Key evidence from clinical trials for nivolumab

Introduction

In December 2014, the U.S. Food and Drug Administration (FDA) granted expedited approval for the use of nivolumab (OPDIVO®; Bristol-Myers Squibb; USA) in the treatment of melanoma based on positive results from a multicenter randomized 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 New Zealand.

Nivolumab is a monoclonal antibody that joins PD-1 receiver and blocks their interaction with PD-L1 and PD-L2, thereby releasing the mediated PD-1 pathway inhibition of the immune response, including the antitumor immune response.

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

Experience in clinical trials.

CheckMate-037: effectiveness

• FDA approval was based on objective response rate (ORR) and durability of response in the first 120 patients in a continuous randomized process, open trial of 370 patients with unresectable or metastatic melanoma treated with nivolumab 3 mg / kg intravenously every 2 weeks (n = 268) or investigator's choice of chemotherapy (n = 102)
• All patients had a minimum of 6 months of follow-up.
• Chemotherapy included 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 a 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.
• The median treatment time was 5.3 months in the nivolumab arm and 2 months in the chemotherapy arm.
• The main efficacy endpoints were confirmed as ORR measured by a blinded independent central review using Response Assessment Criteria in Solid Tumors (RECIST v1.1) and duration of the response.
• The confirmed ORR in patients treated with nivolumab and chemotherapy was 32% (IC 95%: 23, 41) and 11%, respectively.
• The mean response time 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 32% ORR included four complete responses and 34 partial responses in patients treated with nivolumab.
• The median duration of response for nivolumab was not reached (range: 1.4+, 10+ months) at the time of data analysis.
• The median duration of response in patients treated with chemotherapy of the investigator's choice 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 following table summarizes the adverse reactions that were observed in at least 10% of patients treated with nivolumab compared to chemotherapy.

Other clinically important adverse reactions in <10% of nivolumab-treated patients 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.
• Immunomediated pneumonitis: occurred in 3.4% (9/268) of patients who received nivolumab and none of the 102 patients who received chemotherapy.
• Hypothyroidism: Grade 1 or 2 hypothyroidism occurred in the 8% (21/268) of the patients who received nivolumab and none of the 102 patients who received 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, measured by overall survival duration, of nivolumab versus dacarbazine in subjects with metastatic, unresectable, or previously untreated melanoma.
• Is double-blind the study randomized 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 compatible dacarbazine. placebo every 3 weeks) or dacarbazine (1000 mg per square meter of body surface every 3 weeks; n = 208) and placebo combined with nivolumab every 2 weeks.
• Treatment continued until there was disease progression or an unacceptable level of toxicity.
• All randomized patients were followed up for up to 16.7 months.
• the primary The end point was overall survival (OS). Secondary endpoints included progression-free survival (SLP), objective response rate (ORR) according to the RECIST v1.1 criteria, and PD-L1 expression as predictive biomarker of the operating system.
• At one year, the overall survival rate was 72.9% (95% [CI] confidence interval, 65.5 to 78.9) in the nivolumab group, compared to 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine (P <0.001).
• Median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (ratio of risk of death or disease progression, 0.43, 95% CI, 0, 34 to 0.56; P <0.001).
• The objective response rate was 40.0% (IC 95%, 33.3 to 47.0) in the nivolumab group versus 13.9% (IC 95%, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P <0.001).
• In the PD-L1 positive and PD-L1 negative / indeterminate subgroups, patients treated with nivolumab had improved OS versus dacarbazine.
• Nivolumab was associated with significant improvements in overall survival and progression-free survival, compared to dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation.
• The most common adverse events related to nivolumab treatment were fatigue (20%), itching (17%), and nausea (16.5%).
• Common adverse events in the dacarbazine arm included nausea (41.5%), vomiting (21%), fatigue (15%), diarrhea (15%), and hematological 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

