Key clinical-trial evidence for nivolumab

Author: Anoma Ranaweera B.V.Sc; PhD (Clinical Biochemistry, University of Liverpool, UK); Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, January 2015.


In December 2014, the US Food and Drug Administration (FDA) granted accelerated approval for the use of nivolumab (OPDIVO®; Bristol-Myers Squibb; USA) in the treatment of melanoma based on positive results of a multicentre, randomised trial that established the superiority of nivolumab over standard therapy in adult patients with unresectable or metastatic melanoma.

Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumour immune response.

Nivoluamb is approved for the treatment of patients with melanoma who have been previously treated with the anti-CTLA-4 inhibitor ipilimumab and, for patients with melanoma with BRAF V600 mutations who have progressed after treatment with ipilimumab and a BRAF inhibitor (eg vemurafenib or dabrafenib).

Clinical trial experience

CheckMate-037: efficacy

  • FDA approval was based on objective response rate (ORR) and durability of response in the first 120 patients in an ongoing randomised, open-label trial of 370 patients with unresectable or metastatic melanoma treated with nivolumab 3 mg/kg intravenously every 2 weeks (n=268) or investigator choice of chemotherapy (n=102).
  • All patients had a minimum of 6 months follow-up.
  • Chemotherapy included either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC (area under curve) 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks.
  • Patients were excluded from the trial if they had an autoimmune disease, a medical condition that required corticosteroids or immunosuppression, or a history of severe ipilimumab-related adverse reactions.
  • Patients with unresectable or metastatic melanoma were required to have disease progression after treatment with ipilimumab, and a BRAF inhibitor if BRAF V600 mutation positive.
  • Patients were treated until disease progression or unacceptable toxicity.
  • Median time on therapy was 5.3 months in the nivolumab arm and 2 months in the chemotherapy arm.
  • The major efficacy endpoints were confirmed ORR as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumours (RECIST v1.1) and response duration.
  • Confirmed ORR in nivolumab- and chemotherapy-treated patients were 32% (95% CI: 23, 41) and 11%, respectively.
  • Median time to response was 2.1 months (range: 1.6, 7.4) and 3.5 months (range: 2.1, 6.1), in the nivolumab and chemotherapy arms, respectively.
  • The ORR of 32% included four complete responses and 34 partial responses in nivolumab-treated patients.
  • Median duration of response for nivolumab was not reached (range: 1.4+, 10+ months) at the time of data analysis.
  • Median duration of response in patients treated with investigator choice chemotherapy was 3.6 months (range: 1.3+, 3.5).
  • There were objective responses in patients with and without BRAF V600 mutation positive-melanoma.

CheckMate–037: adverse reactions

The table below summarises the adverse reactions that were observed in at least 10% of nivolumab-treated patients compared with chemotherapy.

Adverse reactions reported in >10% of subjects on nivolumab and with greater frequency than the chemotherapy arm
ADVERSE REACTIONNIVOLUMAB (n = 268)CHEMOTHERAPY (n = 102)
  All Grades (% patients) Grades 3-4 (% patients) All Grades (% patients) Grades 3-4 (% patients)
Rash 21 0.4 7 0
Pruritus 19 0 3.9 0
Cough 17 0 6 0
Upper respiratory tract infection 11 0 2 0
Peripheral oedema at injection site 10 0 5 0
Increased AST 28 2.4 12 1
Increased alkaline phosphatase 22 2.4 13 1.1
Hyponatraemia 25 5 18 1.1
Increased ALT 16 1.6 5 0
Hyperkalaemia 15 2 6 0
Diarrhoea or colitis 21 - 18 -

Other clinically important adverse reactions in < 10% of patients treated with nivolumab were:

  • Cardiac disorders: ventricular arrhythmia
  • Eye disorders: iridocyclitis
  • Administration site conditions: infusion-related reactions
  • Laboratory abnormalities: increased amylase, increased lipase
  • Nervous system disorders: dizziness, peripheral and sensory neuropathy
  • Skin and subcutaneous tissue disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis.
  • Immune-mediated pneumonitis: occurred in 3.4% (9/268) of patients receiving nivolumab and none of the 102 patients receiving chemotherapy.
  • Hypothyroidism: Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving nivolumab and none of the 102 patients receiving chemotherapy.
  • Hyperthyroidism: Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving nivolumab and 1% (1/102) of patients receiving chemotherapy.

CheckMate-066: efficacy and adverse events

  • The purpose of this study is to compare the clinical benefit, as measured by duration of overall survival, of nivolumab vs. dacarbazine in subjects with previously untreated, unresectable or metastatic melanoma.
  • This double-blind study randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (3 mg per kilogram of body weight every 2 weeks; n = 210) and dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg per square metre of body-surface area every 3 weeks; n = 208) and nivolumab-matched placebo every 2 weeks.
  • Treatment was continued until there was disease progression or an unacceptable level of toxicity.
  • All randomised patients were followed for up to 16.7 months.
  • The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), objective response rate (ORR) by RECIST v1.1 criteria and PD-L1 expression as a predictive biomarker of OS.
  • At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (P<0.001).
  • The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001).
  • The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001).
  • In both the PD-L1 positive and PD-L1 negative/indeterminate subgroups, nivolumab-treated patients had improved OS vs dacarbazine.
  • Nivolumab was associated with significant improvements in overall survival and progression-free survival, compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation.
  • The most common nivolumab treatment-related adverse events were fatigue (20%), pruritus (17%), and nausea (16.5%).
  • Common adverse events in the dacarbazine arm included nausea (41.5%), vomiting (21%), fatigue (15%), diarrhoea (15%) and haematological toxicities.
  • The frequency of Grade 3/4 treatment-related serious adverse events was similar between the nivolumab and dacarbazine groups (5.8% and 5.9%, respectively).

Future directions for nivolumab

  • Nivolumab has demonstrated safety and efficacy in the treatment of unresectable metastatic melanoma.
  • However, nivolumab has not yet been compared to other approved immunomodulatory treatments for melanoma.
  • Enrollment has been completed for a phase III trial comparing nivolumab plus ipilimumab vs nivolumab or ipilimumab alone.
  • Continued approval of nivolumab for melanoma treatment may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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