Nivolumab (Opdivo): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma

Lisa A. Raedler, PhD, RPh

February 2015, Vol 5, No 1 - Drug Update


Although less common than other skin cancers, melanoma is the most dangerous form of skin cancer.1 According to data collected between 2004 and 2010, the 5-year relative survival rate for Americans with distant melanoma is only 16% for all ages, races, and sexes.2 The National Cancer Institute estimated that there were 76,100 new cases of skin melanoma in 2014, and more than 9700 patients died from this disease during the same period.2

The incidence of melanoma continues to rise, particularly among children and adolescents.3 Analysis of first-time melanoma diagnoses between 1970 and 2009 in patients aged 18 to 39 years showed that the number of new cases of skin melanoma increased 8-fold among young women and 4-fold among young men.3 Using data from 1973 to 2009, another study documented an average increase in melanoma of 2% annually in individuals aged between 0 and 19 years.4

The potential effect on healthcare resource use is just one reason for concern regarding these trends. Based on an assessment of Medicare administrative claims data between 1991 and 2005, patients with melanoma, particularly those with metastatic disease, accrued an average of more than $11,000 monthly in total healthcare costs5; the majority of these costs were related to inpatient hospital services.5 This cost analysis was conducted in 2009, before the approval of novel targeted therapies for metastatic melanoma.

As evidenced by its low 5-year survival rates, metastatic melanoma is difficult to cure.6 Surgery and radiation therapy are feasible options for tumors that are localized to the skin or to the lymph nodes. Depending on their number and location, the surgical removal of melanoma metastases in internal organs is also an option.6

In the past, the management of patients with advanced stages of melanoma was very challenging. Today, however, the development and the introduction of targeted agents have significantly changed the treatment landscape. The current armamentarium of systemic treatments for metastatic melanoma features immunotherapy agents (ie, ipilimumab, pembrolizumab) and BRAF inhibitors (ie, vemurafenib, dabrafenib, trametinib), in addition to traditional chemotherapy.6 Several of these novel agents offer superior efficacy compared with older cytotoxic drugs.6

Immune checkpoint blockade with monoclonal antibodies that are directed toward cytotoxic T-lymphocyte antigen (CTLA)-4, such as ipi­limumab, as well as programmed-cell death (PD)-1 and PD ligand 1 (PD-L1), have emerged as successful treatment options in the treatment of patients with melanoma.7 Ipilimumab was the first CTLA-4 inhibitor to demonstrate an overall survival benefit and highly durable objective tumor responses in patients with advanced melanoma.7 Specifically in the management of patients with metastatic melanoma and the BRAF V600 mutation, a contrast has been observed between the use of BRAF inhibitors, which offer high response rates with limited response durability, and the use of ipilimumab, which offers a relatively low response rate but very durable responses.7

On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab, the first PD-1 inhibitor for the treatment of patients with unresectable or metastatic melanoma.8 This agent demonstrated objective and durable responses in a large phase 1b study that involved patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab and, if the patient had the BRAF V600 mutation, after treatment with a BRAF inhibitor.8,9

To increase the proportion of patients with metastatic melanoma who achieve durable responses with immunotherapy, researchers are exploring potential synergies between immune checkpoint inhibitors that target CTLA-4, PD-1, PD-L1, and kinase-targeted therapies, as well as the concurrent and sequential use of CTLA-4, PD-1, and PD-L1 inhibitors.7

A Novel PD-1 Inhibitor for Unresectable or Metastatic Melanoma

On December 22, 2014, the FDA approved nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy and, if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.10,11 Nivolumab is a monoclonal antibody that blocks PD-1 and is administered via intravenous infusion. This agent was approved under the accelerated approval program based on the surrogate end points, overall response rate, and duration of response.10,11

When discussing data supporting the efficacy of nivolumab in relapsed metastatic melanoma, Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, stated, “These data are important as they mark the first presentation of results from a phase 3 randomized study for the PD-1 immune checkpoint inhibitor class.” He further commented, “the response rate and duration of response in patients treated with Opdivo are consistent with findings from the early phase 1 trial in previously treated advanced melanoma.”12

