Key clinical-trial evidence for nivolumab

Introduction

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.

In April 2016, MedSafe approved nivolumab for the treatment of melanoma patients in NZ.

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.

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).

CheckMate-066: health-related quality of life

• HRQoL was evaluated at baseline and every 6 weeks while on treatment, and at follow-up visits 1 and 2 (30 and 100–114 days, respectively, after discontinuing treatment) using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D).
• The EORTC QLQ-C30 is a validated, self-reported, 30-item, generic measure of HRQoL composed of a global health status/QoL, five functional (physical, role, emotional, social, and cognitive), and nine symptom or single-item (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) questions.
• The EQ-5D 3L is a validated, self-reported, generic measure of HRQoL composed of the EQ-5D utility index and EQ visual analog scale (VAS).
• The EQ-5D utility index comprises five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each having 3 assessment levels (no, some, or extreme problems).
• The EQ VAS evaluates the patient's self-rated health state on a 100-point vertical VAS (0, worst imaginable health state; 100, best imaginable health state).
• The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine.
• Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales.
• At week 25, there was a trend towards worsening in the dacarbazine group but not in the nivolumab group; however, the change from baseline was neither statistically significant nor clinically meaningful.
• In general, both EORTC QLQ-C30 functioning subscale and symptom mean scores remained relatively stable over time compared with baseline for both groups, with a few statistically significant and clinically meaningful changes.
• The exploratory analysis mean (SD) EQ-5D utility scores were higher at baseline for patients treated with nivolumab [0.778 (0.215)] than for those treated with dacarbazine [0.711 (0.310)], and remained higher over time versus dacarbazine.
• Significant improvements from baseline were observed for patients receiving nivolumab from week 7 (P = 0.011) through week 49 (P = 0.034).
• For patients receiving dacarbazine, there were no significant improvements from baseline at any time point.
• These exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, superior to dacarbazine in patients with advanced melanoma.

CheckMate-067: nivolumab combined with ipilimumab or nivolumab alone versus ipilimumab alone

• Checkmate 067 is a first-line placebo-controlled randomized phase III study comparing three arms of treatment, nivolumab combined with ipilimumab (n = 314) or nivolumab alone (316) or ipilimumab alone (315) in patients with metastatic melanoma.
• Adult patients with previously untreated, histologically confirmed stage III (unresectable) or stage IV melanoma, with known BRAF V600 mutation status, and with an Eastern Cooperative Oncology Group performance-status score of 0 or 1 (on a 5-point scale, with higher scores indicating greater disability) were included in the trial.
• Patients received one of the following regimens: nivolumab 1 mg per kilogram of body weight every 3 weeks plus ipilimumab 3 mg per kilogram every 3 weeks for four doses; nivolumab 3 mg per kilogram every 2 weeks (plus ipilimumab-matched placebo); or ipilimumab 3 mg per kilogram every 3 weeks for four doses (plus nivolumab-matched placebo).
• The two primary end points were progression-free survival and overall survival.
• Overall survival was defined as the time from randomization to death, progression-free survival as the time from randomization to the first documented disease progression or death (whichever occurred first), and the objective response rate as the proportion of patients with a best overall response of partial or complete response as assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at 12 weeks after randomization and then every 12 weeks until progression or the discontinuation of treatment.
• The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, compared with 34% in the ipilimumab group.
• At a minimum follow-up of 36 months, median overall survival was 37.6 months in the nivolumab group compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P < 0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P < 0.001].
• The table below summarises data for median progression free survival and best overall response (The best overall response was assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors, version 1.1).

• Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group.
• The incidence of treatment-related adverse events was higher with combination therapy than with nivolumab or ipilimumab alone.
• The most common adverse events (> 20% patients) across the 3 treatment arms were rash, pruritus, fatigue, diarrhoea and nausea.
• It was concluded that among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone.

Future directions for nivolumab

• Given the significant improvements in outcomes associated with nivolumab in clinical trials, nivolumab monotherapy or combination therapy is a valuable first-line or subsequent treatment option for adult patients with unresectable or metastatic melanoma, irrespective of BRAF mutation status.
• In well-designed multinational trials, as monotherapy or in combination with ipilimumab (a cytotoxic T-lymphocyte antigen 4 checkpoint inhibitor), nivolumab significantly improved clinical outcomes and had a manageable tolerability profile in adult patients with advanced melanoma with or without BRAF mutations.
• Additional immune modulators are also being evaluated in combination with nivolumab
• Nivolumab and other anti-PD-1/PD-L1 directed therapies represent a major step forward in melanoma therapeutics.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).