Targeting the PD-1 pathway: a promising future for the treatment of melanoma
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- Mamalis, A., Garcha, M. & Jagdeo, J. Arch Dermatol Res (2014) 306: 511. doi:10.1007/s00403-014-1457-7
Advanced melanoma presents a significant therapeutic challenge to clinicians. Many therapies for metastatic melanoma are limited by low response rates, severe toxicities, and/or relatively short response duration. Cancer immunotherapies that act as immune-checkpoint inhibitors to block the localized immune suppression mechanisms utilized by tumors are undergoing development and clinical trials. A clinically relevant immune escape mechanism in melanoma is the activation of the programmed cell death-1 (PD-1) receptor on infiltrating T cells. Activating PD-1 triggers an immune checkpoint resulting in inhibition of T cells directed against melanoma antigens and prevents the immune system from combating the melanoma. In Phase I clinical trials, two anti-PD1 therapies, Nivolumab and MK-3475, that block the PD-1 receptor to enable T cell killing have demonstrated objective tumor responses in patients with advanced melanoma. The purpose of this review is to present the available clinical evidence on anti-PD-1 and anti-PD-L1 immunotherapy for the treatment of advanced melanoma. We also discuss limitations associated with anti-PD-1 therapy. The blockade of the PD-1–PD-L1 pathway has shown promising results in clinical trials and has revolutionized melanoma immunotherapy.
KeywordsNivolumabMK-3475IpilimumabPD-1PD-L1Programmed cell death receptor 1ImmunotherapyMelanomaBRAF
American Society of Clinical Oncology conference
Cytotoxic T-lymphocyte antigen-4
Programmed cell death-1 receptor
Programmed cell death-1 receptor ligand
Renal cell carcinoma
Response evaluation criteria in solid tumors
In 2014, it is estimated melanoma will contribute to 76,100 new cancer diagnoses and 9,710 deaths in the United States . Advanced melanoma presents a significant therapeutic challenge to clinicians. Many therapies for metastatic melanoma are limited by low response rates, severe toxicities, and/or relatively short response duration . Historically, treatment for advanced melanoma involved the use of cytotoxic therapies, such as dacarbazine, that have response rates of approximately 10–15 % and caused dose-limiting toxicities [11, 20]. The cytokine interleukin-2 (IL-2) is also used to treat advanced melanoma, however, the response rate is only 6–10 % and it too is associated with significant toxicities. Newer oncologic treatments for melanoma include targeted therapies, such as kinase inhibitors that are now a mainstay treatment for melanomas that harbor key mutations contributing to melanoma pathogenesis, such as BRAF .
BRAF mutations are present in 40–60 % of melanoma patients and these mutations lead to the activation of kinase activity [5, 7, 8, 11]. Inhibitors of these BRAF mutations, such as vemurafenib and dabrafenib, have shown response rates of 48–53 % and have revolutionized melanoma treatment, but are limited to treating melanomas that harbor a BRAF mutation [5, 7, 8, 11]. Additionally, the majority of patients treated with BRAF inhibitors go on to relapse within 6–12 months.
In addition to key mutations such as BRAF, human cancers harbor antigens that allow a patient’s immune system to recognize and mount an endogenous immune response against the tumor [23, 27, 28]. However, endogenous anti-tumor immune responses are often ineffective because tumors can activate key immune checkpoints that lead to localized immune suppression [9, 14, 15, 23, 33]. Cancer immunotherapies that act as immune-checkpoint inhibitors to block the localized immune suppression mechanisms utilized by tumors are undergoing development and being put to test in clinical trials .
Summary of PD-1–PD-L1 immunotherapies under development
Fully human IgG4 monoclonal antibody
Merck & Co.
Humanized IgG4 monoclonal antibody
Fully human IgG4 monoclonal antibody
By blocking PD-1 receptors with anti-PD-1 mAbs, T cells are unaffected by the PD-L1 expressed on tumor cells and the patient’s T cells are free to respond to melanoma antigens and attack tumor cells (Fig. 1b). This new class of immunotherapy, based on anti-PD1, is now a validated strategy based on efficacy results in Phase I trials, irrespective of mutation type or previous treatments.
We employed the following search strategy to identify the clinical evidence reported in the biomedical literature: in January 2014, we searched Medline, PubMed, EMBASE, and ClinicalTrials.gov (January 1990-present) using the following search terms: “nivolumab,” “MDX-1106,” “BMS-936558,” “lambrolizumab,” “MK-3475,” “anti-PD-1,” “anti-PD-L1,” “BMS-936559,” “MPDL3280A,” “CD274,” or “CD279”. All clinical trials evaluating anti-PD-1 or anti-PD-L1 therapy for the treatment of melanoma were included.
