On December 22, 2014, Opdivo (nivolumab) was approved by FDA with a breakthrough therapy designation. Nivolumab is the second human programmed death-1 (PD-1) receptor-blocking antibody to gain accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor.
Melanoma is a form of cancer in melanocytes that may begin in a mole (skin melanoma) but can also begin in other pigmented tissues in the eyes or intestines. Approximately 76,100 new cases of melanoma and 9710 deaths from melanoma were anticipated in the United States in 2014.1 Melanoma is more common in men than women, among individuals of fair complexion, and those who have had excessive exposure to natural or artificial sunlight (such as tanning beds). Survival rates vary greatly based on stage at diagnosis. Five-year relative survival is 98% for patients diagnosed with localized disease, but only 16% for patients with metastatic disease at diagnosis.2 Until recently, pharmacologic options for advanced melanoma were very limited.1
On December 22, 2014, Opdivo (nivolumab) was approved by FDA with a breakthrough therapy designation. Nivolumab is the second human programmed death-1 (PD-1) receptor-blocking antibody to gain accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is based on tumor response rate and durability of response. Continued approval of nivolumab for this indication may be contingent on verification and description of clinical benefit in confirmatory trials.3
Nivolumab is available through specialty wholesalers as single-use vials containing 40 mg/4 mL or 100 mg/10 mL solution. Nivolumab requires dilution to its final infusion concentration. Additionally, special storage conditions are required due to lack of a preservative.3
Nivolumab is administered as a 3 mg/kg intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Nivolumab should be withheld or discontinued in patients with select immune-mediated adverse events based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4). Nivolumab may be resumed in patients whose adverse reactions recover to grade 0 to 1.3
|Immune-mediated AE||Withhold nivolumab||Permanently discontinue nivolumab|
|Pneumonitis||Grade 2||Grade 3 or 4|
|Colitis||Grade 2 or 3||Grade 4|
|AST and ALT||>3 to 5 times ULN||>5 times ULN|
|Bilirubin||>1.5 to 3 times ULN||>3 times ULN|
|Creatinine||1.5 to 6 times ULN||>6 times ULN|
|Hypothyroidism and hyperthyroidism||No adjustment required||No adjustment required|
Nivolumab is the second human PD-1 receptor-blocking antibody to gain FDA approval, and similar to its predecessor, Keytruda (pembrolizumab), nivolumab’s approval came months ahead of its scheduled FDA review deadline. Unlike traditional cytotoxic chemotherapy, cancer immunotherapies like these checkpoint inhibitors offer a novel treatment modality that stimulates the immune system and minimizes adverse impact on healthy cells.
Current nonsurgical treatment options for stage III, stage IV, and recurrent melanoma include:
o Checkpoint inhibitors:
§ Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4): ipilimumab
§ Anti-programmed cell death-1 (PD-1): pembrolizumab and nivolumab
o High-dose interleukin-2: Proleukin (aldesleukin)
o Dual immunomodulation (experimental)
· Signal transduction inhibitors:
o BRAF inhibitors: Tafinlar (dabrafenib) and Zelboraf (vemurafenib)
o MEK inhibitor: Mekinist (trametinib)
o Combination therapy
o KIT inhibitors (experimental)
· Palliative local therapy1,4
Nivolumab was approved based on a planned interim analysis of the first 120 patients from a multicenter, single-arm, noncomparative, open-label, phase 3 trial, CHECKMATE 037. Among these patients, 22% were BRAF-V600 mutation positive and 68% had attempted 2 or more systemic therapies for metastatic disease. Major efficacy outcomes for nivolumab were confirmed objective response rate (ORR) and duration of response. ORR was 32% (95% confidence interval [CI], 23–41) consisting of 4 complete responders and 34 partial responders. Among 38 objective responders, 33 (87%) had ongoing responses with durations ranging from 2.6 to 10 months including 13 patients with responses of 6 months or longer.3 Grade 3 and 4 adverse reactions occurred in 42% of patients receiving nivolumab, and the most frequently reported in 2% to less than 5% of patients receiving nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.5
In addition, a double-blind, phase 3, randomized controlled trial (CHECKMATE 066) was conducted to determine whether nivolumab 3 mg/kg every 2 weeks compared with dacarbazine 1000 mg/m2 every 3 weeks improves overall survival (OS) among previously untreated patients who have advanced melanoma without a BRAF mutation. The primary endpoint was OS. Median OS was not reached in the nivolumab group and was 10.8 months (95% CI, 9.3–12.1) in the dacarbazine group. OS rate at 1 year was 72.9% (95% CI, 65.5–78.9) in the nivolumab group and 42.1% (95% CI, 33–50.9) in the dacarbazine group. Incidence of treatment-related adverse events of any grade was similar between the 2 groups. Treatment-related adverse events of grade 3 or 4, however, were reported less frequently in the nivolumab group than in the dacarbazine group (11.7% vs 17.6%, respectively). Most common adverse events related to nivolumab were fatigue (19.9%), pruritus (17%), and nausea (16.5%).6
Cancer immunotherapy includes designing antibodies against the immune system’s negative “checkpoint” proteins. As the second immune checkpoint inhibitor targeting PD-1 to gain FDA approval, nivolumab offers another alternative for patients with advanced melanoma. Unlike conventional and targeted chemotherapy that acts on specific tumor types, checkpoint inhibitors target the immune system. In addition, PD-1 blocking antibodies offer a different adverse effect profile (mostly immune-mediated adverse effects) than traditional treatments. Questions still remain on the survival benefit of nivolumab and other checkpoint inhibitors. The PD-1 blocking antibodies, pembrolizumab and nivolumab, have not been compared in any head-to-head studies.
