Opdivo (Nivolumab), a PD-1 Inhibitor, Receives New Indications for Melanoma, NSCLC, and Renal-Cell Carcinoma

March 2016, Vol 9, Seventh Annual Payers' Guide - Web Exclusive
Lisa A. Raedler, PhD, RPh
Medical Writer

Lung cancer, melanoma, and renal-cell carcinoma represent significant burdens for patients and for the healthcare system. In light of the high morbidity and mortality associated with these malignancies and the quality-of-life challenges, there is a marked need for additional therapeutic options that improve outcomes for patients with melanoma, non–small-cell lung cancer (NSCLC), or renal-cell carcinoma.

Lung Cancer

Lung cancer is the second most often diagnosed cancer in the United States, with an estimated 221,200 new cases projected in 2015.1

Lung cancer claims more lives than any other type of cancer, including colon, breast, and prostate cancer combined, accounting for approximately 27% of all cancer deaths in the United States.1 NSCLC is the most common type of lung cancer, accounting for approximately 85% of all cases of lung cancer.2

Although the 5-year survival rate for localized lung cancer is 54%, only 15% of patients with lung cancer are diagnosed at this early stage.3

Overall, the 5-year survival rate for NSCLC is 21%.3 Lung cancer is currently the fifth costliest cancer in the United States; the total estimated national expenditure for lung cancer in 2015 exceeded $13 billion.4

Melanoma

Although less common than other skin cancers, melanoma represents the most dangerous form of skin cancer.5 Between 2004 and 2010, the 5-year relative survival rate for Americans with distant melanoma was only 16%.6 The National Cancer Institute estimated that there were 73,870 new cases of skin melanoma in 2015, and more than 9900 patients died from the disease.6

As evidenced by its low 5-year survival rates, metastatic melanoma is difficult to cure.6 In the United States, the total estimated national expenditure for the treatment of melanoma in 2015 was $2.8 billion.4

Renal-Cell Carcinoma

Renal-cell carcinoma is the most common type of kidney cancer, comprising approximately 90% of all kidney cancers.3 According to the American Cancer Society, approximately 61,560 new cases of kidney cancer were diagnosed in 2015, and an estimated 14,080 individuals died from this disease.3

Some of the common risk factors for renal-cell carcinoma include smoking, obesity, and high blood pressure.3 The majority of kidney cancers are diagnosed at a local stage, and the 5-year relative survival is 72%.3

Immune Checkpoint Inhibition

Immune checkpoint blockade with monoclonal antibodies directed toward cytotoxic T-lymphocyte antigen (CTLA)-4, as well as programmed-cell death (PD)-1, have emerged as successful treatment options for cancer, including melanoma and lung cancer.7

Opdivo Receives Several New Indications

Lung cancer. On March 4, 2015, nivolumab (Opdivo; Bristol-Myers Squibb), a PD-1 inhibitor, received an accelerated approval for a new indication for patients with advanced squamous NSCLC whose disease progressed during or after platinum-based chemotherapy.8 On October 9, 2015, the US Food and Drug Administration (FDA) issued a new indication for nivolumab for patients with advanced nonsquamous NSCLC whose disease progressed during or after platinum-based chemotherapy.9 On the same day, the FDA also approved the PD-L1 IHC 28-8 pharmDx test, to identify patients with PD-L1 expression.9

The approval of nivolumab for advanced nonsquamous NSCLC was based on the CheckMate-057 study, an open-label, randomized study of 582 patients whose NSCLC progressed after initial treatment.9-11

Advanced melanoma. On September 30, 2015, nivolumab in combination with ipilimumab (Yervoy; Bristol-Myers Squibb) received an accelerated approval for patients with BRAF V600 wild-type unresectable or metastatic melanoma.12 This approval was based on the pivotal CheckMate-069 study, a multicenter, double- blind, randomized, phase 2 clinical trial.12,13

On November 23, 2015, nivolumab was approved as a single agent for patients with previously untreated BRAF V600 wild-type unresectable or metastatic melanoma.14 And on January 23, 2016, nivolumab was approved for patients with previously untreated BRAF V600 mutation, unresectable or metastatic melanoma; this approval was based on data from the CheckMate-067 clinical trial.15,16