Summary of phase I studies investigating anti-PD-1 or anti-PD-L1 immunotherapies
Adverse event rate
Immune-related adverse events
Anti-PD-1 phase I trials
Brahmer et al.  (NCT00441337)
Nivolumab: dosed at 0.3, 1.0, 3.0, or 10 mg/kg
39 patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer (CRPC), non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC)
1 Complete response (1 CRC); 2 partial responses (1 melanoma, 1 RCC)
Most commonly decreased CD4 + lymphocyte counts in 35.9 % (14/39), lymphopenia in 25.6 % (10/39), and fatigue or musculoskeletal events in 15.4 % (6/39) of patients
Grade 3 inflammatory colitis (n = 1), grade 2 hypothyroidism (n = 1)
Topalian et al.  (NCT00730639)
Nivolumab: dosed at 0.1–10 mg/kg every 2 weeks in 8-week cycles for up to 12 cycles or until the patient had a complete response or confirmed disease progression
296 patients with advanced metastatic melanoma, (CRC), (CRPC), (NSCLC), or (RCC)
28 % (26/94) of patients with melanoma responded to therapy. In patients with 1 year or more of follow up, 64.5 % (20/31) of responses lasted at least 1 year
Drug-related pneumonitis occurred in 3 % (9/296) of patients. 3 patients died from pulmonary toxicity
Grade 3 or 4 drug-related adverse events occurred in 14 % of patients
Wolchok et al.  (NCT01024231)
Nivolumab plus ipilimumab: nivolumab 0.3–10 mg/kg; Ipilimumab 3–10 mg/kg
86 patients total. 53 patients received concurrent therapy with nivolumab and ipilimumab. 33 patients received sequenced treatment (had previously taken at least 3 treatments of ipilimumab followed by nivolumab alone)
Concurrent-regimen nivolumab 1 mg/kg and ipilimumab 3 mg/kg results in an objective response of 53 %, all with tumor reduction of 80 % or more. Sequenced-regimen resulted in objective response rate of 20 %
In concurrent-regimen, treatment-related adverse events were observed in 93 % of patients. Most common events were rash (55 % of patients), pruritus (47 %), fatigue (38 %), and diarrhea (34 %)
Grade 3 or 4 adverse events occurred in 53 % of patients in the concurrent-regimen group, and in 18 % of patients in the sequenced-regimen group
Hamid et al.  (NCT01295827)
MK-3475: Dosed at 10 mg/kg every 2–3 weeks or 2.0 mg every 3 weeks
135 patients with advanced melanoma. Patients with and without prior treatment with ipilimumab were included
The response rate across all dose cohorts was 38 %. The response rate across patients in the 10 mg/kg, 2 weeks interval cohort was 52 %. After average 11 months follow-up, 81 % (42 of 52) of patients continued to respond
79 % reported drug-related adverse events of any grade, of these 13 % (n = 17) experienced severe adverse effects. Highest incidence of adverse events in 10 mg/kg group taking every 2 weeks (23 %) versus every 3 weeks (4 %)
Grade 3 or 4 events included: asymptomatic pneumonitis (n = 1), elevated aminotransferase (n = 2), renal failure (n = 2), hypothyroidism (n = 1)
Anti-PD-ligand 1 phase I trials
Brahmer et al.  (NCT00729664)
Anti-PD-L1: dosed at 0.3–10 mg/kg every 2 weeks in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression
55 patients with melanoma, 75 with non-small-cell lung cancer, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer
17.3 % (9/52) of patients with melanoma had an objective response (complete or partial). 7.4 % (2/17) with renal-cell cancer, 10.2 % (5/49) with non–small-cell lung cancer, and 3.7 % (1/17) with ovarian cancer. 50 % (8/16) of patients had responses lasting 1 year or longer
Adverse events of any grade were reported in 188 of 207 patients (91 %) 9 % of patients experienced grade 3 or 4 adverse events related to treatment
39 % (81/207) of patients experienced immune-related adverse events of any grade including rash, hypothyroidism, hepatitis, and one case each of sarcoidosis, endophthalmitis, diabetes mellitus, and myasthenia gravis
Summary of current clinical studies investigating anti-PD-1 or anti-PD-L1 immunotherapies
Recruitment status as of January 2014
A study of MDX-1106 in patients with selected refractory or relapsed malignancies
A phase 1b study of MDX-1106 in subjects with advanced or recurrent malignancies (MDX1106-03)
Active, not recruiting
Dose-escalation study of combination BMS-936558 (MDX-1106) and ipilimumab in subjects with unresectable stage III or stage IV malignant melanoma
Multiple class I peptides and montanide ISA 51 VG w escalating doses of anti-PD-1 ab BMS936558
Multiple class I peptides and montanide ISA 51 VG w escalating doses of anti-PD-1 antibody BMS936558
Phase 1 biomarker study of anti-PD-1 in advanced melanoma
Study of nivolumab given sequentially with ipilimumab in subjects with advanced or metastatic melanoma (checkmate 064)
