Nivolumab is a fully human, intravenous immunoglobulin G4 antagonist monoclonal antibody targeting programmed cell death 1 (PD-1).
Trade name Opdivo.
For intravenous use at 10 mg/mL.
Recommended dose changed from 2mg/kg every 2 weeks to 240 mg IV every 2 weeks.
New dosing recommendation 480 mg infused 30 minutes every 4 weeks.
PD-1 is an inhibitory receptor expressed by activated T cells.
Blocks interaction between PD-1 and its ligand PD-L1 and PD-L2 which is a mechanism that normally leads to immune tolerance.
Targets PD-1 or CD279 cell surface membrane receptor on cancer cells.
The presence of PD-1 can impede immunotherapy.
By blocking PD-1 with nivolumab, it is hypothesized that immunotherapy can be more effective.
When PD-1 binds to its ligands PD-1 ligand 1 and PD-1 ligand 2,lymphocyte activation is down regulated, and masks the cancer cells from the immune system.
By inhibiting the interaction between PD-1 and its ligands, antigen specific immune T-cell responses are promoted, allowing recognition and elimination of cancer cells by the immune system.
It is also speculated that blocking PD-1 may mediate tumor regression in some patients with melanoma.
Approved in the second line setting after platinum-based doublet chemotherapy in non-small cell lung cancer squamous and nonsquamous.
Indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Ipilimumab, and if BRAF V600 mutation positive.
Approved as adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
Approved for renal cancer, and classical Hodgkin lymphoma that has relapsed or progressed after hematopoietic stem cell transplant and posttransplantation brentuximab.
In CheckMate 025 trial in patients with advanced renal cell carcinoma nivolumab demonstrated superior overall survival versus Everiolimus-25 months versus 19.6 months and a higher objective response rate 25% versus 5% in previously treated patients with advanced renal carcinoma.
A BRAF inhibitor.
Patients with advanced melanoma (N = 107) received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation.
Median overall survial in advanced melanoma, nivolumab-treated patients was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively.
Median progression-free survival was 3.7 months, with 1- and 2-year progression-free survival rates of 36% and 27%, respectively.
The most common treatment-related adverse events are skin disorders (36%), gastrointestinal symptoms (18%), and endocrinopathies (13%).
Skin side effects include pruritus, rash, vitiligo, mouth sores, injection site reactions, alopecia and exacerbation of psoriasis.
Grade 3 to 4 treatment-related adverse events were seen in 5% of treated patients.
Combining Nivolumab and Ipilimumab for the treatment of advanced melanoma: ipilimumab was held at a fixed dose of 3 mg/kg while nivolumab was escalated from 0.3 mg/kg to 3 mg/kg. The drugs were given together every 3 weeks for a total of 4 doses demonstrated an objective response rate of 40% and an 80% survival rate at 1 year.
Nivolumab and ipilimubab in metastatic renal cell cancer decrease risk of death by 32% compared with sunitinib with a median overall survival that has not been reached versus 32.9 months with sunitinib (Checkmate 214 study).
In the above study there was a 1-year survival of 85%, 2-year survival rate of 79%, and median survival of 40 months in the first 53 patients.
Durable responses were obtained with the immune checkpoint inhibitor nivolumab in a phase II dose-ranging trial conducted in patients with previously treated metastatic renal cell carcinoma (mRCC).
No apparent dose-response relationship observed for progression-free survival (PFS) in treatment of renal cancer.
Nivolumab, a fully human IgG4 PD-1 immune checkpoint-inhibitor monoclonal antibody that selectively blocks the PD-1 and PD-L1/PD-L2 interaction.
Objective responses in refractory renal cell carcinoma is about 20%, with a median duration of response for the 10-mg/kg dosage arm of 22.3 months.
The median overall survival (OS) for renal cell cancer was 18.2 months, 25.5 months, and 24.7 months in the 0.3-mg/kg, 2-mg/kg, and 10-mg/kg arms, respectively.
The median PFS and median ORR were greater in patients with renal cell cancer who had PD-L1 expression >5% in their tumors, but meaningful responses were observed even in patients without PD-L1 expression.
In a trial of 821 patients with advanced clear-cell renal cell cancer who had previously received treatment with one or two regimens of anti-angiogenesis therapy randomized to receive 3 mg per kilogram of nivolUmab IV every two weeks or 10 mg of everolimus tablet once daily: overall survival was longer with fewer toxic events with nivolumab than with everolimus (Motzer RJ et al).
