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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 6  |  Page : 1167-1175

Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma


1 Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
2 Department of General Medicine, Rangaraya Medical College, NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India

Date of Web Publication28-Nov-2018

Correspondence Address:
Veerendra Koppolu
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66046
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1290_16

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 > Abstract 


Clinical management of metastatic melanoma suffered historically from a lack of effective targeted and immunotherapies due to short-lived clinical responses. Recent advances in our understanding of tumor-immune signaling pathways, discovery of immunosuppressive checkpoints, and subsequent development of antibodies that target these checkpoints reverses the situation to some extent. Two antibodies ipilimumab and nivolumab gained Food and Drug administration approval for the treatment of metastatic melanoma and target two major immunosuppressive checkpoints cytotoxic T lymphocyte antigen and programmed cell death protein 1 (PD-1), respectively. Nivolumab binds to PD-1, prevents PD-1 interaction with ligand Programmed death ligand 1 (PD-L1), and thus releases the T-cell exhaustion events (such as T cell apoptosis, decrease in T cell proliferation, etc.) leading to buildup of potent tumor-specific immune response. Successful Phase I–III results with remarkable antitumor activity and safety led to approval of nivolumab against ipilimumab refractory metastatic melanoma. Nivolumab therapy is exciting in that it not only provides substantial benefit but also provides durable responses. This review focuses on the evolution of immunotherapy leading to nivolumab approval and its potential in treating melanoma either alone or in combination with other therapies.

Keywords: Cancer immunotherapy, check point blockade, cytotoxic T lymphocyte antigen 4, immunosuppression, metastatic melanoma, nivolumab, programmed death 1, programmed death ligand 1


How to cite this article:
Koppolu V, Rekha Vasigala VK. Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma. J Can Res Ther 2018;14:1167-75

How to cite this URL:
Koppolu V, Rekha Vasigala VK. Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma. J Can Res Ther [serial online] 2018 [cited 2018 Dec 13];14:1167-75. Available from: http://www.cancerjournal.net/text.asp?2018/14/6/1167/229518




 > Introduction Top


The incidence of melanoma increased steadily over the past four decades.[1] The main cause of death of melanoma patients is the widespread metastases of cancer to organs such as liver, lung, brain, bone, and lymphatic system. Historically, the major treatment option for treating metastatic melanoma is chemotherapy using drugs such as dacarbazine, temozolomide, fotemustine, or taxanes.[2],[3] However, these chemotherapeutic approaches are focused on reducing the tumor burden and alleviating the symptoms rather than increasing the survival. For example, dacarbazine therapy which is considered as a standard of care induces response rates anywhere between 5% and 25% and does not improve the overall survival (OS) in comparison to the supportive care (5–11 months). The average survival of the metastatic melanoma patients under chemotherapy is 6–12 months with a 5-year survival rate under 10%.[4],[5] Thus, the lack of proper therapies for the treatment of metastatic melanoma spurred great interest in researchers to find novel therapies. Recent understanding of the molecular signaling pathways in the tumor microenvironment (TME) led to discovery of agents that target the tumor directly (targeted therapies) or agents that unleash the immune system potential to fight cancer (Immunotherapies). These agents have dramatically enhanced the treatment options for metastatic melanoma patients. The targeted therapies approved after 2011 includes vemurafenib, dabrafenib, and trametinib.[6],[7],[8] The immunotherapeutic drugs approved are ipilimumab, pembrolizumab, and nivolumab.[9]

Immunotherapy for metastatic melanoma focuses on enhancing the tumor-specific immune system by blocking the checkpoints of the immune system. Immune checkpoints refer to plethora of immunosuppressive pathways hard wired into the immune system to modulate the durability and amplitude of physiological immune responses to antigens so as to promote self-tolerance and prevent collateral tissue damage.[10],[11] It is now clear that tumor cells utilize these pathways to their advantage and prevent buildup of immune response (particularly T-cell responses) against them. The major inhibitory pathways identified are cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway, and PD-1 pathway and both are initiated by ligand-receptor interactions and thus can readily be blocked by antibodies against them.[11],[12],[13],[14],[15] In particular, ipilimumab inhibits CTLA-4 whereas pembrolizumab and nivolumab inhibit PD-1 pathway. The approval of these agents raised the field of immunotherapy to the ranks of chemotherapy, surgery, and radiation as a pillar of cancer therapy. Nivolumab which is the main focus of this review is found to drive antitumor responses against metastatic melanoma and other cancers such as renal carcinoma, nonsmall cell lung cancer (NSCLC), and Hodgkin's lymphoma.[16],[17] The current article reviews the immunotherapeutic approaches leading to discovery of nivolumab and its potential in treating melanoma.


