August 22, 2023

Kristi Rosa

The European Commission has approved single-agent nivolumab for use in the adjuvant treatment of adult and adolescent patients aged 12 years or older who have stage IIB or IIC melanoma and who have undergone complete resection.

Peter Mohr, MD

Peter Mohr, MD

The European Commission has approved single-agent nivolumab (Opdivo) for use in the adjuvant treatment of adult and adolescent patients aged 12 years or older who have stage IIB or IIC melanoma and who have undergone complete resection.1

The regulatory decision is supported by findings from the phase 3 CheckMate-76K trial (NCT04099251). At a minimum follow-up of 7.8 months, the immunotherapy reduced the risk of disease recurrence or death by 58% compared with placebo in this population, with 12-month recurrence-free survival (RFS) rates of 89% (95% CI, 86%-92%) and 79% (95% CI, 74%-84%), respectively (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). Notably, the RFS benefit derived with nivolumab spanned predefined subsets, including T category and disease stage.

“Patients with stage IIB or IIC melanoma are at a high risk of disease recurrence following surgery. This can be a very impactful event for patients,” Peter Mohr, MD, chief physician and head of the Skin Cancer Center, Buxtehude, in the Department of Dermatology, at Elbe-Kliniken, in Germany, stated in a press release. “This approval reinforces the benefit that nivolumab may offer when used after resection, potentially preventing the disease from recurring.”

The double-blind phase 3 trial enrolled patients with histologically confirmed, resected, stage IIB or IIC cutaneous melanoma who had not received prior treatment for their disease, had a negative sentinel lymph node biopsy, and an ECOG performance status of 0 or 1.2

Those with a history of ocular or mucosal melanoma, with known or suspected autoimmune disease, a history of allergy or hypersensitivity to any components of study treatment, or prior receipt of a PD-1, PD-L1, PD-L2, CD137, CTLA-4 antibody, were excluded. Patients also could not have prior exposure to drugs targeting interleukin-2 pathways, T-cell stimulators, or checkpoint pathways.

Study participants were randomly assigned to nivolumab at 480 mg every 4 weeks for up to 1 year or placebo.

In addition to RFS representing the primary end point of the research, secondary end points comprised overall survival, distant metastasis-free survival, progression-free survival on next-line therapy, and safety.

Additional data from CheckMate-76K were presented at the 2022 Society for Melanoma Research Annual Meeting and showed that when broken down by disease stage, the 12-month RFS rates in those with stage IIB disease were 93% with the immunotherapy vs 84% with placebo; in those with stage IIC disease, these rates were 84% and 72%, respectively.3

The safety of single-agent nivolumab was evaluated in a pooled population of 4646 patients spanning tumor types.1 At a minimum follow-up that ranged from 2.3 months to 28 months, the most common toxicities experienced by at least 10% of patients included fatigue (44%), musculoskeletal pain (28%), diarrhea (26%), rash (24%), cough (22%), nausea (22%), pruritus (19%), reduced appetite (17%), arthralgia (17%), constipation (16%), dyspnea (16%), abdominal pain (15%), upper respiratory tract infection (15%), pyrexia (13%), headache (13%), anemia (13%), and vomiting (12%). Most effects were grade 1 or 2 in severity.

This approval builds on a prior approval issued by the European Commission in July 2018 for the use of adjuvant nivolumab in adult patients with completely resected melanoma with lymph node involvement or metastatic disease, irrespective of BRAF mutational status.4

That decision had been supported by data from the phase 3 CheckMate-238 trial (NCT02388906), which had shown that the 12-month RFS rate achieved with nivolumab (n = 453) was higher than that derived with ipilimumab (Yervoy; n = 453) in patients with resected stage III or IV melanoma, at 70.5% (95% CI, 66.1%-74.5%) and 60.8% (95% CI, 56.0%-65.2%), respectively (HR, 0.65; 97.56% CI, 0.51-0.83; P < .001).5

Updated data from the trial published in The Lancet Oncology showed that at a median follow-up of 51.1 months (interquartile range [IQR], 41.6-52.7) with nivolumab and 50.9 months (IQR, 36.2-52.3) with ipilimumab, the 4-year RFS rates were 51.7% (95% CI, 46.8%-56.3%) and 41.2% (95% CI, 36.4%-45.9%), respectively (HR, 0.71; 95% CI, 0.60-0.86; P = .0003).6

“With this [new] approval, we can now offer patients in the European Union with stage IIB or IIC resected melanoma an efficacious treatment option that significantly reduced the risk of disease recurrence,” Gina Fusaro, PhD, vice president and global program lead at Bristol Myers Squibb, added in the press release. “This approval builds on our longstanding commitment to bring innovative medicines to patients across the cancer spectrum, including in earlier stages of cancer. We thank all the patients, researchers, and physicians who were involved along the way to help make this additional option for patients possible.”

References

  1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) as an adjuvant treatment for patients with completely resected stage IIB or IIC melanoma. News release. Bristol Myers Squibb. August 22, 2023. Accessed August 22, 2023. https://news.bms.com/news/details/2023/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab-as-an-Adjuvant-Treatment-for-Patients-with-Completely-Resected-Stage-IIB-or-IIC-Melanoma/default.aspx

  2. Effectiveness study of nivolumab compared to placebo in prevention of recurrent melanoma after complete resection of stage IIB/C melanoma (CheckMate76K). ClinicalTrials.gov. Updated July 27, 2023. Accessed August 22, 2023. https://clinicaltrials.gov/study/NCT04099251

  3. Bristol Myers Squibb presents data from CheckMate -76K showing Opdivo (nivolumab) reduced the risk of recurrence or death by 58% versus placebo in patients with completely resected stage IIB or IIC melanoma. News release. Bristol Myers Squibb. October 19, 2022. Accessed August 22, 2023. https://news.bms.com/news/corporate-financial/2022/Bristol-Myers-Squibb-Presents-Data-from-CheckMate--76K-Showing-Opdivo-nivolumab-Reduced-the-Risk-of-Recurrence-or-Death-by-58-Versus-Placebo-in-Patients-with-Completely-Resected-Stage-IIB-or-IIC-Melanoma/default.aspx

  4. European Commission approves Bristol-Myers Squibb’s Opdivo (nivolumab) for the adjuvant treatment of adult patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. News release. Bristol Myers Squibb. July 31, 2018. Accessed August 22, 2023. https://news.bms.com/news/corporate-financial/2018/European-Commission-Approves-Bristol-Myers-Squibbs-Opdivo-nivolumab-for-the-Adjuvant-Treatment-of-Adult-Patients-with-Melanoma-with-Involvement-of-Lymph-Nodes-or-Metastatic-Disease-Who-Have-Undergone-Complete-Resection/default.aspx

  5. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835. doi:10.1056/NEJMoa1709030

  6. Ascierto PA, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(11):1465-1477. doi:10.1016/S1470-2045(20)30494-0