec (T-VEC) is an oncolytic virus derived from herpes simplex virus type 1 that is FDA-approved for the treatment of advanced melanoma. It is the first oncolytic virus to produce meaningful clinical benefit in a randomized clinical trial for patients with solid tumors. Administration of oncolytic viruses in patients with melanoma enhanced tumor antigen–specific T-cell response and abrogated the immunosuppressive function of regulatory T cells, suppressor CD8+ T cells, and myeloid-derived suppressor cells, providing a rationale for exploring T-VEC in combination with checkpoint inhibition.[29,30] Data were recently presented from an open-label, randomized phase II trial of 198 patients with advanced, unresectable stage IIIB–IV melanoma with injectable tumors who were given ipilimumab (3 mg/kg) with or without T-VEC. The ORR was 38.8% for T-VEC plus ipilimumab vs 18.0% for ipilimumab alone (P = .002). In total, 28% of patients who received T-VEC plus ipilimumab and 18% of patients who received ipilimumab alone had grade 3/4 toxicity. These results are quite promising, and additional data are expected that will further inform decisions about this combination. Given the higher response rate and no obviously increased toxicity for the T-VEC + ipilimumab combination, for patients with unresectable or metastatic melanoma who have injectable lesions and for whom treatment with ipilimumab is appropriate, we favor combining ipilimumab with T-VEC, although we acknowledge this is not an approved combination.
T-VEC has also been studied in combination with anti–PD-1 therapy, including in a recently reported phase Ib trial with pembrolizumab that demonstrated a 62% confirmed response rate in patients with injectable melanoma lesions and advanced disease. Despite this promise in a nonrandomized study, randomized data for T-VEC plus pembrolizumab are needed; a phase III randomized trial of pembrolizumab with or without T-VEC is ongoing (ClinicalTrials.gov identifier: NCT02263508).
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