Nivolumab

Nivolumab (nye vol' ue mab; ONO-4538, BMS-936558, or MDX1106), marketed as Opdivo, is a human IgG4 anti-PD-1 monoclonal antibody developed by Ono Pharmaceutical and Medarex (later acquired by Bristol-Myers Squibb) for the treatment of cancer.^[1][2] Nivolumab acts as an immunomodulator by blocking ligand activation of the programmed cell death 1 (PD-1) receptor on activated T cells.

Nivolumab is approved by the Food and Drug Administration for treatment of patients with unresectable or metastatic melanoma who no longer respond to other drugs.^[3] In addition, it is approved for the treatment of squamous non-small cell lung cancer.^[4]

Mechanism of action

Nivolumab is an inhibitory ligand blocking antibody against the programmed death receptor. In contrast to traditional chemotherapies and targeted anti-cancer therapies, which exert their effects by direct cytotoxic or tumor growth inhibition, nivolumab acts by blocking a negative regulator of T-cell activation and response thus allowing the immune system to attack the tumor.^[5][6] This is an example of immune checkpoint blockade.

PD-1 is a protein on the surface of activated T cells. If another molecule, called programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), binds to PD-1, the T cell becomes inactive. This is one way that the body regulates the immune system, to avoid an overreaction. Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor. Nivolumab blocks PD-L1 from binding to PD-1, allowing the T cell to work.^[5][6]

PD-1 blockade reinvigorates immune cells that are able to target cancer cells, which is speculated but not proven to reduce side effects.^[5]

Approvals and indications

Nivolumab received FDA approval for the treatment of melanoma in December 2014.^[7] On 24 April 2015, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended approval of Nivolumab for metastatic melanoma as a monotherapy.^[8]

In March 2015 the US FDA approved it for the treatment of squamous non-small cell lung cancer.^[4]

Clinical trials

Metastatic melanoma

A phase 1 dose-optimization trial of nivolumab was performed in people with melanoma, lung cancer, kidney cancer and other cancers. Among the 107 melanoma patients in this trial, nivolumab demonstrated one-, two-year and three year survival rates of 62%, 48%, and 41%.

Toxicities, which were not cumulative and which mostly occurred during the first 6 months of therapy, included pneumonitis, low grade fatigue, diarrhea, pruritus, nausea, and decreased appetite. Pneumonitis was the most important adverse effect, leading to 3 deaths. Twenty-two percent of people in the trial experienced a treatment-related Grade 3 or Grade 4 toxicity.^[9][7]

A second phase 1 trial examined combination treatment of metastatic melanoma with nivolumab and ipilimumab. Among 53 people treated concurrently with the highest dose (1 mg/kg nivolumab and 3 mg/kg ipilimumab), 53% had an objective response, all of whom saw their tumors shrink by 80% or more. An updated report from this trial, including an additional 41 people treated with the highest dose, stated that 79% were still alive after 2 years.^[7][10]

In a phase 3 trial comparing nivolumab monotherapy to treatment with traditional chemotherapy, nivolumab gave superior results in terms of response rate (40% vs. 13.9%), progression-free survival (5.1 months vs. 2.2 months), and the percentage of people still alive after one year (72.1% vs. 42.1%).^[7]

Lung cancer

One hundred and twenty nine people with non-small cell lung cancer were included in a phase 1b trial of nivolumab in various cancers. Most of the 129 non-small cell lung cancer patients had received multiple chemotherapies. The overall response rate in this group was 17%, with a median duration of response of 74 weeks. At the highest dose, 45% were still alive after 2 years.^[11]

A multi-arm phase 1 trial examined the use of nivolumab as a single agent or as part of combination therapy. In the first arm, 56 chemotherapy-naive patients were treated with nivolumab plus one of three chemotherapy regimens: cisplatin/gemcitabine, cisplatin pemetrexed, or carboplatin/paclitaxel. Response rates ranged from 33-50%, and 59-87% of the patients were still alive after one year. Serious adverse events were experienced by 45%. In a second arm chemotherapy-naive patients were treated with nivolumab monotherapy. 71-80% of these 20 patients were still alive after one year. In a third arm, patients were treated with a combination of nivolumab and ipilimumab. Median overall survival in this group was 44.3 weeks.^[11][11]

In a phase II safety trial patients with metastatic NSCLC who failed two treatments were given 3 mg/kg nivolumab every 2 weeks. In the phase 3 CheckMate-017 and CheckMate-017 nivolumab improved survival compared to docetaxel in patients with previous treatments.^[12]

Hodgkin's lymphoma

In Hodgkin’s lymphoma, Reed-Sternberg cells harbor amplification of chromosome 9p24.1, which encodes PD-L1 and PD-L2 and leads to their constitutive expression. In a 2015 preclinical study, nivolumab elicited an objective response rate of 87% in a cohort of 20 patients. For this cancer, amplification of chromosome 9p24 or up-regulate PD-L1 or PD-L2 in response to an oncogenic signal, may serve as a predictive biomarker.^[10]

External links

• OPDIVO
• OPDIVO full prescribing information

References