• HRQL was evaluated in base and every 6 weeks during treatment, and at follow-up visits 1 and 2 (30 and 100–114 days, respectively, after stopping treatment) using the European Organization for Research and Quality of Life Central Questionnaire Treatment of Attention (EORTC) (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D).
• The EORTC QLQ-C30 is a validated, self-reported, generic measure of 30 items of HRQL composed of a global health status / CV, five functional (physical, role, emotional, social and cognitive), and nine symptom or individual questions (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties).
• The EQ-5D 3L is a validated, self-reported generic HRQL measurement consisting of the EQ-5D utility index and the visual analog EQ scale (YOU GO).
• The EQ-5D utility index comprises five dimensions (mobility, self-care, habitual activities, pain / discomfort and anxiety / depression), each with 3 levels of evaluation (no, some or extreme problems).
• The EQ VAS evaluates the patient's self-assessed health status on a vertical 100-point VAS (0, worst health condition imaginable; 100, best health status imaginable).
• The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine.
• Patients who received nivolumab deteriorated significantly later than those who received dacarbazine on various EORTC QLQ-C30 scales.
• At week 25, there was a worsening trend in the dacarbazine group but not in the nivolumab group; however, the change from baseline was neither statistically significant nor clinically significant.
• In general, both the EORTC QLQ-C30 functional subscale and the mean symptom scores remained relatively stable over time compared to baseline for both groups, with some statistically significant and clinically significant changes.
• The mean exploratory analysis (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 with time versus dacarbazine.
• Significant improvements from baseline were observed for patients receiving nivolumab from week 7 (P = 0.011) until week 49 (P = 0.034).
• For patients receiving dacarbazine, there were no significant improvements from baseline at any time.
• These exploratory HRQL results show that nivolumab maintains baseline HRQL levels to provide long-term quality of survival benefit, higher 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, phase III randomized study comparing three treatment arms, nivolumab combined with ipilimumab (n = 314) or nivolumab alone (316) or ipilimumab alone (315) in patients with metastatic melanoma.
• Adult patients with previous treatment, histologically confirmed stage III (unresectable) or stage IV melanoma with known history BRAF Mutation status V600 was included in the trial, with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a 5-point scale, with higher scores indicating greater disability).
• 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 placebo combined with ipilimumab); or ipilimumab 3 mg per kilogram every 3 weeks for four doses (plus placebo combined with nivolumab).
• The two primary endpoints 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 first progression or documented disease death (whichever occurs first), and objective response rate such as proportion of patients with a better overall response than partial or complete response as assessed by researchers according to the Solid Tumor Response Assessment Criteria (RECIST), version 1.1, at 12 weeks after randomization and then every 12 weeks until progression or discontinuation of treatment.
• The overall 3-year survival rate was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, compared to 34% in the ipilimumab group.
• At a minimum follow-up of 36 months, the median overall survival was 37.6 months in the nivolumab group compared to 19.9 months in the ipilimumab group (ratio of risk of death with nivolumab plus ipilimumab versus ipilimumab, 0.55 [P <0.001], ratio of risk of death with nivolumab vs. ipilimumab, 0.65 [P <0.001].
• The following table summarizes the data for median progression-free survival and best overall response (The investigator assessed the best overall response according to the Response Assessment Criteria for Solid Tumors, version 1.1).

• Grade 3 or 4 treatment-related adverse events occurred in 59% of 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 greater with combination therapy than with nivolumab or ipilimumab alone.
• The most common adverse events (> 20% in patients) in the 3 treatment arms were rash, itching, fatigue, diarrhea, and nausea.
• It was concluded that among patients with advanced melanoma, significantly greater overall survival occurred with combination treatment 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 posterior treatment option for adult patients with unresectable or metastatic melanoma, regardless of BRAF mutation.
• In well-designed multinational trials, as monotherapy or in combination with ipilimumab (a cytotoxic T-lymphocyte antigen 4 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 therapies directed against PD-1 / PD-L1 represent a great step forward in the treatment of melanoma.