Nivolumab

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

In the United States, 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.^[2] In addition, it is approved for the treatment of squamous non-small cell lung cancer.^[3]

Mechanism of action

Nivolumab is a programmed death receptor blocking antibody used for the treatment of melanoma and for the treatment of metastatic squamous non-small cell lung cancer. In contrast to traditional chemotherapies and targeted anti-cancer therapies, which exert their effects by direct cytotoxic or tumor growth inhibition, nivolumab acts by inducing the immune system to attack the tumor.

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 a way that the body regulates the immune system, to avoid an overreaction. Since many cancer cells make PD-L1, the cancer cells can disarm the T cells and inhibit them from attacking the tumor. Nivolumab blocks PD-L1 from binding to PD-1, allowing the T cell to attack the cancer again.

PD-1 blockers appear to free up the immune system only around the tumor, rather than more generally, which could mean they can have fewer side effects as well.^[4]

Clinical trial results

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.^[5][6]

A second phase 1 trial examined combination treatment of metastatic melanoma with nivolumab plus 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]

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%). Nivolumab received FDA approval for the treatment of melanoma in December 2014.^[8]

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.^[9]

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/gemicitabine, 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.^[10][11]

References

1. ↑ Statement On A Nonproprietary Name Adopted By The USAN Council - Nivolumab, American Medical Association.
2. ↑ "FDA approves Opdivo for advanced melanoma". Food and Drug Administration. December 22, 2014. 
3. ↑ "FDA expands approved use of Opdivo to treat lung cancer (FDA.gov)". Retrieved March 4, 2015. 
4. ↑ http://www.nytimes.com/2012/06/02/business/drug-helps-immune-system-fight-cancer.html?_r=0
5. ↑ Topalian SL et al. (June 2012). "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer". New England Journal of Medicine 366. doi:10.1056/NEJMoa1200690. PMC 3544539. PMID 22658127. Lay summary – New York Times.  CS1 maint: Explicit use of et al. (link)
6. ↑ Johnson DB, Peng C, Sosman JA (2015). "Nivolumab in melanoma: latest evidence and clinical potential". Ther Adv Med Oncol 7 (2): 97–106. doi:10.1177/1758834014567469. PMC 4346215. PMID 25755682. 
7. ↑ Johnson DB, Peng C, Sosman JA (2015). "Nivolumab in melanoma: latest evidence and clinical potential". Ther Adv Med Oncol 7 (2): 97–106. doi:10.1177/1758834014567469. PMC 4346215. PMID 25755682. 
8. ↑ Johnson DB, Peng C, Sosman JA (2015). "Nivolumab in melanoma: latest evidence and clinical potential". Ther Adv Med Oncol 7 (2): 97–106. doi:10.1177/1758834014567469. PMC 4346215. PMID 25755682. 
9. ↑ Sundar R, Cho BC, Brahmer JR, Soo RA (2015). "Nivolumab in NSCLC: latest evidence and clinical potential". Ther Adv Med Oncol 7 (2): 85–96. doi:10.1177/1758834014567470. PMC 4346216. PMID 25755681. 
10. ↑ Sundar R, Cho BC, Brahmer JR, Soo RA (2015). "Nivolumab in NSCLC: latest evidence and clinical potential". Ther Adv Med Oncol 7 (2): 85–96. doi:10.1177/1758834014567470. PMC 4346216. PMID 25755681. 
11. ↑ Sundar R, Cho BC, Brahmer JR, Soo RA (2015). "Nivolumab in NSCLC: latest evidence and clinical potential". Ther Adv Med Oncol 7 (2): 85–96. doi:10.1177/1758834014567470. PMC 4346216. PMID 25755681.