Opdivo is a human programmed death receptor-1 (PD-1)-blocking antibody. It is an immunotherapy that helps the body’s immune system attack cancer cells. Opdivo is a breakthrough therapy that was granted accelerated approval.

FDA approval was based on an interim analysis of a Phase III trial that showed an objective response rate of 32% in the nivolumab group compared to 11% in the chemotherapy group. Response rates in PD-L1 positive vs PD-L1 negative patients were 44% vs 20% and in BRAF mutant vs wild-type patients were 23% vs 34%. The effect lasted more than six months in approximately one-third of patients who experienced tumor shrinkage. BMS will be conducting a confirmatory trial to verify that the drug provides a clinical benefit in these patients. Long-term safety follow-up for nivolumab is up to 96 weeks.

In March 2015, the FDA approved Opdivo for a second indication in patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. On June 2015, the National Comprehensive Cancer Network (NCCN) published an interim update to the NCCN Clinical Practice Guidelines in Oncology to change the recommendation for nivolumab to a category 1 for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. The NCCN Guidelines do not include testing for PD-L1 because the clinical trials included patients regardless of their PD-L1 status.

In September 2015, the FDA approved Opdivo for a third indication in patients with BRAF V600 wild-type unresectable or metastatic melanoma in combination with Yervoy (ipilimumab). The approval is based on data from the CheckMate-069 trial. Results from the trial demonstrated a statistically significant increase in confirmed objective response rate, the study’s primary endpoint, in patients with BRAF wild-type melanoma treated with the Opdivo + Yervoy (60% vs 11%). Partial responses were seen in 43% of the Regimen group and 11% of the Yervoy monotherapy group. The Opdivo + Yervoy Regimen demonstrated a 60% reduction in the risk of progression vs. Yervoy alone. Median PFS was 8.9 months with the Regimen and 4.7 months with Yervoy alone.

In October 2015, the FDA approved Opdivo to treat patients with advanced (metastatic) non-squamous non-small cell lung cancer whose disease progressed during or after platinum-based chemotherapy. The safety and effectiveness of Opdivo for this use was demonstrated in an international, open-label, randomized study of 582 participants with advanced NSCLC whose disease progressed during or after treatment with platinum-based chemotherapy and appropriate biologic therapy. Participants were treated with Opdivo or docetaxel. Those treated with Opdivo lived an average of 12.2 months compared to 9.4 months in those treated with docetaxel. Additionally, 19 percent of those treated with Opdivo experienced a complete or partial shrinkage of their tumors, an effect that lasted an average of 17 months, compared to 12 percent among those taking docetaxel, which lasted an average of six months. An evaluation of samples from a subgroup of patients’ tumors suggests that the level of PD-L1 expression in NSCLC tumors may help identify patients who are more likely to live longer due to treatment with Opdivo.

In November 2015, the FDA approved Opdivo to treat patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. The safety and efficacy of Opdivo for this use were demonstrated in an open-label, randomized study of 821 patients with advanced renal cell carcinoma whose disease worsened during or after treatment with an anti-angiogenic agent. Patients were treated with Opdivo or another type of kidney cancer treatment called everolimus (Afinitor). Those treated with Opdivo lived an average of 25 months after starting treatment compared to 19.6 months in those treated with Afinitor. This effect was observed regardless of the PD-L1 expression level of patients’ renal cell tumors. Additionally, 21.5 percent of those treated with Opdivo experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared to 3.9 percent of those taking Afinitor, lasting an average of 13.7 months. The most common side effects of Opdivo for this use are conditions relating to abnormal weakness or lack of energy, cough, nausea, rash, difficulty breathing (dyspnea), diarrhea, constipation, decreased appetite, back pain and joint pain (arthralgia).