Most common adverse effects are: fatigue, nausea, anemia and stomatitis.
Precautions include: Immune mediated pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, and embryofetal toxicity.
Immune-mediated adverse reactions may require corticosteroids and/or interruption or discontinuation of therapy.
Serious adverse reactions occurred in 41% of patients and grade 3 and 4 adverse reactions occurred to-5% of patients and include abdominal pain, hyponatremia, increase ALT and increased lipase.
Immune-mediated pneumonitis occurs in approximately 0.9% of patients.
Diarrhea or colitis occurs in about 21% of patients.
Immune-mediated hepatitis occurs in about 1% of patients.
Immune-mediated nephritis of renal dysfunction occurs in about 0.7% of patients.
Immune-mediated hypothyroidism occurs in approximately 8% of patients and hyperthyroidism about 3% of cases.
Approved for use in metastatic melanoma in patients with advanced disease who previously received ipilimumab on the basis of study Check-mate-037 clinical trial.
In the above study a 32% overall response rate was reported.
In melanoma recommended dosage is 3 mg per kilogram administered as an intravenous infusion for 60 minutes every two weeks.
The drug should be used in melanoma until disease progression or until unacceptable toxicity occurs.
Ligand activation of programmed cell death 1 (PD-1) is common in Hodgkin’s disease and nivolumab induced an 87% response rate in heavily pretreated patients with refractory or relapsed disease.
The combination of Brentuximab and nivolumab effective in relapsed or refractory Hodgkin lymphoma.
Has efficacy in primary CNS lymphoma.
Approved for hepatocellular cancer after prior sorafenib.
Approved therapy for patients for adjuvant therapy with completely respected melanoma with lymph node involvement.
Approved for treatment of patients with metastatic squamous cell carcinoma of the lung who progressed on or after platinum based chemotherapy.
In a study of randomly assigned 272 patients to receive Nivolumab at a dose of 3 mg/kg every 2 weeks or docetaxel every 3 weeks: Among previously treated squamous cell NSCLC overall survival, response rates, progression free survival were significantly better with Nivolumab, regardless of PD-L1 expression level (Brahmer J et al).
In a phase III trial of head and neck cancer patients refractory to platinum treatment there was a 30% reduction in risk of death compared to other treatments, and 1 year survival double to 36% vs 16% for controls.
Nivolumab prolongs survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck that has progressed after platinum-based chemotherapy compared with those who received standard single agent systemic chemotherapy.
Response rate in gastric, gastroesophageal junction cancers 14%.
Treatment with immunomodulatory agents may be associated with tumor flare.
In combination with ipilimubab recommended dose is nivolumab 1 mg/kg Iv followed by ipilimubab on the same day every 3 weeks for 4 doses.
Following the above nivolumab 240 mg every 2 week until disease progression or unacceptable toxicity for metastatic disease.
Recommended dose for Hodgkin’s disease is 3mg/kg IV every 2 weeks.
In chemo refractory squamous cell carcinoma of the esophagus treated with nivolumab had a 17% response rate with an overall survival at 10.8 months (Kudo T).
Nivolumab is associated with significant improvement in overall survival versus chemotherapy in previously treated patients with the best esophageal squamous cell carcinoma.
Nivolumab (Opdivo) is approved for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine-and platinum-based chemotherapy.
Patients with colorectal cancer with microsatellite instability-high have a high response to nivolumab.
Nivolumab appproved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
The addition of ipilmubab increases the response rate of nivolumab from 50% to 80% in miscrosatellite instability-high patients, and the combination is approved by FDA.
Associated with durable responses, disease control and long-term survival in in patients with DNA mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer.
Has signficant antitumor activity in HIV-positive Kaposi sarcoma.
Nivolumab first checkpoint inhibitor approved for small cell lung cancer was based on efficacy and safety data from the phase 1/2 CheckMate-032 trial: 109 patients received nivolumab after platinum-based chemotherapy and at least one other prior line of therapy, and 12% responded.
Estimated five-year survival rates are 34% for melanoma, 27.7% for renal cell carcinoma, and 15.6% for NSCLC (Topalian S).
Among patients with resected esophageal gastroesophageal junction cancer who receive neoadjuvant chemo radiotherapy, disease free survival was significantly longer among those are received nivolumab therapy than among those who receive placebo.
In patients with resectable non-small cell lung cancer, neoadjuvant Nivolumab plus chemotherapy resulted in significant longer event free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone.
In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival, than chemotherapy alone (Provencio, M).