Summary of Clinical Use

In December 2014 nivolumab was approved under the FDA's accelerated approval program for the treatment of advanced (metastatic) melanoma, following review of positive clinical trial results [15]. The FDA expanded nivolumab's approval in 2015 to include treatment of advanced (metastatic) squamous and non-squamous non-small cell lung cancer (NSCLC) in patients with disease progression on or after platinum-based chemotherapy. Nivolumab outperformed standard chemotherapy with everolimus, in a randomized, open-label, Phase 3 clinical study in patients with previously treated renal-cell carcinoma [13]. Consequently, in November 2015, FDA approval was extended further to include treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy. Combination therapy with ipilimumab and nivolumab has been reported to exhibit >60% objective-response rate (ORR) in treatment-naive advanced melanoma patients with BRAF wild-type tumours [17] (results from Phase 1 study NCT01927419). This is in comparison to ipilimumab alone which provided only 11% confirmed ORR. These findings have been confirmed by Phase 3 study (NCT01844505) results showing significantly longer progression-free survival in patients given the combination therapy vs. the nivolumab only group [11]. Combination ipilimumab/nivolumab therapy has been FDA approved (2015) for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma [3,11]. In May 2016, the FDA granted accelerated approval for nivolumab to be used as a therapy for patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. In November 2016, the FDA further expanded approval to include treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy. February 2017 saw accelerated approval for locally advanced or metastatic urothelial carcinoma, for those patients with disease progression despite receiving platinum-containing chemotherapy. The accelerated approval programme saw nivolumab's authorisation as a treatment for paediatric patients, 12 years and older, with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in August 2017. Accelerated approval was granted by the FDA in September 2017 for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib, based on preliminary results from clinical trial NCT01658878. A combination therapy of nivolumab plus ipilimumab was granted FDA approval in April 2018 , for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma [2], based on results from the CheckMate 214 trial (NCT02231749) [14]. Later in 2018 (August) the FDA approved nivolumab for patients with metastatic small cell lung cancer (SCLC; with progression after platinum-based chemotherapy and at least one other line of therapy) under their accelerated approval program.

Mechanism Of Action and Pharmacodynamic Effects

Nivolumab binds to the programmed cell death 1 (PD-1, PDCD1) receptor on activated T cells and prevents receptor activiation by endogenous ligands PD-L1 and PD-L2. PD-L1 has an immuno-inhibitory effect on T cells, whereby activation of PD-1 by PD-L1 results in T cell death or quiescence. Many cancer cells express PD-L1 [4,8,18], and this permits these malignant cells to 'evade' destruction by the immune system. By preventing binding of the cancer cell-derived PD-L1, nivolumab restores local immune detection/destruction by T cells. The mechanism of action by which this antibody works has potential to be a useful strategy in treating many different types of cancer [1,6-7]. The list of clinical trials assessing the efficacy of this treatment testify to its potential usefulness. Click here to view nivolumab trials registered with ClinicalTrials.gov.

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT01658878	An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab or Nivolumab in Combination With Other Agents in Patients With Advanced Liver Cancer	Phase 1/Phase 2 Interventional	Bristol-Myers Squibb
NCT01844505	Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067)	Phase 3 Interventional	Bristol-Myers Squibb
NCT01927419	Study of Nivolumab (BMS-936558) Plus Ipilimumab Compared With Ipilimumab Alone in the Treatment of Previously Untreated, Unresectable, or Metastatic Melanoma	Phase 2 Interventional	Bristol-Myers Squibb
NCT02231749	Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)	Phase 3 Interventional	Bristol-Myers Squibb

External links

For extended ADME data see the following: Electronic Medicines Compendium (eMC) Drugs.com European Medicines Agency (EMA)