Phase 2, randomized, double blinded, study of nivolumab (BMS-936558) in combination with ipilimumab vs ipilimumab alone in subjects with previously untreated, unresectable or metastatic melanoma (checkmate 069)
A study to compare BMS-936558 to the physician’s choice of either dacarbazine or carboplatin and paclitaxel in advanced melanoma patients That have progressed following anti-CTLA-4 therapy (checkmate 037)
Nivolumab, dacarbazine, carboplatin, paclitaxel
Active, not recruiting
Study of BMS-936558 versus dacarbazine in untreated, unresectable or metastatic melanoma (checkmate 066)
Phase 3 study of nivolumab or nivolumab Plus ipilimumab versus ipilimumab alone in previously untreated advanced melanoma (checkmate 067)
Study of MK-3475 in participants with progressive locally advanced or metastatic carcinoma, melanoma, or non-small cell Lung carcinoma (P07990/MK-3475-001)
Merck Sharp & Dohme Corp.
Study of MK-3475 versus chemotherapy in participants with advanced melanoma
MK-3475, carboplatin, paclitaxel, dacarbazine, temozolomide
Merck Sharp & Dohme Corp.
Active, not recruiting
Study to evaluate the safety and efficacy of two different dosing schedules of MK-3475 compared to ipilimumab in participants with advanced melanoma (MK-3475-006 AM1)
Merck Sharp & Dohme Corp.
Anti-PD-ligand 1 Trials
A study of the safety and pharmacology of MPDL3280A administered in combination with vemurafenib in patients with previously untreated BRAFV600-mutation positive metastatic melanoma
Study of the safety and pharmacokinetics of MPDL3280A administered intravenously as a single agent to patients With locally advanced or metastatic solid tumors or hematologic malignancies
Multiple ascending dose (MDX1105-01)
Active, not recruiting
Our review of the literature demonstrates that nivolumab is a promising treatment for patients with advanced melanoma. One phase I trial conducted by Brahmer et al. investigated the safety, tolerability, and anti-tumor activity of nivolumab in 39 patients with either treatment-refractory advanced melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small cell lung cancer, or renal cell carcinoma (RCC) . This early study found 1 out of 10 patients with melanoma treated with nivolumab experienced a partial response to therapy, as measured by a reduction in tumor size using the RECIST 1.1 . Investigators also reported another partial response in a patient with RCC and one complete response in CRC . Since only 31 % (12/39) of patients received multiple doses of nivolumab, interpretation of the reported response rates is limited because many patients may not have responded due to an ineffective dose . Investigators reported no dose-limiting toxicities; however, they report a drug-related episode of grade 3 inflammatory colitis and an episode of grade 2 hypothyroidism in another patient. These immune-related adverse events are of particular interest in anti-PD-1 trials and are similar to those seen in ipilimumab trials [3, 22]. Immune-related adverse events are likely a critical dose-limiting toxicity of PD-1 inhibitors.
Another phase I trial investigating the use of nivolumab for the treatment of a variety of solid tumors reported 28 % (26/94) of patients with advanced melanoma who had melanoma progression while on previous tumor therapies showed an objective response to treatment after receiving nivolumab at a dose of 0.1–10.0 mg/kg of body weight every 2 weeks over an 8-week cycle period. In addition, objective responses were observed in 41 % (7/17) of patients receiving nivolumab at a dose of 3 mg/kg. Patients received treatment for up to 12 cycles until disease progression was noted or complete response occurred . This study also reported similar objective response rates in patients with renal cell carcinoma and non-small cell lung cancer. In addition, 72 % (13/18) of patients who responded to nivolumab treatment with adequate follow-up had responses lasting 1 year or longer . The investigators found that drug-related grade 3 or 4 toxic effects occurred in 14 % (41/296) of patients with advanced melanoma, renal cell cancer, or non-small cell lung cancer . This study also assessed the role of tumoral PD-L1 expression on treatment response and found that 36 % (9/25) of patients with PD-L1-positive tumors had an objective response, while no patients with PD-L1-negative tumors had an objective response . However, due to the limited patient sample size, conclusions regarding the predictive power of PD-L1 expression are difficult to make. Preliminary results from another clinical trial investigating the use nivolumab with or without a multi-peptide vaccine reported nivolumab response rates by RECIST were 28 % in 34 patients who were naïve to ipilimumab, and 32 % in 46 patients who had failed prior ipilimumab therapy .