Dosing and Administration

The recommended dosage of nivol­umab is 3 mg/kg administered as an intravenous infusion for 60 minutes every 2 weeks. Nivolumab should be administered until disease progression or until unacceptable toxicity.11

No dose adjustment of nivolumab is required for patients with renal impairment or for patients with mild hepatic impairment, defined as total bilirubin upper limit of normal or less and aspartate aminotransferase (AST) more than upper limit of normal or total bilirubin <1 to 1.5 times upper limit of normal and any AST.11

Mechanism of Action

Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands, PD-L1 and PD-L2. This binding releases PD-1 pathway-mediated immune responses against tumor cells. Blocking PD-1 activity resulted in decreased tumor growth in syngeneic mouse tumor models.11

Clinical Trial: Checkmate-037

The approval of nivolumab was based on the results of Checkmate-037, a phase 3 randomized, controlled, open-label study of nivolumab versus investigator’s choice chemotherapy in patients with advanced melanoma who previously received ipilimumab.11

A total of 370 patients with previously treated unresectable or metastatic melanoma enrolled in the Checkmate-037 clinical trial.11 All patients’ disease had progressed after previous therapy with ipilimumab and, if the patients were positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.11 These patients were randomized to receive nivolumab 3 mg/kg (N = 268) or investigator’s choice chemotherapy (N = 102) with dacarbazine 1000 mg/m2 every 3 weeks or with carboplatin (area under the curve, 6 mg•min/mL) plus paclitaxel 175 mg/m2 every 3 weeks until disease progression or until unacceptable toxicity.11

The efficacy of nivolumab was evaluated in a single-arm, noncomparative, planned interim analysis of the first 120 patients who received nivolumab in the Checkmate-037 clinical trial and in whom the minimum duration of follow-up was 6 months.11 The primary efficacy end points were confirmed overall response rate according to the Response Evaluation Criteria in Solid Tumors, as assessed by a blinded independent review committee, and duration of response. Tumor assessments were conducted 9 weeks after randomization, followed by every 6 weeks for the first year, and then every 12 weeks.11

The Checkmate-037 clinical trial excluded patients with an autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled after 12 weeks.11

Patient Population

Among the 120 patients who received nivolumab, the median age was 58 years.11 The majority of the patients were male (65%) and white (96%). All the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ disease characteristics included stage M1c disease (76%), 2 or more previous therapies for advanced or metastatic disease (68%), elevated lactate dehydrogenase (56%), positive for a BRAF V600 mutation (22%), and a history of brain metastases (18%).11

Efficacy

The planned interim analysis of the Checkmate-037 clinical trial documented a 32% overall response rate for nivolumab 3 mg/kg in patients with unresectable or metastatic melanoma who previously received ipilimumab therapy and, if relevant, a BRAF inhibitor (95% confidence interval, 23%-41%).11

Of the 38 patients whose disease responded to nivolumab therapy, 4 patients achieved complete responses and 34 patients achieved partial responses.11 The majority (87%) of patients responding to nivolumab had ongoing responses with durations ranging from 2.6+ to 10+ months, including 13 patients with ongoing responses of at least 6 months.11

Objective responses were observed in patients with and without BRAF V600 mutation–positive melanoma.11

Safety

The cohort of 268 patients with previously treated unresectable or metastatic melanoma in Checkmate-037 received a median of 8 doses (range, 1-31 doses) of nivolumab (3 mg/kg).11 The patients’ median duration of exposure to nivolumab was 5.3 months (range, 1 day-9.6 months).11

In this clinical trial, 24% of patients were exposed to nivolumab for more than 6 months, and 3% of patients were exposed to nivolumab for more than 1 year.11 The Table summarizes the adverse reactions that occurred in ?10% of patients and at a higher incidence rate compared with patients who received chemotherapy.11

Table

Grade 3 and 4 adverse reactions occurred in 42% of nivolumab recipients.11 These events included abdominal pain, hyponatremia, elevated AST levels, and increased lipase levels; these adverse reactions occurred at rates ranging from 2% to <5%.11

Nivolumab was discontinued as a result of adverse reactions in 9% of patients, and 26% of patients who received nivolumab experienced a drug delay for an adverse reaction.11

Nivolumab has no contraindications.