 > Immunotherapy Approaches in Treating Metastatic Melanoma Top


Early immunotherapy

Early immunotherapy approaches to treat metastatic melanoma revolved around infusion of cytokines such as interleukin-2 (IL-2) and interferon-γ. IL-2 is a pro-inflammatory cytokine with immunomodulatory activities and is approved by the Food and Drug Administration (FDA) in 1998.[18],[19] High doses of IL-2 showed durable (>3 years) immune responses in 6%–8% of patients but was also associated with toxicities such as fever, hypotension, cardiac arrhythmias, and multiorgan dysfunction.[18],[20],[21] Interferon-γ treatment when given to metastatic melanoma patients after tumor resection showed an improved relapse-free survival. However, the OS is only moderate with a relative improvement of 10% but is often associated with chronic and dose-limiting toxicities.[22],[23],[24],[25],[26],[27] Although these early immunotherapy options have shown some signs of treating the metastatic melanoma, they did not exhibit a long-term survival benefit.

Cytotoxic T-lymphocyte antigen 4 antibody therapy

CTLA-4 is the first immunosupressor/immune checkpoint that is clinically targeted, is expressed exclusively on the surface of T cells, and is involved in regulating the amplitude of early events of T cell activation in lymphoid organs.[10] CTLA-4 counteracts the activity of CD28, a T cell costimulatory receptor that interacts with B7.1/B7.2 of antigen presenting cells (APC) after initial engagement of T-cell receptor with cognate antigen on APC.[28],[29],[30],[31],[32],[33],[34] Thus, CTLA-4 prevents B7.1/B7.2-CD28 interaction that is crucial for continuous tumor antigen-specific T-cell activation.[35],[36] Antibodies that target CTLA-4 (ipilimumab) inhibits CTLA-4 engagement with B7.1/B7.2, which will facilitate normal costimulatory events of T-cell activation leading to buildup of a robust immune response (particularly cytotoxic T-cell response) specific to tumor antigens.

Ipilimumab is a fully human IgG1 CTLA-4 antibody approved by the US FDA in 2011 for treating late-stage refractory metastatic melanoma.[15],[37] Ipilimumab enhanced the OS benefit for both the previously treated (MDX 010-20 trial by Bristol-Mayer Squibb) and untreated (CA 184-024 trial) metastatic melanoma patients and became the first immunotherapeutic agent to improve the OS of metastatic melanoma patients. In MDX 010-20 trial, 676 patients who underwent previous standard chemotherapy and with unresectable Stage III or Stage IV metastatic melanoma were randomized to give either ipilimumab or Gp100 peptide vaccine.[37] Ipilimumab-treated patients showed a survival of 45.6% after 1 year and 25.6% after 2 years, while Gp100 vaccine-treated patients showed 23.5% and 13.7% survival after 1 and 2 years, respectively. The median OS benefit of ipilimumab is 10 months compared to 6.4 months of Gp100. Later in CA 184-024 trial, ipilimumab is tested as a first-line therapy along with a standard dacarbazine chemotherapy in previously untreated 502 patients.[38] Patients who received both ipilimumab and dacarbazine showed an OS of 11.2 months versus 9.2 months for dacarbazine alone. The long-term survival of these patients after 3 years is 20.8% for ipilimumab/dacarbazine and 12.2% for dacarbazine.[38] In another Phase III clinical trial with ipilimumab and dacarbazine, long-term survival benefit occurred at 18.2% compared to 8.8% for dacarbazine.[39] In another Phase III clinical trials involving completely resected Stage III melanoma patients, ipilimumab showed a recurrence-free benefit of 46.5%.[40] Most notably, meta-analysis of Phase II and Phase III clinical data showed a survival benefit of 20% to advanced metastatic melanoma patients with the maximum survival extending up to 10 years.[41],[42],[43] These data suggest ipilimumab as an exciting therapy for at least a subset of patients. Along with the improved survival benefit in a subset of patients, many toxic Grade III or IV side effects also started to emerge mainly because of the immune system activation for prolonged periods. These include colitis, gastritis, dermatitis, endocrinopathies, and neurotoxicity.[37],[44],[45] In addition, the activation of immune response by ipilimumab is a slow process leading to increased tumor burden before the tumor regression and thus makes it a challenging option for patients with high tumor burden.[37],[46],[47]