In January 2016, the FDA approved Opdivo® (nivolumab) as a single agent indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. The approval was based on a multicenter, double-blind, randomized study of 418 patients receiving either Opdivo® (n=210) or dacarbazine (n=208). Patients were randomized to receive Opdivo® 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m2 by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and objective response rate (ORR). The OS for Opdivo® was 24% compared to 46% with dacarbazine. The PFS for Opdivo® was 51% compared to 78% with dacarbazine. The ORR for Opdivo® was 34% compared to 9% with dacarbazine. Additionally, the complete response rate with Opdivo® and dacarbazine was 4% and 1%, respectively and a partial response rate of 30% and 8%, respectively. At the time of analysis, 88% of Opdivo®-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. The study demonstrated a statistically significant improvement in OS for the Opdivo® arm compared with the dacarbazine arm in an interim analysis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In May 2016, the FDA approved Opdivo (nivolumab) for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. The efficacy of Opdivo in patients (n=95) with cHL after failure of auto-HSCT and post-transplantation brentuximab vedotin was evaluated in the combined analysis from two studies. CheckMate -205 is a Phase 2, single-arm, open-label, multicenter, multicohort study. CheckMate -039 is a Phase 1, open-label, multicenter, dose escalation study. In the combined analysis, efficacy was evaluated by ORR, and an additional outcome measure was duration of response. Patients received 3 mg/kg of single-agent Opdivo administered as an intravenous infusion over 60 minutes every two weeks until disease progression, maximal clinical benefit or unacceptable toxicity. In adults with cHL who have relapsed or progressed after auto-HSCT and post-transplantation brentuximab vedotin (n=95), Opdivo demonstrated the following response rates: ORR was 65% (CI 95%: 55-75; 62/95 patients), including a 7% complete response rate (CI 95%: 3-15; 7/95 patients) and a 58% partial response rate (CI 95%: 47-68; 55/95 patients). The median time to response was 2.1 months (range: 0.7-5.7). Among responders, Opdivo demonstrated an 8.7 month median duration of response (95% CI: 6.8-NE; range 0.0+, 23.1+).

In November, 2016, the FDA approved Opdivo (nivolumab) for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck. The FDA approval of Opdivo for head and neck cancer was based on the Phase III trial. The global open-label, randomized, trial evaluated Opdivoversus investigator’s choice of therapy in patients with recurrent or metastatic SCCHN who had tumor progression during or within six months of receiving platinum-based therapy administered in the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. Patients were included regardless of their HPV or PD-L1 status. Patients were randomized 2:1 to receive Opdivo 3 mg/kg intravenously over 60 minutes every two weeks (n=240), or investigator’s choice (n=121) of: methotrextate 40 to 60 mg/m2 intravenously weekly, docetaxel 30 to 40 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly. Opdivo demonstrated statistically significant and clinically meaningful superior overall survival vs the comparator arm, with a 30% reduction in the risk of death (p=0.0101]). The median overall survival was 7.5 months for Opdivo compared to 5.1 months for investigator’s choice.

In February 2017, the FDA approved Opdivo (nivolumab) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. FDA approval was based on a single-arm study treating 270 patients with locally advanced or metastatic urothelial carcinoma who progressed during or following platinum-containing chemotherapy, or progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Patients received nivolumab, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. Objective response rate, confirmed by an independent radiographic review committee using Response Evaluation Criteria in Solid Tumors 1.1, was 19.6% (53/270; 95% CI: 15.1, 24.9). Seven patients had complete responses and 46 had partial responses. Estimated median response duration was 10.3 months with responses ongoing at data cutoff.

In August 2017, the FDA approved Opdivo (nivolumab) for the treatment of adults and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. This indication has been granted under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. FDA approval was based on a multicenter, open-label, single-arm study evaluating patients with locally determined dMMR or MSI-H mCRC whose disease had progressed during, after, or were intolerant to, prior treatment with fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. Patients received nivolumab 3mg/kg administered every 2 weeks, until disease progression or unacceptable toxicity. The overall response rate, confirmed by an independent radiographic review committee-assessed using Response Evaluation Criteria in Solid Tumors 1.1, was 28% (95% CI: 17-42; 15/53). One patient had complete response and 14 had partial responses. The median duration of response in these patients was not reached.