A phase I trial of the anti-PD-1 antibody MK-3475 included 135 patients with advanced melanoma. The trial demonstrated an overall objective response of 38 % (44/117) and an objective response of 52 % (27/52) in patients receiving the maximum dose of 10 mg/kg every 2 weeks . The authors report that 13 % (17/135) of patients experienced grade 3 or 4 toxicities. In addition, they report that prior exposure to ipilimumab or IL-2, did not appear to have a major effect on response to MK-3475 treatment .
Taken together, the promising response rates from these phase I monotherapy trials demonstrate that anti-PD-1 mAbs have the potential to alter the melanoma treatment paradigm. Anti-PD-1 mAbs are associated with adverse events, including immune-related events. However, the results of nivolumab and MK-3475 indicate that as the immunotherapy drug class continues to expand, PD-1 inhibitors will be an effective therapy to combat advanced. In addition, further research to identify biomarkers beyond PD-L1 tumor expression, may allow clinicians to identify patients who are most likely to respond to anti-PD-1 therapy while minimizing adverse events. Merck has begun a phase III clinical trial comparing MK-3475 against ipilimumab in patients with advanced melanoma.
Immune checkpoint combination therapies
Combining multiple immune checkpoint blocker therapies has demonstrated beneficial results for the treatment of advanced melanoma. One recent clinical trial showed nivolumab combined with ipilimumab resulted in greater response rates than monotherapy with either drug . Fifty-three patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment (nivolumab administered within 4–12 weeks following last ipilimumab dose) . The authors report that 53 % of patients who received combination therapy with nivolumab 1 mg/kg and ipilimumab 3 mg/kg had an objective response versus only 20 % of patients who received the sequential treatment. All responders had tumor reductions of 80 % or more . The trial observed Grade 3 or 4 adverse events occurred in 53 % of patients in the concurrent-regimen group, and in 18 % of patients in the sequenced-regimen group. This study illustrated that concurrent therapy with nivolumab and ipilimumab may act synergistically and result in improved response rate versus monotherapy while maintaining a manageable rate of adverse events . In addition, the authors reported that concurrent nivolumab plus ipilimumab therapy resulted in objective response in both patients with PD-L1-positive tumors (6/13) and with PD-L1-negative tumors (9/22). The effectiveness of nivolumab on PD-1-negative tumors is uncertain, further evaluation of tumor PD-L1 expression in clinical trials may clarify PD-1’s utility as a biomarker for response rate to mono and combination therapy.
These promising synergistic findings have resulted in a phase III clinical trial to further investigate the utility of nivolumab plus ipilimumab combination therapy for the treatment of melanoma. Other combinations of nivolumab with existing or newly developed therapies for melanoma may provide enhanced survival benefit and decreased immunotherapy-related adverse effects. In addition, future Phase III trials will likely elucidate further details regarding the safety and effectiveness of PD-1 inhibitors alone and in combination with existing melanoma chemotherapeutics.
In addition to mAbs targeting the PD-1 receptor, mAbs have also been developed that target PD-L1. A phase I trial of the anti-PD-L1 antibody BMS-936559 reported objective responses to therapy in 17 % (9/52) of patients with melanoma . The trial also demonstrated prolonged stabilization of disease in 27 % (14/52) of patients assessed 24 weeks after beginning therapy . The investigators found that 39 % (81/207) of patients experienced immune-related adverse events of any grade . This study also assessed the median anti-PD-1 receptor occupancy in peripheral blood T cells and found it was more than 65 % in all 29 patients tested with melanoma . Further studies are needed to evaluate if peripheral blood receptor occupancy correlates with treatment outcomes.
Roche Genentech is developing another anti-PD-L1 mAb known as MPDL3280A. Data on MPDL3280A presented at the annual 2013 American Society of Clinical Oncology conference (ASCO) reported that objective responses were observed in 29 % (10/35) of patients with advanced metastatic melanoma receiving the PD-L1 antibody . Further studies on the efficacy of anti-PD-L1 therapies are forthcoming and we anticipate that combination therapies may prove to be a promising option when utilizing anti-PD-L1.