Anti PD-1/PD-L1 therapy

The clinical experiences and lessons learned from ipilimumab therapy have enhanced the research interest in targeting other tumor immunosuppressive pathways leading to subsequent development of pembrolizumab and nivolumab. Both pembrolizumab and nivolumab target immunosuppression caused by interaction of immune checkpoints programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1).[48] PD-1 is a surface receptor expresses mainly on immune cells such as CD4+ and CD8+ T cells, B cells, and natural killer cells whereas its ligand PD-L1 (also PD-L2) expresses mainly on tumor cells.[49],[50],[51],[52],[53],[54] These interactions have immunosuppressive effects leading to T-cell exhaustion in the TME characterized by T-cell apoptosis, decrease in T-cell proliferation, and decrease in release of cytokines such as IL-2 and interferon-gamma [Figure 1]a.[55],[56],[57],[58],[59],[60],[61] Physiologically, T-cell exhaustion events are the result of PD-1 overexpression on T cells during T cell-antigen interaction and are found to play a significant role in inhibiting prolonged activation of immune cells after the antigen is removed successfully. Thus, PD-1 expression is required to inhibit immune cells from attacking normal tissues (autoimmunity) and to promote immune tolerance.[62] However, tumor cells exploit this mechanism by promoting the T-cell exhaustion events through overexpression of PD-L1 and consequently inhibiting the buildup of robust antitumor immune responses. Recent understanding of this PD-1/PD-L1 inhibitory pathway paved the way for the accelerated development of antibodies that target PD-1 or PD-L1 leading to FDA approval of two antibodies pembrolizumab and nivolumab that target PD-1. Many antibodies such as durvalumab (MEDI4736) and MPDL3280A were designed to block PD-L1 and are in clinical stages of investigation against several other malignancies.[63],[64] Studies on efficacy of PD-1-targeted therapies on NSCLC patients suggested a need for high CD28 expression for CD8 T-cell responses.[65] This would help in determining the patient populations that may benefit from treatment, although specific studies are needed to test the applicability for metastatic melanoma patients.
Figure 1: Checkpoint inhibition through PD-1 pathway puts brakes on tumor-specific immune response while PD-1 antibodies release those brakes. (a) Engagement of PD-L1 receptor on T cell with tumor cells or antigen presenting cells PDL-1/PDL-2 ligands leading to recruitment of phosphatase SRC Homology 2-Domain-Containing protein Tyrosine Phosphatase 2 (SHP-2) to PD-1, dephosphorylation of T-cell receptor signaling kinases by SHP-2 and subsequent T-cell energy or exhaustion. (b) Administration of PD-1 blocking agents such as nivolumab inhibits PD-1 and PDL-1/PDL-2 interactions and the events that put brakes on T cells from building an antigen-specific T-cell response

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 > Nivolumab Top


Nivolumab is a fully human IgG4 antibody which specifically binds to PD-1 and releases the immune system brakes applied through PD-1/PD-L1 pathway [Figure 1]b. PD-1 is principally believed to act on the effector phases of T cells in the TME on chronic antigen exposure and thus antibodies blocking PD-1 are thought to deliver quick and specific antitumor responses with fewer side-effects. Compared to PD-1, CTLA-4 acts systemically at secondary lymphoid tissues mainly during early events of T-cell activation and locally in the TME.[10] The local responses of CTLA-4 antibodies at TME is mainly through inhibiting suppressive responses of CD4 positive T regulatory cells in the TME.[10],[66],[67] PD-1 plays subtle roles in peripheral immune tolerance and PD-1 knockouts are well tolerated in mice.[68],[69] However, CTLA-4 plays more active roles in immune tolerance and CTLA-4 knockout mice exhibit hyperproliferation of lymphocytes leading to more T lymphocyte infiltration and organ failure.[70],[71] Thus, it is hypothesized that inhibition of the PD-1 inhibitory pathway by specific antibodies such as nivolumab are better tolerated than CTLA-4 blockade by ipilimumab.