In September 2017, the FDA approved Opdivo (nivolumb) for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication has been granted under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. FDA approval was based on an open-label, multicenter trial evaluating the the safety and effectiveness of patients with HCC who did not respond or were intolerant to sorafenib. Of the enrolled 154 participants with Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib, nivolumab was administered through an intravenous infusion every other week. Results from the trial showed that 22 patients, or 14.3% (95% CI: 9.2-20.8; 22/154), responded to Opdivo, including three who saw a complete eradication of their tumor. The responses were sustained for six months or longer in 91% of patients. 55% of patients had responses lasting at least one year.

In December 2017, the FDA approved Opdivo (nivolumab) for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. Adjuvant therapy can reduce the risk of recurrence following surgical removal of the tumor and lymph nodes that contain cancer. The FDA approval was based on a randomized double-blind study of 906 patients who have undergone complete resection of stage IIIB/C or stage IV melanoma. Patients received either Opdivo or ipilimumab administered as an intravenous infusion. The primary endpoint was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause. At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) for patients taking Opdivo and 60.8% (95% CI, 56.0 to 65.2) for patients taking ipilimumab (HR for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with Opdivo resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the Opdivo group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively.

In April 2018, the FDA approved Opdivo, in combination with Yervoy (ipilimumab), for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma. The safety and efficacy of Opdivo for this use were demonstrated in a randomized, open-label, phase 3 trial of Opdivo plus Yervoy followed by Opdivo monotherapy versus Sutent (sunitinib) monotherapy. Patient included in the trial had measurable disease, and a Karnofsky performance-status score of at least 70. The co-primary endpoints were overall survival, overall response rate, and overall survival. The median overall survival has not yet been reached. The overall response rate was 41.6% for Opdivo and Yervoy compared to 26.5% with Sutent (P<0.0001). There was not a statistically significant improvement in progression free survival (11.6 months Opdivo + Yervoy vs. 8.4 months Sutent). Grade 3 or 4 events occurred in 46% of patients treated Opdivo and Yervoy compared to 63% of the Sutent group. 22% of patients discontinued treatment in the Opdivo and Yervoy group compared to 12% in the Sutent group.

In July 2018, the FDA approved Opdivo, in combination with Yervoy (ipilimumab), for the treatment of patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The approval was based on the results from a multicenter, non-randomized, multiple parallel-cohort, open-label study (CHECKMATE 142) in patients with dMMR or MSI-H mCR whose disease progressed during or following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Patients were eligible to enter the trial if they were 18 years of age or older with recurrent or metastatic colorectal cancer, ECOG Performance Status of 0 or 1, and absence of active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Of the 6 different treatment arms, the 2 of interest that led to the FDA approval were 1) Opdivo 3mg/kg IV in combination with Yervoy every 3 weeks for 4 doses, followed by Opdivo 3mg/kg IV as a single agent every 2 weeks, and 2) Opdivo monotherapy 3mg/kg IV every 2 weeks. Treatment was continued until unacceptable toxicity or radiographic progression. Efficacy outcome measures were overall response rate (ORR) and duration of response (DOR). The overall response rate was 46% for Opdivo and Yervoy compared to 28% with Opdivo monotherapy. Response duration of ≥ 6 months was also higher in the arm treated with Opdivo and Yervoy compared to Opdivo alone (89% vs. 67%). The most common adverse reactions (≥20%) in those receiving Opdivo and Yervoy are fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, dyspnea, decreased appetite, and vomiting. Efficacy for adolescent patients (12 years and older) with MSI-H or dMMR metastatic CRC is extrapolated from the results in the respective adult population. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In August 2018, the FDA approved Opdivo for the treatment of patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. The safety and efficacy of Opdivo for this use were demonstrated in Checkmate-032, a multicenter, multi-cohort, open-label, ongoing trial that enrolled 245 patients with metastatic SCLC, regardless of PD-L1 tumor status, with disease progression after platinum-based chemotherapy and at least one other prior line of therapy. The major efficacy outcome measures were overall response rate (ORR), which was further characterized by duration of response (DOR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR). Opdivo demonstrated an ORR of 12% (95% CI: 6.5 – 19.5), among which 0.9% achieved complete response, and 11% achieved partial response. Opdivo demonstrated a median duration of response of 17.9 months (95% CI: 7.9 – 42.1; range: 3.0 – 42.1 months) and median time to response of 1.6 months. Serious adverse reactions occurred in 45% of patients receiving Opdivo (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. 10% of patients discontinued treatment due to an adverse reaction. The toxicity profile observed in patients with metastatic SCLC was generally similar to that observed in patients with other cancers.