Nivolumab was originally approved by the FDA on December 22, 2014, for patients with unresectable or metastatic melanoma and disease progression after ipi­limumab, and, if BRAF V600 mutation–positive melanoma, a BRAF inhibitor.17

Renal-cell carcinoma. On November 23, 2015, the FDA approved nivolumab for the treatment of patients with advanced renal-cell carcinoma who received previous antiangiogenic therapy.18 This approval was based on an open-label, randomized clinical trial of 821 patients with advanced renal-cell carcinoma whose disease progressed during or after treatment with an antiangiogenic agent.10,18,19

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.10

Dosing and Administration

When administered as a single agent, the recommended dosage of nivolumab is 3 mg/kg every 2 weeks.10

When given in combination with ipilimumab for patients with advanced melanoma, the recommended dosage of nivolumab is 1 mg/kg administered as an intravenous infusion for 60 minutes; ipilimumab should be given on the same day every 3 weeks for a total of 4 doses, followed by nivolumab 3 mg/kg every 2 weeks.10

For patients with metastatic NSCLC and for patients with advanced renal-cell carcinoma, the recommended dosage of nivolumab is 3 mg/kg administered as an intravenous infusion for 60 minutes every 2 weeks.10

Nivolumab should be administered until disease progression or until unacceptable toxicity.10

Clinical Trials
Nonsquamous NSCLC

The CheckMate-057 clinical trial, a multinational, randomized, open-label study comparing nivolumab and docetaxel, included 582 patients with stage IIIB or IV or with recurrent nonsquamous NSCLC after radiation therapy or surgical resection and disease recurrence or progression during or after 1 previous platinum-based doublet chemotherapy regimen. Patients (median age, 62 years) were randomized to receive nivolumab (3 mg/kg) every 2 weeks or docetaxel (75 mg/m2) every 3 weeks.10,11

The primary efficacy outcome measure was overall survival, and the secondary efficacy end points included progression-free survival, objective response, efficacy according to tumor PD-L1 expression level, and patient-reported outcomes.10,11

The overall survival was 12.2 months with nivolumab compared with 9.4 months with docetaxel (Table 1).10,11 The objective response rate was also significantly better with nivolumab (19%) versus 12% with docetaxel. Nivolumab therapy did not, however, extend progression-free survival versus docetaxel.10,11

Table 1

In addition, median response duration was 17.5 months with nivolumab versus 5.6 months with docetaxel. Nivolumab’s duration of response was also longer than seen with other treatments for NSCLC in patients whose disease progressed after chemotherapy or therapy with targeted agents.11

Untreated Advanced Melanoma

The pivotal, multicenter, double-blind, randomized clinical trial CheckMate-069 study showed that nivolumab plus ipilimumab was associated with an increased objective response rate, prolonged response duration, and improvement in progression-free survival compared with ipilimumab alone in patients with previously untreated BRAF V600 wild-type unresectable or metastatic melanoma.13

The approval of nivolumab as a single agent for patients with untreated BRAF V600 wild-type unresectable or metastatic melanoma was based on the CheckMate-066 study, a multicenter, double-blind, randomized clinical trial.10,20 A total of 418 patients with BRAF V600 wild-type unresectable or metastatic melanoma were randomized to nivolumab or to dacarbazine until disease progression or unacceptable toxicity.10,20 The median overall survival was 10.8 months with dacarbazine and was not reached with nivolumab. The progression-free survival was 5.1 months with nivolumab versus 2.2 months with dacarbazine.10,20

The approval of nivolumab in combination with ipi­limumab for patients with untreated, unresectable or metastatic melanoma, regardless of the BRAF V600 mutation status, was based on the CheckMate-067 clinical trial, which was also used as the basis for the FDA approval of nivolumab as a single agent for patients with BRAF V600 mutation unresectable or metastatic melanoma.10,16

In the CheckMate-067 study, 945 patients (median age, 61 years) were randomized to receive nivolumab plus ipilimumab, nivolumab, or ipilimumab.10,16 Progression-free survival was 11.5 months with nivolumab plus ipilimumab and 6.9 with nivolumab monotherapy compared with only 2.9 months with ipilimumab alone (Table 2).10