Clinical trials with nivolumab showed a remarkable activity against metastatic melanoma with quick and durable responses, although some toxic effects that are mostly preventable or reversible with close monitoring and appropriate management. Consequently, nivolumab was approved in US and Japan primarily for treating ipilimumab refractory melanoma (patients with melanoma progressed after ipilimumab treatment) with a B-raf kinase (BRAF) mutation (a mutation common in 50% of melanomas).[72] Although the majority of mature data on nivolumab is pertinent to metastatic melanoma, FDA also approved nivolumab use for squamous NSCLC whose disease have progressed during or after platinum-based chemotherapy.[73],[74],[75] In addition, FDA had earlier granted breakthrough therapy designation for nivolumab in treating Hodgkin lymphoma and subsequently approved it in 2016.[76],[77] Many Phase I and Phase II trials also proved the nivolumab effectiveness in treating multiple other cancer types such as urothelial bladder cancer and triple-negative breast cancer.[78],[79]

Clinical trials with nivolumab

Phase I trials with nivolumab against late-stage refractory metastatic melanoma

Initial Phase I clinical trial with nivolumab against melanoma is performed on 94 patients at doses of 0.1, 0.3, 1, 3, and 10 mg of nivolumab/kg body weight for every 2 weeks.[80] Among the treated patients, 28% (26 of 94) reached an objective response rate (ORR). The ORR was highest at 41% (7 out of 17) for patients from 3 mg/kg treatment cohort. Among the 26 patients with ORR, 18 patients received treatment for >:1 year, and 13 of them showed durable response even after 1 year. The rest of the eight patients received treatment for less than a year among which 6 showed objective response ranging from 1.9 to 5.6 months. The long-term survival among all the dose cohorts is found to be 63%, 48%, 42%, and 42% after 1, 2, 3, and 4 years.[81] The major toxic side effects of the treatment include nausea, decreased appetite, pruritus, and diarrhea. Immune-related side effect such as severe pneumonitis is also occurred in six patients.[80],[82] Overall, the treatment showed impressive antitumor responses with manageable side effects.

Phase I trial with nivolumab against ipilimumab treated or naïve melanoma

Nivolumab was further tested in a second Phase I trial on 90 Stage 3 or Stage 4 refractory metastatic melanoma patients that were either ipilimumab naïve (never received ipilimumab but had received other chemotherapies) or received previous ipilimumab treatment.[83] Nivolumab was given to both cohorts at 1, 3, and 10 mg/kg at 2 weeks interval for a total of 24 weeks, along with or without a multipeptide vaccine. Nivolumab was found to be safe and tolerable with or without multipeptide vaccine in both ipilimumab refractory and ipilimumab naïve patients. About one-quarter of the total patients showed ORR irrespective of the prior treatment. Tumor regression was found to be starting as early as 5 weeks after the treatment. Five of the patients showed minor toxicity symptoms and are recovered after corticosteroid treatment. The patients showing objective responses were both positive and negative for PD-L1 expression, although the responses were higher against PD-L1 expressing tumors. Responses were also not specific to presence or absence of a common metastatic melanoma mutation in BRAF encoding proto-oncogene. Mutations in BRAF encoding proto-oncogene is common in 50% of melanomas and the fact that nivolumab works in both wild-type and mutated BRAF (most commonly BRAF V600E) was considered as a promising sign for the future potential of nivolumab.

Phase III trials with nivolumab against metastatic melanoma in patients treated by ipilimumab/chemotherapy

A large Phase III study involving 90 sites in 14 countries was performed to test nivolumab therapy in advanced melanoma patients with metastasis progressed after ipilimumab immunotherapy or ipilimumab and BARF inhibitor therapy.[72] The patients were administered with either nivolumab (3 mg/kg every 2 weeks) or other chemotherapy options such as dacarbazine or carboplatin or paclitaxel. Nivolumab administered patients showed a better response with an ORR of 31.7% compared to 10.6% response for chemotherapy. The ORR observed with nivolumab are irrespective of patients BRAF mutations, previous benefits of ipilimumab, and presence of poor prognosis factors. In addition, the responses were observed in both PD-L1 positive and negative melanomas, although the responses were greater with 44% in PD-L1 positive compared to 22% in PD-L1 negative melanomas. The median time for the response was 2.2 months for nivolumab and 3.5 months for chemotherapy. Notably, the adverse events were less severe with nivolumab and were easily manageable. Drug toxicity caused treatment discontinuation in only 2% of nivolumab-treated patients compared to 9% in the chemotherapy. In addition, Grade 3 or Grade 4 side effects were only 9% for nivolumab but 31% for chemotherapy. Overall, nivolumab showed an astounding response rate and was very well tolerated than did chemotherapy. Based on these results, US FDA has given accelerated approval for nivolumab on December 22, 2014, for treating patients with unresectable metastatic melanoma with the disease progressed even after previous ipilimumab therapy and with BRAF V600E mutation.

