Aditya K. Gupta, MD, PhD, FRCPC1,2 and Deanne Daigle, MSc2
1Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
2Mediprobe Research Inc., London, ON, Canada
Conflict of interest: None Reported.
Melanoma is an aggressive skin cancer with a generally poor prognosis at Stage III-IV disease. Traditionally, metastatic melanoma was treated by surgical resection, when possible, and with systemic chemotherapy. New developments in molecular biology have led to the identification of immune checkpoints which are exploited by malignant cells, allowing them to go undetected by the immune system. Nivolumab (Opdivo®) is a human monoclonal antibody which prevents immune inhibition by interacting with PD-1 on tumor cells; thus, increasing tumor-specific T cell proliferation. Nivolumab has demonstrated efficacy superior to that of standard chemotherapy and relative safety in clinical trials. Indeed, the outcomes for patients with advanced melanoma are being improved by novel biologic agents such as nivolumab.
antineoplastic agent, melanoma, Opdivo®, PD-1 inhibitor, programmed cell death 1 receptor, signal transduction, skin neoplasms
A melanoma is an aggressive tumor often occurring on the skin that is caused by the transformation of melanocytes into malignant cells.1 Many cases are classified as melanoma in situ, with tumors localized only to the epidermis (Stage 0); however, some melanomas are invasive and infiltrated the dermis (Stage I-II), and still others spread to nearby lymph node(s) (Stage III), or to distant lymph nodes and/or organ systems (Stage IV).2 Stage III- IV disease is termed ‘metastatic melanoma’ and occurs in roughly 30% of patients after excision of the primary tumor.2,3 The 5-year survival rate is 23% when metastatic melanoma presents in the skin.4 In order to evade immune recognition, certain tumors may exploit immune-regulatory checkpoints which suppress excessive T lymphocyte function in normal physiologic conditions; thereby permitting unregulated proliferation of malignant cells.5
Preclinical cancer studies suggest that interrupting co-receptor interactions responsible for inhibitory signaling on tumor- specific T cells would activate the anti-tumor immune response.5 One such co-receptor is programmed death receptor-1 (PD-1). PD-1 inhibits T cell activation, leading to reduced proliferation, cytokine production, and cytolysis via interactions with its ligands PD-L1 and PD-L2.6 On December 22, 2014, nivolumab (Opdivo®), a human monoclonal antibody against PD-1 receptor, was approved by the US FDA for the treatment of unresectable or metastatic melanoma that is unresponsive to other drugs.7 Nivolumab binds PD-1 with high affinity and impedes both PD-L1 and PD-L2 interaction; thus, increasing tumor-specific T cell proliferation.
Phase I and II
Two phase I dose-escalation trials were performed to assess the preliminary efficacy, safety and pharmacokinetics of nivolumab.6,8 Both trials enrolled participants with advanced metastatic non- small cell lung cancer (NSCLC), melanoma, castrate-resistant prostate cancer, renal cell carcinoma, and colorectal cancer. Doses ranging from 0.1-10 mg/kg of nivolumab were administered by intravenous (IV) infusion every 2 weeks. Pharmacokinetic data from these studies showed that the median time to peak serum concentration of nivolumab is 1 to 4 hours after dosing.8 Nivolumab yields an approximate serum half-life (t1/2) of 12 days for 0.3, 1, and 3 mg/kg doses and up to 20 days for the 10 mg/kg dose.6 Maximum concentration (Cmax) and area under the curve (AUC) are directly related to dose.6,8 PD-1-receptor occupancy on the surface of circulating CD3+ cells was also assessed.6,8 After one infusion at a dose of 0.1 to 10 mg/kg, surface occupancy was dose-independent with a mean peak occupancy of 85% (70% to 97%) observed at 4 to 24 hours and a mean plateau occupancy of 72% observed at ≥57 days;6 however, another study of cell surface occupancy in participants with melanoma showed that the median occupancy was 64% to 70% and varied according to dose.8 Tumor biopsies from phase I suggested a potentially significant association between PD-L1 cell surface expression and clinical response to nivolumab (P=0.048)6 which was further investigated in subsequent studies.