Warnings and Precautions

Immune-mediated pneumonitis
Overall, 5 (0.9%) fatal cases of pneumonitis occurred among 574 patients with solid tumors who received nivolumab in clinical trials.11 Pneumonitis, including interstitial lung disease, occurred in 3.4% of patients who received nivolumab in the Checkmate-037 clinical trial.11

Immune-mediated pneumonitis, which requires the use of corticosteroids and has no clear alternate etiology, occurred in 6 (2.2%) patients who received nivolumab. The median time to onset for these 6 cases was 2.2 months (range, 25 days-3.5 months).11 Grade 2 pneumonitis led to the interruption or the permanent discontinuation of nivolumab in 4 patients. The other 2 patients discontinued nivolumab for other reasons. In all 6 patients, immune­mediated pneumonitis improved to grade 0 or 1 with corticosteroids.11

Patients who received nivolumab should be monitored for signs and symptoms of pneumonitis. Corticosteroids should be administered if grade 2 or higher pneumonitis is detected.11 Nivolumab should be withheld for moderate (grade 2) pneumonitis, and permanently discontinued for severe (grade 3) or life-threatening (grade 4) pneumonitis.11

Immune-mediated colitis
Colitis or diarrhea occurred in 21% of patients who received nivolumab, and in 18% of patients who received chemotherapy in the Checkmate-

037 clinical trial.11 Immune-mediated colitis was observed in 6 patients who received nivolumab. The median time to onset of immune-mediated colitis was 2.5 months.11

Patients who receive nivolumab should be monitored for signs and symptoms of colitis. Corticosteroids should be administered for grade 2 or higher colitis. Nivolumab should be withheld for moderate (grade 2) or severe (grade 3) colitis, and permanently discontinued for life­threatening (grade 4) colitis or recurrent colitis upon restarting nivolumab therapy.11

Immune-mediated hepatitis
An increased incidence of liver test abnormalities was observed in the nivolumab group compared with the chemotherapy group, including increases in AST levels (28% vs 12%, respectively), alkaline phosphatase levels (22% vs 13%, respectively), alanine aminotransferase levels (16% vs 5%, respectively), and total bilirubin levels (9% vs 0%, respectively).11 Overall, 1.1% of patients who received nivolumab had immune-mediated hepatitis, which requires the use of corticosteroids and has no clear alternate etiology.11

Patients who receive nivolumab should be monitored for changes in liver function. Corticosteroids should be administered for grade 2 or higher hepatitis. Nivolumab should be withheld if grade 2 hepatitis is observed, and discontinued for grade 3 and grade 4 immune-mediated hepatitis.11

Immune-mediated nephritis and renal dysfunction
An increased incidence of elevated creatinine levels was observed in patients who received nivolumab compared with patients who received chemotherapy (13% vs 9%) in the Checkmate-037 clinical trial.11 Grade 2 or 3 immune-mediated nephritis or renal dysfunction, defined as grade 2 or higher increased creatinine levels, need for corticosteroids, and no clear etiology, occurred in 0.7% of patients after 3.5 months and 6 months of nivolumab therapy, respectively.11

Patients should be monitored for elevated serum creatinine levels before and during treatment with nivolumab.11 If grade 4 elevation in serum creatinine levels is observed, corticosteroid therapy should be tapered and nivolumab should be permanently discontinued. Nivolumab therapy should be withheld if grade 2 or 3 elevation in serum creatinine levels is observed.11

Immune-mediated hypothyroidism and hyperthyroidism
Thyroid function was evaluated for all patients at baseline and during the Checkmate-037 clinical trial.11 Grade 1 or 2 hypothyroidism occurred in 8% of patients who received nivolumab and was not observed among patients who received chemotherapy. The median time to onset was 2.5 months (range, 24 days-11.7 months). The majority of patients with hypothyroidism received levothyroxine and restarted nivolumab therapy.11

Grade 1 or 2 hyperthyroidism occurred in 3% of patients who received nivolumab and in 1% of patients who received chemotherapy. The median time to onset in patients who received nivolumab was 1.6 months (range, 0-3.3 months).11