Table 2

Renal-Cell Carcinoma

The approval of nivolumab for advanced renal-cell carcinoma was based on the CheckMate-025 clinical trial, an open-label study involving 821 patients with advanced renal-cell carcinoma who had disease progression during or after 1 or 2 previous antiangiogenic therapies.10,19 Patients were randomized to nivolumab or to everolimus. The median survival was 25 with nivolumab versus 19.6 months with everolimus (Table 3). In addition, the median duration of response was 23 months with nivolumab versus 13.7 with everolimus.10,19

Table 3

Adverse Reactions

The most common adverse reactions (all grades) with nivolumab monotherapy in patients with melanoma were fatigue (49%), musculoskeletal pain (32%), rash (28%), and pruritus (23%). The most common adverse reactions with nivolumab plus ipilimumab included rash (67%), pruritus (37%), headache (24%), vomiting (23%), and colitis (22%).10

The most common adverse reactions in patients with metastatic NSCLC were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%).10

The most common adverse reactions in patients with advanced renal-cell carcinoma were asthenic conditions (56%), cough (34%), nausea (28%), rash (28%), dyspnea (27%), diarrhea (25%), constipation (23%), decreased appetite (23%), back pain (21%), and arthralgia (20%).10

Warnings and Precautions

Immune-mediated pneumonitis. Immune-mediated pneumonitis or interstitial lung disease has been reported with nivolumab. Corticosteroids should be administered if grade ≥2 pneumonitis is detected. Nivolumab should be withheld for grade 2 pneumonitis, and permanently discontinued for grade 3 or 4 pneumonitis.10

Immune-mediated colitis. Because colitis or diarrhea can occur with nivolumab, patients taking nivolumab should be monitored for the related signs and symptoms. When administered in combination with ipilimumab, nivolumab should be withheld for grade 2 colitis, and permanently discontinued for grade 3 or 4 colitis.10

Immune-mediated hepatitis. Immune-mediated hepatitis has occurred with nivolumab treatment. Corticosteroids should be administered for grade ≥2 hepatitis. Nivolumab should be withheld if grade 2 hepatitis is observed, and discontinued for grade 3 or 4 immune-
mediated hepatitis.10

Immune-mediated nephritis and renal dysfunction. An increased incidence of elevated creatinine levels was observed in patients receiving nivolumab. Patients should be monitored for elevated serum creatinine levels before and during treatment with nivolumab. Nivolu­mab should be withheld if grade 2 or 3 elevations in serum creatinine levels occur, and discontinued if grade 4 elevations in serum creatinine levels are observed.10

Immune-mediated endocrinopathies. Hypophysitis, adrenal insufficiency, and changes in thyroid function have been observed in patients taking nivolumab. Thyroid function should be monitored before and during treatment with nivolumab.10

Immune-mediated rash. Immune-mediated rash has been reported in patients taking nivolumab. Corticosteroid therapy should be initiated if grade 3 or higher rash occurs. Nivolumab therapy should be withheld for grade 3 rash, and permanently discontinued if grade 4 rash is observed.10

Immune-mediated encephalitis. Immune-mediated encephalitis has been documented with nivolumab. Nivolumab should be withheld if new-onset moderate-to-severe neurologic symptoms occur, and the patient should be evaluated to rule out infectious or other causes of neurologic deterioration. Nivolumab should be permanently discontinued if immune-mediated encephalitis occurs.10

Other immune-mediated adverse reactions. Other clinically important immune-mediated adverse reactions can occur while taking nivolumab, including pancreatitis, uveitis, demyelination, autoimmune neuropathy, diabetic ketoacidosis, sarcoidosis, duodenitis, and gastritis. Nivolumab therapy should be withheld, and corticosteroid therapy should be administered based on the severity of the immune-mediated adverse reaction.10

Infusion reactions. Severe infusion reactions have been reported in <1% of patients who received nivolumab monotherapy. Treatment should be discontinued if grade 3 or 4 infusion reactions occur. Infusion can be interrupted or slowed in patients with grade 1 or 2 reactions.10

Use in Specific Populations

Pregnancy. Nivolumab use during pregnancy can result in fetal harm. Pregnant women should be advised of this potential risk.10

Nursing mothers. It is not known whether nivolu­mab is present in human milk. Women who are receiving nivolumab should stop breast-feeding.10

Pediatric use. The safety and efficacy of nivolumab in pediatric patients have not been established.10