One-hundred and seven advanced melanoma participants from the phase I trial were followed for up to 4 years after treatment initiation to monitor survival, tumor remission and the long-term safety of nivolumab.8 Sixty-two percent of these participants had received at least two prior systemic treatments.9 The objective response rate (ORR), defined as the proportion of participants who had a complete or partial response was 25%, 18/26 participants were treated for a year or more.8 The ORR increased to 33% at 4 years’ follow-up, with a median response duration of 2 years.8,9 Stable disease lasting ≥24 weeks was originally observed in 6% of participants and increased by another 1% at 4 years’ follow-up.8,9 Median overall survival was 16.8 months (95% confidence interval [CI] = 12.5-31.6), and 1 and 2 year survival rates were 62% (95% CI = 53%-72%) and 44% (95% CI = 32%-53%), respectively.9
The most common treatment emergent adverse events (TEAEs) in participants treated with nivolumab were fatigue (32%), rash (23%), and diarrhea (18%).9 TEAEs of immunologic significance included skin disorders (35%), gastrointestinal disorders (18%), and endocrinopathies (13%). Five participants experienced Grade 3 or 4 TEAEs.9 The majority of AEs occurred within the first 6 months of treatment and the frequency of AEs did not increase with prolonged use.9
Yamazaki and colleagues reported preliminary results from their phase II study of 35 participants with advanced melanoma.10 Nivolumab was administered at a dose of 2 mg/kg every 3 weeks until unacceptable toxicity, disease progression, or complete response. The ORR was 23% (8/35) with median progression- free survival of 6.14 months. TEAEs occurred in 45.7% of participants and consisted mainly of elevated gamma-glutamyl transpeptidase, anemia, decreased hematocrit, hemoglobin and red blood cell counts, and loss of appetite. No drug-related deaths were reported.
A randomized, double-blind, phase III trial assessed the efficacy and safety of nivolumab versus standard chemotherapy (dacarbazine) in melanoma without BRAF mutation.11 Four- hundred and eighteen participants were randomized to nivolumab 3 mg/kg every 2 weeks (N=210) or dacarbazine 1000 mg/m2 every 3 weeks (N=208). ORRs and median progression-free survival are presented in Table 1. The ORR was significantly higher in the nivolumab group compared to the dacarbazine group and the proportion of participants with a complete response was higher with nivolumab than with dacarbazine (7.6% vs. 1.0%). The duration of progression-free survival was also longer in participants treated with nivolumab compared to those treated with dacarbazine.
The trial was stopped early due to nivolumab’s clear benefit over standard chemotherapy in improving overall survival.12 The median overall survival was not reached in the nivolumab group and was 10.8 months (95% CI = 9.3%-12.1%) in the dacarbazine group.11 Overall survival rates at 1 year were 72.9% (95% CI = 65.5%-78.9%) and 42.1% (95% CI = 33%-50.9%) in the nivolumab and dacarbazine groups, respectively. Nivolumab significantly increased overall survival compared to dacarbazine (hazard ratio for death = 0.42; 99.79% CI = 0.25-0.73; P<0.001).
The incidence of AEs was similar between treatments (74.3% vs. 75.6% in the nivolumab and dacarbazine groups, respectively); yet the frequency of AEs of grade 3 or 4 was lower for participants treated with nivolumab than with dacarbazine (11.7% vs. 17.6%).11 The most common TEAEs with nivolumab were fatigue (19.9%), pruritus (17.0%), and nausea (16.5%). The proportion of participants who discontinued the study due to TEAEs was 6.8% and 11.7% in the nivolumab and dacarbazine groups, respectively. No drug-related deaths occurred in either group.
Nivolumab’s efficacy in treating ipilimumab- or ipilimumab/ BRAF inhibitor-refractory melanoma was investigated in 405 participants.13 Participants were randomized to receive an IV infusion of nivolumab at a dose of 3 mg/kg, or investigator’s choice of chemotherapy (ICC), either dacarbazine 1000 mg/m2 every 3 weeks or carboplatin AUC 6 plus paclitaxel 175 mg/m2 every 3 weeks by IV infusion, until disease progression or unacceptable toxicity. Tumors were assessed at baseline, 9 weeks, and every 6 weeks for the first year, then every 12 weeks until disease progression, death or study withdrawal. Safety was assessed in all participants who received at least one dose of study drug. The primary endpoint was the proportion of participants who had an OR. Secondary endpoints included progression-free survival rates, and PD-L1 tumor expression.