On March 10, 2020, the FDA granted accelerated approval to the combination of nivolumab and ipilimumab (Opdivo and Yervoy) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Efficacy of the combination was investigated in Cohort 4 of CHECKMATE-040, (NCT01658878) a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. A total of 49 patients received nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity. The main efficacy outcome measures were overall response rate and duration of response. ORR was 33% (n=16; 95% CI: 20, 48), with 4 complete responses and 12 partial responses. Response duration ranged from 4.6 to 30.5+ months, with 31% of responses lasting at least 24 months. The most common adverse reactions (20%) with nivolumab in combination with ipilimumab are: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness. For HCC, the recommended doses are nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

On May 15, 2020, the FDA approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as first-line treatment for patients with metastatic non-small cell lung cancer whose tumors express PD-L1(≥1%), as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Efficacy was investigated in CHECKMATE-227 (NCT02477826), a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC and no prior anticancer therapy. In Part 1a of the trial, 793 patients with PD-L1 tumor expression ≥1% were randomized to receive either the combination of nivolumab plus with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397). The trial demonstrated a statistically significant improvement in overall survival (OS) for patients with PD-L1 tumor expression ≥1% receiving nivolumab plus ipilimumab compared to those treated with  platinum-doublet chemotherapy. Median OS was 17.1 months (95% CI: 15, 20.1) versus 14.9 (95% CI: 12.7, 16.7) (HR 0.79; 95% CI: 0.67, 0.94; p=0.0066). Median progression-free survival (PFS) per blinded independent central review (BICR) was 5.1 months (95% CI: 4.1, 6.3) in the nivolumab plus ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm (HR 0.82; 95% CI: 0.69, 0.97). Confirmed overall response rate (ORR) per BICR was 36% (95% CI: 31, 41) and 30% (95% CI: 26, 35), respectively. Median response duration was 23.2 months in the nivolumab plus  ipilimumab arm and 6.2 months in the platinum-doublet chemotherapy arm.The most common adverse reactions in ≥20% of patients receiving the combination of nivolumab plus ipilimumab in CHECKMATE-227 were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, pruritis, nausea, and hepatitis.The recommended doses for metastatic NSCLC are nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

On May 26, 2020, the FDA approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) and 2 cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Efficacy was investigated in CHECKMATE-9LA (NCT03215706), a randomized, open-label trial in patients with metastatic or recurrent NSCLC. Patients were randomized to receive either the combination of nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy for 4 cycles (n=358). The trial demonstrated a statistically significant benefit in overall survival (OS) for patients treated with nivolumab plus ipilimumab plus chemotherapy compared to those who received chemotherapy. Median OS was 14.1 months (95% CI: 13.2, 16.2) versus 10.7 months (95% CI: 9.5, 12.5), HR 0.69; 96.71% CI: 0.55, 0.87). Median progression-free survival (PFS) per blinded independent central review (BICR) was 6.8 months (95% CI: 5.6, 7.7) in the nivolumab plus ipilimumab and chemotherapy arm and 5 months (95% CI: 4.3, 5.6) in the chemotherapy arm (HR 0.70; 95% CI: 0.57, 0.86). Confirmed overall response rate (ORR) per BICR was 38% (95% CI: 33, 43) and 25% (95% CI: 21, 30) respectively. Median response duration was 10 months in the nivolumab plus ipilimumab and chemotherapy arm, and 5.1 months in the chemotherapy arm. The most common adverse reactions in ≥20% of patients receiving nivolumab in combination with ipilimumab and platinum-doublet chemotherapy were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. The recommended nivolumab dose for this indication is 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. The nivolumab and ipilimumab is continued until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.