Read more: Drugs in Perspective
Current wholesale acquisition cost (WAC) and average wholesale price (AWP) for the 4-mL vial are $959.20 and $1,151.04, respectively. Similarly, WAC and AWP for the 10-mL vial are $2398 and $2,877.60, respectively.7 Based on the standard dose of 3 mg/kg, patients weighing 70 kg would receive 210 mg (21 mL) every 2 weeks. The estimated cost /adult/year would be $130,931 (WAC) or $157,117 (AWP).
Nivolumab serves as an important immunotherapy option for treatment of advanced melanoma. Additionally, its adverse effect profile is different from traditional cytotoxic chemotherapy.
Based on CHECKMATE 066 trial results, nivolumab demonstrated significant improvement in OS compared to dacarbazine in patients with advanced melanoma without a BRAF mutation. Its approval, however, was based on results from an incomplete phase 3 trial, CHECKMATE 037. Although promising, data remain immature.
The novel mechanism of action and the role of PD-1 blocking antibodies like pembrolizumab and nivolumab have not yet been fully elucidated. However, the European Society for Medical Oncology (ESMO) Clinical Practice Guideline for Cutaneous Melanoma identifies these agents among treatment options for systemic metastatic disease (stage IV) with impressive antitumor activity in clinical trials. The available nonsurgical treatment modalities for advanced melanoma have not been compared in head-to-head trials. Studies are under way to determine if combination treatments are more effective than monotherapy.8
Pharmacologic treatments for melanoma have been limited especially for advanced melanoma that is resistant and/or refractory to ipilimumab and/or BRAF inhibitors. Nivolumab generated an overall response in a single-arm, open-label, planned interim analysis of a phase 3 trial of initial 120 patients with advanced melanoma who had been previously treated and progressed with ipilimumab and, if BRAF mutation positive, a BRAF inhibitor. The estimated completion date for CHECKMATE-037 is January 2016.9 Nivolumab also showed greater OS than dacarbazine in patients with previously untreated advanced melanoma without a BRAF mutation in a single phase 3 trial (CHECKMATE-066). Durability of response and survival benefits over time remains an area of ongoing research.
Unlike conventional chemotherapy such as dacarbazine and targeted agents such as signal transduction inhibitors, checkpoint inhibitors like ipilimumab, pembrolizumab, and nivolumab represent exciting treatment options in cancer therapy with broader uses in other cancer types based on their broader immunotherapeutic effects. Both of the PD-1 inhibitors are in ongoing development for other cancer indications. Specifically, nivolumab is under study in non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, chronic myelogenous leukemia, colon cancer and hepatitis C virus infection, follicular lymphoma, ovarian cancer, head and neck carcinoma, renal cell carcinoma, and chronic lymphocytic leukemia.10 On March 4, 2015, Bristol-Myers Squibb received FDA approval for an expanded indication for nivolumab in the treatment of patients with advanced (metastatic) squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy.11
Pembrolizumab and nivolumab have the potential for broader use in multiple cancer indications with estimated sales projections in 2020 of $3.8 billion and $6.7 billion, respectively.10 Payers may consider reserving use of these expensive biologic cancer immunotherapies until they show sustained survival benefits and value when compared to other treatments in both clinical trials and real-world experience.
National Cancer Institute. Melanoma Treatment (PDQ®). Bethesda, MD: National Cancer Institute. September 12, 2014. http://www.cancer.gov/cancertopics/types/melanoma. Accessed March 16, 2015.
Surveillance Epidemiology and End Results (SEER). SEER Stat Fact Sheets: Melanoma of the Skin. http://seer.cancer.gov/statfacts/html/melan.html. Accessed March 16, 2015.
Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; December 2014.
Drugs@FDA. Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research; 2014. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed March 16, 2015.
Bristol-Myers Squibb press release. Bristol-Myers Squibb receives accelerated approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration. December 22, 2014. http://news.bms.com/press-release/bristol-myers-squibb-receives-accelerated-approval-opdivo-nivolumab-us-food-and-drug-a. Accessed March 16, 2015.
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–330.
PriceRx. Medispan. Available by subscription. Updated periodically. https://pricerx.medispan.com. Accessed March 16, 2015.
Dranoff G. Immunotherapy at large: balancing tumor immunity and inflammatory pathology. Nat Med. 2013;19(9):1100–1101.
Clinicaltrials.gov NCT01721746. 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). Last updated February 12, 2015. https://clinicaltrials.gov/ct2/show/NCT01721746?term=checkmate+037&rank=1. Accessed March 16, 2015.
Thomson Cortellis. Available by subscription. Updated February 27, 2015. http://cortellis.thomsonreuterslifesciences.com. Accessed March 16, 2015.
FDA News Release. FDA expands approved use of Opdivo to treat lung cancer. March 4, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed March 16, 2015.
Dr McKnight-Smith is a clinical pharmacist with the Drug Intelligence Department at Catamaran.