Geriatric use. The study of nivolumab plus ipilimu­mab did not include a sufficient number of patients with advanced melanoma who were aged ≥65 years to compare their responses with younger patients. No differences in the safety or efficacy of single-agent nivolumab were observed when comparing younger and older patients with advanced NSCLC.10

Renal or hepatic impairment. No dose adjustment is recommended in patients with renal impairment or with mild liver impairment who are taking nivolumab. Nivolumab has not been studied in patients with moderate or severe liver impairment.10

Reproductive potential. Women of reproductive potential should use effective contraception during treatment with nivolumab and for at least 5 months after the last dose.10

Conclusion

Nivolumab, a PD-1 inhibitor, received FDA approval for multiple indications in 2015—as a single agent for the treatment of previously treated advanced NSCLC (both squamous and nonsquamous histology); as a single agent and in combination with ipilimumab for the treatment of previously untreated, unresectable or metastatic melanoma; and as a single agent for patients with advanced renal-cell carcinoma. In patients with advanced melanoma, nivolumab alone and in combination with ipilimumab demonstrated significant improvements in progression-free survival and overall response rate compared with ipilimumab monotherapy. Compared with docetaxel, nivolumab monotherapy improved overall survival and overall response rate in patients with advanced nonsquamous NSCLC. Nivolumab also significantly improved overall survival in patients with advanced renal-cell carcinoma.

Nivolumab’s promising clinical activity, in addition to other PD-1 and PD-L1 inhibitors, continues to be evaluated in patients with solid tumors, as well as with hematologic malignancies.21

References

1. American Cancer Society. What are the key statistics about lung cancer? Revised March 4, 2015. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics. Accessed November 30, 2015.
2. American Cancer Society. Non-small cell lung cancer. www.cancer.org/cancer/lungcancer-non-smallcell/. Accessed November 30, 2015.
3. American Cancer Society. Cancer facts & figures 2015. 2015. www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed December 9, 2015.
4. National Cancer Institute. Financial burden of cancer care. Updated November 2015. http://progressreport.cancer.gov/after/economic_burden. Accessed November 30, 2015.
5. Skin Cancer Foundation. Melanoma: what is melanoma? www.skincancer.org/skin-cancer-information/melanoma. Accessed November 30, 2015.
6. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer.cancer.gov/statfacts/html/melan.html. Accessed November 30, 2015.
7. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.
8. US Food and Drug Administration. FDA expands approved use of Opdivo to treat lung cancer. Press release. March 4, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm. Accessed November 30, 2015.
9. US Food and Drug Administration. FDA expands approved use of Opdivo in advanced lung cancer: Opdivo demonstrates survival benefit in squamous and non-squamous non-small cell lung cancer. Press release. October 9, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466413.htm. Accessed November 30, 2015.
10. Opdivo (nivolumab) injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; January 2016.
11. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373:1627-1639.
12. US Food and Drug Administration. Nivolumab in combination with ipilimumab. Updated October 1, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/ucm465274.htm. Accessed November 30, 2015.
13. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-2017.
14. Bristol-Myers Squibb. Bristol-Myers Squibb announces U.S. Food and Drug Administration approval for Opdivo (nivolumab) as a single agent for the treatment of patients with previously untreated BRAF wild-type advanced melanoma. Press release. November 24, 2015. http://news.bms.com/press-release/bristol-myers-squibb- announces-us-food-and-drug-administration-approval-opdivo-nivolum. Accessed February 4, 2016.
15. Business Wire. Bristol-Myers Squibb’s Opdivo (nivolumab) + Yervoy (ipilimu­mab) regimen receives expanded fda approval in unresectable or metastatic melanoma across BRAF Status1. www.businesswire.com/news/home/20160123005053/en/Bristol-Myers-Squibb%E2%80%99s-Opdivo-nivolumab-Yervoy-ipilimumab-Regimen. Accessed February 4, 2016.
16. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
17. US Food and Drug Administration. FDA approves Opdivo for advanced melanoma. Press release. December 22, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm427716.htm. Accessed November 30, 2015.
18. US Food and Drug Administration. FDA approves Opdivo to treat advanced form of kidney cancer. Press release. November 23, 2015. http://www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm473971.htm. Accessed December 28, 2015.
19. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.
20. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
21. ClinicalTrials.gov. Nivolumab. Search results. https://clinicaltrials.gov/ct2/results?term=nivolumab&Search=Search. Accessed December 14, 2015.

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