Bristol-Myers Squibb Company announced that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection for intravenous use for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. The purpose of adjuvant therapy is to reduce the risk of recurrence following surgical removal of the tumor and lymph nodes that contain cancer. In the Phase 3 CheckMate -238 trial, Opdivo significantly improved recurrence-free survival (RFS) versus an active comparator, Yervoy (ipilimumab), in patients with stage IIIB/C or stage IV melanoma after surgery. This benefit was observed across important subgroups, including in both BRAF mutant and BRAF wild-type patients. Opdivo is the first and only agent approved for the adjuvant treatment of melanoma based on a head-to-head trial against an active comparator with a proven overall survival benefit.
“Today’s approval builds on our leadership in melanoma, offering physicians a new option with the potential to change the course of the disease through earlier intervention. Opdivo is the first PD-1 inhibitor approved as an adjuvant treatment for any cancer,” said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. “Our decision to study Opdivo versus Yervoy – an established standard of care with a proven survival benefit – represents our relentless pursuit to bring more effective treatments to patients.”
In the CheckMate -238 clinical trial, Opdivo demonstrated an 18-month RFS rate of 66.4% [95% confidence interval (CI): 61.8 to 70.6] compared with 52.7% for Yervoy (95% CI: 47.8 to 57.4), with the median RFS not yet reached in either group. Opdivo reduced the risk of disease recurrence by 35% versus Yervoy [hazard ratio (HR): 0.65; 95% CI: 0.53 to 0.80; p <0.0001].
Opdivo is associated with the following Warnings and Precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity. Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions, as well as additional information on the CA 184-029 trial.
Opdivo received Breakthrough Therapy Designation from the FDA for the adjuvant treatment of patients with high-risk, fully resected melanoma in September 2017. Approximately three in every 10 patients with stage III melanoma currently receive adjuvant therapy after surgery. Even with available treatment options, the majority of stage IIIB and IIIC melanoma patients (71% and 85%, respectively) experience disease recurrence within five years.
Opdivo is the first programmed death-1 (PD-1) immune checkpoint inhibitor to demonstrate superiority, including better tolerability, versus Yervoy, a standard of care in this patient population. Based on data from the CheckMate -238 trial, the National Comprehensive Cancer Network (NCCN) recently added nivolumab to its treatment guidelines for completely resected stage IIIB/C melanoma and completely resected stage III melanoma with clinical satellite or in-transit metastases.
In CheckMate -238, adverse events (AEs) leading to discontinuation were reported in 9% of Opdivo-treated patients (n=44/452) and in 42% of Yervoy-treated patients (n=193/453). Adverse reactions leading to one or more omitted doses occurred in 28% of patients who received Opdivo. Grade 3 or 4 AEs were experienced by 25% of patients (n=115/452) in the Opdivo group and 55% of patients (n=250/453) in the Yervoy group. Serious adverse reactions occurred in 18% of patients treated with Opdivo.
“Immuno-Oncology has transformed the treatment of metastatic melanoma and many other cancers over the last decade, and we are now extending the use of novel agents to help prevent the recurrence of melanoma,” said Jeffrey S. Weber, M.D., Ph.D., deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, and Professor of Medicine at NYU School of Medicine. “When melanoma has been removed surgically, physicians and patients alike sometimes struggle with the idea of further adjuvant treatment because the disease is no longer detectable, even though it may be likely to return. We recognized a need to develop new adjuvant treatments with lower toxicity compared to ipilimumab to help address this challenge. With its impressive efficacy and broad applicability within stage III and IV melanoma, nivolumab has the potential to become the next standard of care in preventing recurrence of melanoma following surgical resection.”
Bristol-Myers Squibb pioneered the use of immune checkpoint inhibitors for the adjuvant treatment of melanoma, beginning with Yervoy. Five-year overall survival data from the Phase 3 CA184-029 trial were recently added to the prescribing information for Yervoy for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. In the trial, 65% of patients treated with Yervoy were alive at five years, compared with 54% of patients who received placebo (HR: 0.72; 95% CI: 0.58-0.88; p <0.002). This analysis was conducted at a median follow-up of 5.3 years.
“Although there are approved therapies to help prevent melanoma recurrence, around seven out of 10 patients with stage III disease do not receive treatment following surgery,” said Valerie Guild, co-founder and president, AIM at Melanoma Foundation. “As an advocate, I have witnessed countless times the frustration and fear patients experience when their cancer returns – even after it was removed by surgery. Today’s approval offers new hope for people with melanoma that their disease may not come back.”
About the Pivotal CheckMate -238 Study
CheckMate -238 is an ongoing Phase 3, randomized double-blind study of Opdivo versus Yervoy in patients who have undergone complete resection of stage IIIB/C or stage IV melanoma. The trial randomized 906 patients 1:1 to receive either Opdivo 3 mg/kg every two weeks (n=453) or Yervoy 10 mg/kg (n=453) every three weeks for four doses and then every 12 weeks starting at week 24. Patients were treated until disease recurrence, unacceptable toxicity or consent withdrawal for up to one year. The primary endpoint is RFS defined as the time between randomization and the date of first recurrence, new primary melanoma or death. After meeting the primary endpoint, the trial will continue to evaluate for overall survival, a secondary endpoint. Interim data were presented at the European Society for Medical Oncology 2017 Congress in Madrid, Spain, with simultaneous publication in The New England Journal of Medicine.
Select Safety Profile from the CheckMate -238 Trial
The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of Opdivo-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions, reported in at least 20% of Opdivo-treated patients, were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%) and hepatitis (3%).
About the CA184-029 Study
The Phase 3 CA184-029 trial, a randomized (1:1), double-blind, placebo-controlled study, investigated the use of Yervoy for the adjuvant treatment of melanoma. A total of 951 enrolled patients with resected stage IIIA (>1 mm nodal involvement), IIIB and IIIC (with no in-transit metastases) melanoma received either Yervoy 10 mg/kg (n=475) or placebo (n=476) every three weeks for four doses, followed by every 12 weeks from week 24 to week 156 or until documented disease recurrence or unacceptable toxicity. The major efficacy outcomes were independent review committee-assessed RFS and OS. Yervoy reduced the risk of recurrence or death by 25% versus placebo (HR: 0.75; 95% CI: 0.64 to 0.90; p <0.002). Median RFS was 26 months for Yervoy (95% CI: 19 to 39) and 17 months for placebo (95% CI: 13 to 22). There were 234 RFS events in the Yervoy arm (49% of patients; 220 recurrences, 14 deaths) and 294 events in the placebo arm (62% of patients; 289 recurrences, 5 deaths).
Select Safety Profile from the CA184-029 Trial
In the CA184-029 trial, severe to fatal immune-mediated adverse reactions were reported, and included enterocolitis (16%), hepatitis (11%), endocrinopathy (8%), hypopituitarism (7%), dermatitis (4%), neuropathy (1.7%), hyperthyroidism (0.6%), meningitis (0.4%), primary hypothyroidism (0.2%), myocarditis (0.2%), pericarditis (0.2%), pneumonitis (0.2%), and uveitis (0.2%). The most common adverse reactions were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%). Yervoy was discontinued for adverse reactions in 52% of patients.
Filed Under: Drug Discovery