ORRs and median progression-free survival are displayed in Table 1. ORRs were higher with nivolumab than with ICC, although no statistical comparison was made. Median time to response was 2.1 months and 3.5 months in the nivolumab and ICC groups, respectively. Median progression-free survival was not significantly different between nivolumab and ICC. The ORR with nivolumab was higher for PD-L1 positive tumors (43.6%) than PD-L1 negative tumors (20.3%), while ORRs were similar with ICC in both types of tumors (9.0% vs. 13.0%).
Rates of TEAEs were 68% in the nivolumab group and 79% in the ICC group. Fatigue, pruritus and diarrhea were the most common AEs with nivolumab, while nausea, alopecia and fatigue were the most common AEs with ICC. Grade 3 to 4 AEs occurred in 9% of participants treated with nivolumab and in 31% of participants treated with ICC. Drug toxicity led to the discontinuation of treatment in 3% and 7% of the participants in the nivolumab and ICC groups, respectively.
Clinical trials have also assessed the safety and efficacy of nivolumab in combination with ipilimumab for the treatment of advanced melanoma.14,15 Eighty-six participants in a phase I trial were treated either concurrently with escalating doses of nivolumab (cohort 1: 0.3 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 3: 3 mg/kg nivolumab + 1 mg/kg ipilimumab, cohort 4: 3 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 5: 10 mg/kg nivolumab + 3 mg/kg ipilimumab, 10 mg/kg nivolumab + 10 mg/kg ipilimumab), or sequentially with nivolumab 1 mg/kg and 3 mg/kg every 2 weeks for up to 48 doses.14 Participants were followed for 2.5 years after the start of treatment. Clinical activity was assessed at weeks 12, 18, 24, 30 and 36, and every 12 weeks thereafter in the concurrent therapy cohorts, while the sequentially treated cohorts were assessed at week 8 and every 8 weeks thereafter. PD-L1 tumor-cell expression was also characterized.
The ORR in the concurrent regimen cohorts was 40% (95% CI = 27-55) across all doses.14 Sixteen participants experienced a ≥80% reduction in tumor size. Five complete responses were included among those with a ≥80% reduction. Nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg were the maximum doses associated with an acceptable safety profile in the sequential treatment cohort. The ORR in participants who received the sequential regimen was 53% (95% CI = 28%-77%), including three complete responses; all participants who attained OR had a ≥80% tumor reduction at the rst scheduled assessment. Twenty percent of participants (95% CI = 8%-39%) in the sequenced regimen cohorts had an OR, including one complete response. Four participants in the sequenced regimen cohorts had a tumor reduction of ≥80%. ORs were noted in 6/13 and 9/22 participants with PD-L1 positive and PD-L1 negative tumors, respectively. Ninety-three percent of participants experienced TEAEs, the most common being rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Eleven participants (11%) in the concurrent regimen group and three (9%) in the sequenced regimen discontinued treatment due to TEAEs.
|Study Arms||Objective Response (%)||95% CI (%)||P-value||Median Progression- free Survival (months)||95% CI||P-value|
|Robert et al. 2015||Nivolumab 3 mg/kg a|
Dacarbazine 1000 mg/m2
|Weber et al. 2015||Nivolumab 3 mg/kg|
Investigator’s choice of chemotherapy
|Larkin et al. 2015||Nivolumab 3 mg/kg|
Ipilimumab 3 mg/kg
Nivolumab 1 mg/kg +
ipilimumab 3 mg/kg +
nivolumab 3 mg/kg
|Table 1: Objective response and median-progression-free survival11,13,15|
a Objective response was 52.7% (95% CI = 40.8%-64.3%) in PD-L1 positive tumors and 33.1% (95% CI = 25.2%-41.7%) in PD-L1 negative tumors.
* Comparing nivolumab + ipilimumab to ipilimumab alone and comparing nivolumab alone to ipilimumab alone. ns = not significant
In a double-blind, phase III study, 945 participants were randomized to receive either: 1) nivolumab 3 mg/kg every 2 weeks (plus ipilimumab matched placebo) for 4 doses; 2) nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks for cycle 3 and thereafter; or 3) ipilimumab 3 mg/kg every 3 weeks (plus nivolumab-matched placebo) for 4 doses by IV infusion.15 Treatment continued until disease progression, unacceptable toxicity or study withdrawal.