Phase III trial of nivolumab in previously untreated melanoma without B-raf kinase mutation

Another Phase III trial was performed on previously untreated melanoma patients without BRAF mutation.[84] Patients were treated with nivolumab or dacarbazine therapy and observed for ORR and adverse events. The patients treated with nivolumab showed an OS rate of 72.9% and was significantly much higher than 42.1% noticed for dacarbazine after 1 year. The ORR was found to be 40% (nivolumab) versus 13.9% (dacarbazine), and the progression-free survival (PFS) was 5.1 months (nivolumab) versus 2.2 months (dacarbazine). The toxic profiles for nivolumab were similar to the ones observed in previous trials with majority of them being nausea, fatigue, pruritus, and diarrhea. Grade 3 or Grade 4 adverse events with nivolumab was less severe (11.7%) when compared to chemotherapy (17.6%). This trial proved the effectiveness of using nivolumab as a first-line therapy for metastatic melanoma.

Biomarkers for nivolumab therapy

Nivolumab therapy has resulted in durable and tolerable responses in many metastatic melanoma patients. However, the treatment is only helping ~30% of the patients and thus still challenges physicians to predict whether or not nivolumab therapy is best for any patient. Currently, an exciting area of work is to search for biomarkers that would help us to identify patient population that may benefit from the nivolumab treatment. Since nivolumab works by binding to PD-1 and inhibiting PD-1 interaction with PD-L1, it was hypothesized that the expression of PD-L1 in tumor tissues may serve as a biomarker for successful patient response to nivolumab. To test this scenario, immunohistochemistry for tumor samples was performed to identify PD-L1 positive tumors in advanced melanoma patients in Phase I trials and the ORRs were observed after treatment with nivolumab.[81] The results showed zero ORR to nivolumab treatment in 17 PD-L1-negative patients while 9 of 25 PD-L1 expressed patients responded to the treatment. In another Phase II trial, a statistically significant association of PD-L1 expression and positive nivolumab response was achieved with 67% of PD-L1-positive patients showing ORR, although PD-L1-negative patients still responded with 19% ORR.[83] These results indicate that PD-L1 negative tumors can respond to nivolumab treatment and thus complicate the presence of PD-L1 as the only scenario for administering nivolumab therapy. In addition, PD-L1 expression is dynamic and is affected by multiple factors leading to more complications in deciding PD-L1 as biomarker for a response.[85],[86] Studies from NSCLC patients treated with PD-1 therapy suggested the need for CD28 expression for expansion of PD-1 positive CD8 T cells, adding another angle to consider for a successful therapy.[65] Therefore, at this point, a further investigation is needed to consider PD-L1 expression as biomarker for decision-making on nivolumab therapy.

Nivolumab in combination therapies

The next frontier in the immunotherapy is combination therapy including if and how to combine immunotherapy with chemotherapy or other immunotherapy drugs. Combination therapies that provide rapid and substantial tumor regression would undoubtedly revolutionize the melanoma treatment. Given the potential benefits, nivolumab is being investigated in combination with chemotherapies, immunotherapies, and vaccine-based therapies such as dendritic vaccines, NY-ESO-1, and Tri-Mix in advanced melanoma patients.[83] A combination therapy involving nivolumab and ipilimumab was considered promising based on rapid and durable immune response in pre-clinical and clinical trials.[87],[88] Phase I studies receiving this combination therapy of ipilimumab and nivolumab demonstrated a tumor regression in ~50% of metastatic melanoma patients with 85% of patients surviving even after 1 year of the treatment. In addition, the response rates were found to be similar irrespective of BRAF mutation and PD-L1 expression. The combination therapies proved to be more effective than either of the individual therapies, although higher Grade 3–4 adverse effects than individual monotherapies. Based on the exciting data obtained from ipilimumab and nivolumab combination therapy, Phase III trials are being conducted.