On June 10, 2020, the FDA approved nivolumab (Opdivo) for patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. Efficacy was investigated in ATTRACTION-3 (NCT02569242), a multicenter, randomized (1:1), active-controlled, open-label trial in 419 patients with unresectable advanced, recurrent, or metastatic ESCC. Patients who were refractory or intolerant to at least one fluoropyrimidine- and platinum‑based regimen received nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=210), or investigator’s choice of taxane chemotherapy consisting of docetaxel (75 mg/m² intravenously every 3 weeks) or paclitaxel (100 mg/m² intravenously once a week for 6 weeks followed by 1 week off) (n=209). The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were overall response rate (ORR), response duration, and progression-free survival (PFS) as assessed by the investigator using RECIST 1.1. The trial demonstrated a statistically significant improvement in OS. Median OS for patients receiving nivolumab was 10.9 months (95% CI: 9.2, 13.3) compared with 8.4 months (95% CI: 7.2, 9.9) for patients receiving investigator’s choice of taxane chemotherapy (HR: 0.77; 95% CI: 0.62, 0.96; p=0.0189). OS benefit was observed regardless of tumor PD-L1 expression level. The ORR was 19.3% (95% CI: 13.7, 26) in the nivolumab arm versus 21.5% (95% CI: 15.4, 28.8) in the taxane chemotherapy arm (not statistically significant), with median response duration of 6.9 months (95% CI: 5.4, 11.1) and 3.9 months (95% CI: 2.8, 4.2), respectively. The trial did not demonstrate an improvement in PFS (HR: 1.1; 95% CI: 0.9, 1.3) as the median PFS was 1.7 months for nivolumab versus 3.4 months in the chemotherapy arm. The most common adverse reactions in 10% patients receiving nivolumab were rash, decreased appetite, diarrhea, constipation, musculoskeletal pain, upper respiratory tract infection, cough, pyrexia, pneumonia, anemia, fatigue, pruritus, nausea, and hypothyroidism. The recommended nivolumab dose for ESCC is 240 mg every 2 weeks or 480 mg every 4 weeks.

Policy:
[(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)

The requirements of the Horizon BCBSNJ Nivolumab (Opdivo) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).]

I. Prior to initiating therapy with Nivolumab (Opdivo), the following must be documented:

• Member does not have active autoimmune disease or medical condition that requires immunosuppression
• Member does not have history of Human Immunodeficiency Virus (HIV) or active Hepatitis B (HBV) or Hepatitis C (HCV) infection
  · This does not apply for the indication of hepatocellular carcinoma as members are eligible for therapy for this indication if they have only active HBV or HCV
• Member has not received previous therapy with a programmed death (PD-1/PD-L1)-directed therapy (e.g. avelumab, durvalumab, pembrolizumab, atezolizumab, cemiplimab, etc.)