Median progression-free survival was significantly longer with nivolumab plus ipilimumab than with ipilimumab alone and with nivolumab than with ipilimumab (Table 1).15 No significant difference in the hazard of death or disease progression between the combination treatment and nivolumab only groups was found. The ORRs were highest among participants treated with nivolumab plus ipilimumab, followed by those treated with nivolumab only, and ipilimumab only (Table 1). Median time to OR was similar in the three groups (2.76, 2.78, and 2.79 months in the nivolumab plus ipilimumab, nivolumab, and ipilimumab groups, respectively). Complete response rates were also highest with nivolumab plus ipilimumab (11.5%), than with nivolumab (8.9%) or ipilimumab (2.2%) alone. The highest ORRs were observed in participants with PD-L1-positive tumors treated with nivolumab plus ipilimumab (72.1%; 95% CI = 59.9%-82.3%) or nivolumab only (57.5%; 95% CI = 45.9%-68.5%).
TEAEs occurred in 95.5% of the nivolumab plus ipilimumab group, in 86.2% of the ipilimumab group, and in 82.1% of the nivolumab group.15 The most common TEAEs in all groups were diarrhea, fatigue, pruritus and rash. The incidence of grade 3 or 4 AEs was highest in the combination group (55.0%), compared to the ipilimumab (27.3%) and nivolumab-only (16.3%) groups. TEAEs led to study discontinuation in 36.4%, 14.8% and 7.7% of the nivolumab plus ipilimumab, ipilimumab only and nivolumab only groups, respectively. One participant in the nivolumab group died of neutropenia and one participant in the ipilimumab group died of cardiac arrest. No deaths were reported with the combination treatment.
Nivolumab has demonstrated greater efficacy when compared to standard chemotherapy in clinical trials.11,13 Nivolumab produced higher objective response rates, longer median progression-free survival, and increased overall survival compared to standard chemotherapy.11,13 Participants with ipilimumab- or ipilimumab/ BRAF inhibitor-refractory melanoma treated with nivolumab also had higher response rates and a faster time to response than those treated with investigator’s choice of chemotherapy.13 Participants treated with nivolumab had significantly longer progression-free survival and higher OR and complete response rates compared to participants treated with ipilimumab monotherapy.14 Furthermore, patients who did not respond to previous ipilimumab therapy did have a response to treatment with nivolumab.14 Nivolumab/ipilimumab combination therapy is also encouraging.15 Nivolumab treatment is associated with a risk of immune-mediated pneumonitis, colitis, hepatitis, renal dysfunction and endocrinopathy.16 The most common TEAEs with nivolumab were fatigue, pruritus, rash, diarrhea and nausea; however, AE rates were similar or lower with nivolumab than with dacarbazine or carboplatin plus paclitaxel.11,13 Furthermore, the incidence of grade 3 or 4 AEs was lower with nivolumab compared to standard chemotherapy or with ipilimumab monotherapy.11,13,15
Until recently, surgical resection, when possible, coupled with standard chemotherapy was the rst-line treatment for Stage III melanoma and for palliation of Stage IV disease. However, the rates of recurrence and metastasis remained high, as the disease is often refractory to surgery and/or systemic treatment. Advances in genetics and tumor biomarker recognition have led to the synthesis of novel biological agents for the treatment of metastatic melanoma. Nivolumab is one such agent and with an improved safety and efficacy profile over traditional therapy, it proves a promising development in the treatment of advanced melanoma.
- Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. 2011 Nov;65(5):1032-47.
- Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206.
- Essner R, Lee JH, Wanek LA, et al. Contemporary surgical treatment of advanced- stage melanoma. Arch Surg. 2004 Sep;139(9):961-6; discussion 6-7.
- Sandru A, Voinea S, Panaitescu E, et al. Survival rates of patients with metastatic malignant melanoma. J Med Life. 2014 Oct-Dec;7(4):572-6.
- Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015 Apr 13;27(4):450-61.
- Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti- programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75.
- Gohil K. Pharmaceutical approval update. P T. 2015 Mar;40(3):172-3.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54.
- Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30.
- Yamazaki N, Tahara H, Uhara H, et al. Phase 2 study of nivolumab (Anti-PD-1; ONO-4538/BMS-936558) in patietns with advanced melanoma. Eur J Cancer. 2013;49(s2):s868.
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30.
- Improved survival ends nivolumab trial early. Cancer Discov. 2014 Sep;4(9): 979-80.
- Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84.
- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34.
- Opdivo® (nivolumab) injection, for intravenous use [Full prescribing information]; revised January 2016. Bristol-Myers Squibb Company Princeton, NJ. Available at: http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed February 1, 2016.