Thyroid function should be monitored before and during treatment with nivolumab. Hormone replacement therapy for hypothyroidism should be administered as needed, and hyperthyroidism should be controlled. There are no recommended dose adjustments for nivolumab.11

Other immune-mediated adverse reactions
Other clinically impor­tant immune-mediated adverse reactions can occur while patients with unresectable or metastatic melanoma are receiving nivolumab.11

Clinically significant, immune-­mediated adverse reactions that were observed in <1% of patients who received nivolumab included pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis.11

When nivolumab was administered at doses of 3 mg/kg and 10 mg/kg, clinically significant, immune-­mediated adverse reactions were observed, including hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome.11

If an immune-mediated adverse reaction is suspected, patients who receive nivolumab must be evaluated to exclude other causes.11 Nivolu­mab therapy should be withheld, and corticosteroid therapy should be administered based on the severity of the reaction. Upon improvement of the immune-mediated adverse reaction to grade 1 or less, a corticosteroid taper can be started and continued for at least 1 month. Depending on the severity of the event, nivolu­mab can be restarted.11

Embryofetal toxicity
Nivolumab therapy may cause fetal harm when it is administered to a pregnant woman.11 Women of reproductive potential should use effective contraception during nivolumab therapy and for at least 5 months after the last dose. Women who become pregnant while taking nivolumab should be made aware of the potential risk of nivolumab to the fetus.11

Use in Specific Populations

Pediatric patients
The safety and efficacy of nivolumab in pediatric patients have not been established.11

Geriatric use
The clinical studies of nivolumab did not include sufficient numbers of patients aged ?65 years to determine whether they respond differently compared with younger patients.11

Pregnancy
There are no human data to describe the risk associated with nivolumab use during pregnancy. Pregnant women should be advised of the potential risk of nivolu­mab therapy to the fetus.11

Nursing mothers
It is not known whether nivolumab is present in human milk. Because many drugs, including antibodies, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from nivolumab, women should be advised to discontinue breastfeeding during treatment with nivolumab.11

Conclusion

Nivolumab is the second PD-1 inhibitor approved by the FDA for the treatment of patients with un­resectable or metastatic melanoma. Based on an interim analysis of phase 3 clinical data, this novel agent is an effective and safe alternative for patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy, and if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.

Nivolumab was approved under the FDA’s accelerated approval program based on the response rate data. As a condition of accelerated approval, the FDA requires confirmatory trials to verify the agent’s clinical benefit. The Checkmate-037 clinical trial is designed to compare the overall survival rate of patients who receive nivolumab therapy with the overall survival rate of patients who receive chemotherapy. An interim analysis of overall survival was not performed at the time of the response rate analysis.

The efficacy and safety of nivolu­mab are being evaluated in several other tumors; these include metastatic nonsquamous non–small-cell lung cancer, metastatic breast cancer, metastatic colon cancer, follicular lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.13

Copyright © 2015 American Health & Drug Benefits. All rights reserved. Used with permission.




References

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  2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer.cancer.gov/statfacts/html/melan.html. Accessed January 23, 2015.
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  9. Keytruda (pembrolizumab) for injection [prescribing information]. Whitehouse Station, NJ: Merck & Co; January 2015.
  10. US Food and Drug Administration. FDA approves Opdivo for advanced melanoma. Press release. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm 427716.htm. Accessed January 29, 2015.
  11. Opdivo (nivolumab) injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2014.
  12. Bristol-Myers Squibb. Positive phase 3 data for Opdivo (nivolumab) in advanced melanoma patients previously treated with Yervoy (ipilimumab) presented at the ESMO 2014 Congress; first phase 3 results presented for a PD-1 immune checkpoint inhibitor. September 29, 2014. http://news.bms.com/press-release/rd-news/positive-phase-3-data-opdivo-nivolumab-advanced-melanoma- patients-previously-t. Accessed January 27, 2015.
  13. ClinicalTrials.gov. Nivolumab. Search results. http://clinicaltrials.gov/ct2/results?term=nivolumab&Search=Search. Accessed January 27, 2015.