A. Patients with BRAF V600 wild-type unresectable or metastatic melanoma as a single agent when ALL of the following criteria are met
• Member is ≥18 years of age, AND
• ECOG score 0-1
B. Patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as a single agent when ALL of the following criteria are met:
• Member is ≥18 years of age, AND
• ECOG score 0-1
C. Patients with unresectable or metastatic melanoma, in combination with ipilimumab (Yervoy) when ALL of the following criteria are met
• Member is ≥18 years of age, AND
• ECOG score 0-1
D. Patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting when ALL of the following criteria are met:.
• Member is ≥18 years of age
• Stage IIIB/C or Stage IV disease before complete resection
• Completely removed melanoma by surgery within 12 weeks prior to starting treatment with nivolumab (Opdivo)

E. Patients with metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy when ALL of the following criteria are met:
• Member is ≥18 years of age, AND
• ECOG score 0-1, AND
• Documentation of treatment with a platinum-based chemotherapy AND
• Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab (Opdivo)
F. Patients with metastatic non-small cell lung cancer (NSCLC) expressing PD-L1 (≥1%), with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab (Yervoy) when ALL of the following criteria are met:
• Member is ≥18 years of age, AND
• ECOG score 0-1, AND
• Member has confirmed Stage IV or recurrent NSCLC, AND
• Member has not used prior anticancer therapy
G. Patients with metastatic or recurrent non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic aberrations as first-line treatment, in combination with ipilimumab (Yervoy) and 2 cycles of platinum-doublet therapy when ALL of the following criteria are met:
• Member is ≥18 years of age, AND
• ECOG score 0-1, AND
• Member has confirmed Stage IV or recurrent NSCLC, AND
• Member has not used prior anticancer therapy

• Member is ≥18 years of age, AND
• Karnofsky performance status of 70 or greater, AND
• Member had disease progression during or after treatment with an anti-angiogenic agent
I. Patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC) given in combination with ipilimumab when ALL of the following criteria are met:
• Member is ≥18 years of age, AND
• Karnofsky performance status of 70 or greater
J. Patients with Classical Hodgkin lymphoma who have relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin OR after 3 or more lines of systemic therapy that includes autologous HSCT when ALL of the following criteria are met
• Member is ≥ 18 years of age, AND
• ECOG score 0-1
K. Patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy when ALL of the following criteria are met:
• Member is ≥ 18 years of age AND
• ECOG score 0-1

L. Patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy OR have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy when ALL of the following criteria are met:
• Member is ≥ 18 years of age, AND
• ECOG score 0-1
M. Adult and pediatric patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer when ALL of the following criteria are met:
• Member is ≥ 12 years of age, AND
• ECOG score 0-1, AND
• Member had disease progression following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, AND
• Used as a single agent or in combination with ipilimumab (Yervoy), AND
• Member does NOT have any of the following:
  • Active brain metastases
  • Prior treatment with PD-1, anti-PD-L1, anti-PD-L2, anti-Cytotoxic T-Cell Lymphoma-4 Antigen (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathway
N. Patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib when ALL of the following criteria are met:
• Member has histologically confirmed advanced hepatocellular carcinoma
• Member has disease progression or intolerance following treatment with sorafenib
• Member is ≥18 years of age
• ECOG score 0-1
• Used as a single agent or in combination with ipilimumab (Yervoy)

• Member has histologically confirmed metastatic disease of small cell lung cancer, AND
• ECOG score of 0-1, AND
• Absence of active brain metastases or leptomeningeal metastases
P. Patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy when ALL of the following criteria are met:
• Member has histologically confirmed unresectable, advanced or recurrent esophageal cancer, AND
• Member is refractory to or intolerant to at least one fluoropyrimidine- and platinum-based regimen; AND
• ECOG score of 0-1, AND
• Absence of active/symptomatic brain metastases requiring treatment

• Grade 0: fully active, able to carry on all pre-disease performance without restriction
• Grade 1: restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
• Grade 2: ambulatory and capable of all self care but unable to carry out any work activities, up and about more than 50% of waking hours
• Grade 3: capable of only limited self care, confined to bed or chair more than 50% of waking hours
• Grade 4: completely disabled, cannot carry on any self care, totally confined to bed or chair
• Grade 5: dead]