Several other combinations involving immunotherapy alone or immunotherapy and chemotherapy are being investigated in clinical trials. A detailed list of these therapeutic agent combinations is provided in [Table 1]. The information gained from these trials would hopefully help guide the physicians to choose best-treatment choices in the near future.
Table 1: Ongoing combination studies involving nivolumab

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Reported side effects for nivolumab therapy

Although majority of the adverse events associated with nivolumab are less severe and manageable, some events are life-threatening and thus demands a thorough understanding of the potential side effects so as to manage them effectively.[82],[89],[90],[91] Awareness on the potential PD-1 therapy side effects would help physicians in avoiding delays in diagnosis and treatment. The common side effects observed from various trials include nausea, diarrhea, decreased apatite, pruritus, and pneumonitis.[92] Grade 3–4 adverse events were usually noticed in 5%–10% of patients while the same is around 22%–24% for ipilimumab treatment. Severe adverse events leading to abandoning of the therapy is in ~5% of the patients. Some severe side effects also emerge after cessation of the therapy including severe skin reactions, diabetes mellitus, acute heart failure, myositis, and rhabdomyolysis.[92]

Recently in 2016 Hofmann et al. reported adverse events associated with nivolumab therapy from a large retrospective study on 496 patients from 15 skin cancer centers.[92],[93] Out of the total patients treated, 136 of them experienced a total of 242 side effects. Out of 136 patients, 118 patients experienced side effects associated with skin, liver, renal system, gastrointestinal tract, and endocrine system. Nearly 78 patients experienced side effects related to nervous system, heart, blood, eyes, respiratory tract, and musculoskeletal system. Although rare, some side effects such as polyradiculitis, cardiac arrhythmia, asystolia, paresis, pancreatitis, and diabetes mellitus are also observed.[92],[93]

In another retrospective study, Eigentler et al. in 2016 summarized the safety data of immune-related toxicities for both nivolumab and pembrolizumab using publicly available assessment reports from US FDA and European medicines agency.[90] The toxic profiles for both drugs are similar with major adverse events being mild-to-moderate (Grade 1–2) and with idiopathic Grade 3–4 events ≤2% for any event term. Adverse events such as dermatological (Grade 3–4: 0.8%) gastrointestinal (Grade 3–4: 1.6%), pulmonary (Grade 3–4: 2%), endocrine (Grade 3–4: 1%), and renal and hepatic (Grade 3–4: 1%) toxicities were noticed. The onset of adverse events varies anywhere from 1 to 6 months after the treatment, and many of them are reversible with treatment irrespective of their time of onset. Many of the adverse events are manageable by the use of glucocorticoids. Some preclinical toxicity studies have showed that nivolumab causes embryological toxicity. Thus, it is not recommended for pregnant women, and contraception is recommended for 4–5 months after the final dose of treatment.

Other PD-1/PD-L1 pathway inhibitors in treating metastatic melanoma

Before the approval of nivolumab by FDA for unresectable or advanced metastatic melanoma, another PD-1 inhibitor pembrolizumab was also approved by FDA in September 2014 for the same indication. Just like nivolumab, pembrolizumab is also a fully human IgG4 PD-1 specific antibody and showed similar efficacy and safety profiles in clinical trials. In brief, the initial Phase I trials were done on patients refractory to ipilimumab treatment with 2 mg/kg and 10 mg/kg pembrolizumab treatment at every 3 weeks.[94] The pembrolizumab treatment was effective with an overall ORR of 26%. Successful initial trial led to a Phase II clinical trial, in which an ORR of 21%–25%, and PFS of 34%–38% was noticed.[95] Finally, Phase III trial demonstrated a prolonged 1-year survival of 72.1%, PFS survival at 47.3%, and Grade 3 or 4 toxicities in 13.3% of patients.[96]

In addition to PD-1 targeting antibodies such as nivolumab and pembrolizumab, antibodies that target PD-L1 such as BMS-936559 and MPDL3280A are in Phase I clinical trials against metastatic melanoma and demonstrated a high ORR of 17% and 29%, respectively, with a manageable safety profile.[64],[97]


 > Conclusion Top


Improvements in understanding of the biology of tumor immune regulatory pathways are rapidly evolving the treatment choices for metastatic melanoma. Immune checkpoint PD-1 blockade by nivolumab would be an attractive option because of the durable antitumor immune responses and low adverse events compared to the currently available targeted and immunotherapies. The overall patient response rate for nivolumab is found to be 32% and is much higher than other metastatic melanoma therapies (for example, patient response rate to ipilimumab therapy is 10%–15%). The clinical validation and favorable toxicity profile of nivolumab will drive researchers to further test its potential in combination of other targeted therapies as well as immunotherapies. Identification of good combination partners to build a rapid and effective antitumor response and identification of biomarkers to assist in better judgment on the use of nivolumab would be of future interests in nivolumab therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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