Limitations and future directions
Similar to other cancer therapies, nivolumab treatment is commonly associated with adverse events that include fatigue, decreased appetite, diarrhea, nausea, cough, dyspnea, constipation, vomiting, dermatitis, pyrexia, and headache . Additional immune-related adverse events include pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis . These immune-related adverse events may prove to be a limitation of PD-1 inhibitors for some patients; however, adverse events are less frequent and severe than with ipilimumab and most patients who discontinue due to toxicity still have durable and ongoing response . Larger studies may reveal how to best manage immune-related adverse events when taking immunotherapy anti-PD-1 mAbs without limiting clinical efficacy.
Due to the cost of immunotherapy, chance of adverse events, and heterogeneity of individual tumors, it is important for clinicians and researchers to be able to predict a patient’s likelihood of response and adverse events. One method is to utilize biomarkers to predict likelihood of response to stratify patients prior to therapy. Initial data on nivolumab showed that 36 % (9 out of 25) of patients with PD-L1-positive tumors responded to therapy and 0 out of 17 patients with PD-L1-negative tumors responded to therapy . Reports at ASCO 2013 have suggested that PD-L1 detected in biopsy samples by immunohistochemistry may be capable of predicting activity of nivolumab in advanced cancer [16, 35]. In addition, a recent study noted that PD-L1 tumor expression and T cell gene signature correlated with responses to MPDL3280A . However, data presented at the annual 2013 ASCO conference have also reported objective responses to nivolumab in patients with PD-L1-negative tumors . This may be due to heterogenous tumor expression of PD-1, thus making a single negative biopsy insufficient to determine if a tumor is truly PD-L1 negative. Further randomized clinical trials are needed to evaluate the utility of PD-L1 as biomarker for patient selection.
Given the uncertainty of predictions based on PD-L1 expression or any other single biomarker, clinicians may choose to utilize a panel of specific biomarkers that can accurately predict and stratify patients based on their likelihood of response, should a useful biomarker panel become available [1, 2]. The use of biomarkers to profile immune cells that have infiltrated a tumor may also prove valuable to clinicians . These profiling tools could be used to understand the dynamic state of the immune system in the individual tumor and tailor immunotherapy selection accordingly.
In addition, translational research on serial tumor biopsies from patients treated with BRAF-inhibitors has demonstrated that BRAF inhibition is associated with an increase in melanoma antigen expression and T cell infiltrate, and a decrease in immunosuppressive cytokines in tumors of treated patients [12, 36]. These findings suggest that BRAF inhibitors may work synergistically with immunotherapy agents such as PD-1 inhibitors. Clinical trials that are currently in progress investigate combining BRAF-targeted therapy and immunotherapy for the treatment of advanced melanoma.
Although the results of the phase I clinical trials are impressive, it remains to be seen if PD-1 inhibitors demonstrate improved patient survival in phase III trials. In addition, because immunotherapies require time for induction of an immune response, they take longer to show an effect compared to cytotoxic or targeted therapies. Due to this delay, immunotherapies have been reported to cause transient progression in disease prior to objective reductions in tumor size . Therefore, phase I trials may underestimate the actual response rate to immunotherapy using objective response measurements that capture transient progression in disease prior to reductions in tumor size . As new immunotherapies are developed, we anticipate additional targets involved in the PD-1–PD-L1 signaling pathway, as well as additional pathways related to tumor immune suppression, will likely emerge.
The treatment of advanced melanoma is evolving as exciting new drugs that inhibit immune checkpoints are developed. These immune-checkpoint inhibitors allow a patient’s endogenous immune response to assist in combating advanced melanoma or other types of cancer. Nivolumab alone and in combination with ipilimumab has been shown to be effective in the treatment of advanced melanoma. Moving forward, there is a need to develop biomarkers to predict response to anti-PD-1 mAbs and design strategies to manage and avoid adverse immune-related events. We anticipate that as immunotherapies continue to develop, additional targets involved in the PD-1–PD-L1 signaling pathway, as well as additional related immunotherapy pathways, will likely emerge. The use of antibodies targeting the PD-1–PD-L1 pathway, in combination with existing and new immunotherapies, has the potential to alter the current melanoma treatment paradigm and usher in an exciting new era of advanced melanoma treatment with improved patient outcomes.
The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000002 and linked award TL1 TR000133.
The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000002 and linked award KL2 TR000134.
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R33AI080604.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.