• Dosing should be calculated using actual body weight and not flat dosing (as applicable) based on the following:
  • Weight ≥ 74 kg: Standard dose 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks
  • Weight is 67 kg to 73 kg: Use 440 mg IV every 4 weeks
  • Weight is ≤ 66 kg: Use 400 mg IV every 4 weeks
  • Note: This information is not meant to replace clinical decision making when initiating or modifying medication therapy and should only be used as a guide. Patient-specific variables should be taken into account.
A. Unresectable or metastatic melanoma
i. Nivolumab (Opdivo) monotherapy: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.
ii. Nivolumab (Opdivo) in combination with ipilimumab (Yervoy): Nivolumab (Opdivo) 1 mg/kg, followed by ipilimumab (Yervoy) on the same day, every 3 weeks for 4 doses, then nivolumab (Opdivo) 240 mg every 2 weeks or 480 mg every 4 weeks as a single agent until disease progression or unacceptable toxicity

B. Adjuvant treatment of melanoma
i. 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease recurrence or unacceptable toxicity.

C. Metastatic non-small cell lung cancer
i. Nivolumab (Opdivo) monotherapy: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.
ii. Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) (metastatic NSCLC expressing PD-L1): Nivolumab (Opdivo) 3 mg/kg every 2 weeks with ipilimumab (Yervoy) 1 mg/kg every 6 weeks administered as an intravenous infusion over 30 minutes until disease progression, unacceptable toxicity.
iii. Nivolumab (Opdivo) in combination with ipilimumab (Yervoy) (metastatic or recurrent NSCLC): Nivolumab (Opdivo) 360 mg every 3 weeks with ipilimumab (Yervoy) 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy administered as an intravenous infusion over 30 minutes until disease progression, unacceptable toxicity.

D. Advanced renal cell carcinoma
i. Nivolumab (Opdivo) monotherapy: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.
ii. Nivolumab (Opdivo) in combination with ipilimumab (Yervoy): 3 mg/kg every 3 weeks with ipilimumab 1 mg/kg as an intravenous infusion over 30 minutes on the same day for 4 doses. After completion of combination therapy, administer Opdivo as a single agent at 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

E. Classical Hodgkin lymphoma
i. Nivolumab (Opdivo) monotherapy: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity
ii. Nivolumab (Opdivo) in combination with ipilimumab (Yervoy): Nivolumab (Opdivo) 3mg/kg, followed by ipilimumab (Yervoy) on the same day, every 3 weeks for 4 doses, then nivoulumab (Opdivo) 240 mg every 2 weeks or 480 mg every 4 weeks as a single agent until disease progression or unacceptable toxicity

i. 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

H. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

• Adult and pediatric patients ages 12 years and older weighing ≥40 kg: 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity.
• Pediatric patients ages 12 years and older weighing < 40 kg: 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity.
ii. Nivolumab (Opdivo) combination with ipilimumab (Yervoy):
• Adult and pediatric patients ages 12 years and older weighing ≥ 40 kg: Nivolumab (Opdivo) 3 mg/kg followed by ipilimumab (Yervoy) 1 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab (Opdivo) 240 mg every 2 weeks or 480 mg every 4 weeks as a single agent until disease progression or unacceptable toxicity.
• Pediatric patients ages 12 years and older weighing < 40 kg: Nivolumab (Opdivo) 3 mg/kg followed by ipilimumab (Yervoy) 1 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab (Opdivo) 3 mg/kg every 2 weeks as a single agent until disease progression or unacceptable toxicity.

I. Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
i. Nivolumab (Opdivo) monotherapy: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.
ii. Nivolumab (Opdivo) combination with ipilimumab (Yervoy): nivolumab (Opdivo)1 mg/kg IV, followed by ipilimumab (Yervoy) 3 mg/kg IV infusion on the same day, every 3 weeks for 4 doses, then nivolumab (Opdivo) 240 mg every 2 weeks or 480 mg every 4 weeks

J. Patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy
i. 240 mg every 2 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity

K. Esophageal squamous cell carcinoma with progression after fluoropyrimidine- and platinum-based therapy
i. 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity

IV. Continuation of Nivolumab (Opdivo) will be approved every 6 months at the FDA approved dose as noted above if there are no unacceptable toxicities (e.g.: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated hypophysitis, immune-mediated nephritis, immune-mediated hyperthyroidism, immune-mediated hypothyroidism, immune-mediated skin adverse reactions, immune-mediated encephalitis, infusion-related reactions, etc.) or disease progression confirmed by imaging. For subsequent renewals, for the following indications approve for an additional 6 months up to the following limitations:

A. Adjuvant treatment of melanoma - up to 1 year total since the start of therapy
B. Metastatic non-small cell lung cancer expressing PD-L1 - up to 2 years total since the start of therapy
C. Metastatic or recurrent non-small cell cancer - up to 2 years total since the start of therapy

There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this drug. Therefore, Medicare Advantage will follow the Horizon BCBSNJ Medical Policy. See generally: Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available at: https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=53049&ver=44&name=314*1&UpdatePeriod=711&bc=AQAAEAAAAAAAAA%3d%3d&.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Nivolumab (Opdivo)
Opdivo (Nivolumab)
Metastatic Melanoma (Opdivo)
Non-Small Cell Lung Cancer (Opdivo)
Renal Cell Carcinoma (Opdivo)
Colorectal cancer (Opdivo)
Hepatocellular carcinoma (HCC) (Opdivo)
Small Cell Lung Cancer (Opdivo)

References:
1. Opdivo Prescribing Information. Opdivo U.S. Product Information. Princeton, NJ: Bristol-Myers Squibb Company. Updated June 2020.

2. Opdivo^® Dossier. BMS. Princeton, NJ. December 2014.

3. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Melanoma. Version 1.2018. Available at: https://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Accessed November 2019.

4. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 9.2017. Available at http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [Accessed November 2019]

5. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small Cell Lung Cancer. N Engl J Med. 2015.

6. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.

18. Zhao X, Suryawanshi M, Hruska M, et al. Assessment of nivolumab benefit-risk profile of a 240 mg flat dose relative to 3 mg/kg dosing regimen in patients with advanced tumors. Ann Oncol 2017; 28:2002-2008.

19. Feng Y, Xiaoning W, Bajaj G, et al. Nivolumab exposure-response analyses of efficacy and safety in previously treated squamous or nonsquamous non-small cell lung cancer. Clin Ca Res 2018;23(18): 5394-5405

20. FDA grants accelerated approval to nivolumab and ipilmumab combination for hepatocellular carcinoma. U.S. Food & Drug Administration. FDA approved drugs. March 11, 2020. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma

21. ClinicalTrials.gov. An Immuno-therapy Study to Evaluate the Effectiveness, Safety, and Tolerability of Nivolumab or Nivolumab in Combination With Other Agent in Patients With Advanced Liver Cancer (CheckMate040). NCT01658878. Available at: https://clinicaltrials.gov/ct2/show/NCT01658878

22. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. U.S. Food & Drug Administration. FDA approved drugs. May 26, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc

23. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). U.S. Food & Drug Administration. FDA approved drugs. May 15, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1

24. ClinicalTrials.gov. A Study of Nivolumab and Ipilimumab Combined With Chemotherapy Compared to Chemotherapy Alone in First Line NSCLC (CheckMate 9LA). NCT03215706. Available at: https://clinicaltrials.gov/ct2/show/NCT03215706

25. ClinicalTrials.gov. An Investigational Immuno-therapy Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC) (CheckMate 227). NCT02477826. Available at: https://clinicaltrials.gov/ct2/show/NCT02477826

26. ClinicalTrials.gov. Study of Nicolumab in Unresectable Advanced or Recurrent Esophageal Cancer. NCT02569242. Available at: https://clinicaltrials.gov/ct2/show/NCT02569242

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

J9299