European Commission Approves 4-Week Nivolumab Dosing Schedule in Adjuvant Melanoma

Ralu Vlad, PharmD, development team lead, product design and delivery, Bristol-Myers Squibb

Ralu Vlad, PharmD

The European Commission has approved nivolumab (Opdivo) at a flat dosing schedule of either 240 mg over 30 minutes every 2 weeks, or 480 mg infused over 60 minutes every 4 weeks, for the adjuvant treatment of patients with melanoma who have involvement of lymph nodes or metastatic disease who have undergone complete resection.¹

“The approval of Opdivo two- and four-week flat dosing schedule in the adjuvant melanoma setting is an important milestone for patients across the European Union who now have additional treatment flexibility,” Ralu Vlad, PharmD, development team lead, product design and delivery, Bristol-Myers Squibb, the developer of the PD-1 inhibitor, stated in a press release. “Bristol Myers-Squibb is committed to empowering patients with cancer and their families to regain control of their lives through more flexible treatment options that fit their individual needs.”

The approval follows a positive opinion granted in September 2019 by the European Medicines Agency’s Committee for Medicinal Products for Human Use.

In July 2018, the European Commission approved nivolumab as an adjuvant treatment for adult patients with completely resected melanoma with lymph node involvement or metastatic disease, regardless of BRAF mutation status.

The decision was based on findings from the phase III CheckMate-238 trial, in which the recurrence-free survival rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.7% (95% CI, 47.8%-57.4%) for ipilimumab (Yervoy) in patients with stage IIIB/C or IV melanoma.² There was a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor (HR, 0.65; 95% CI, 0.53-0.80; P <.0001).

Three-year follow-up data from the CheckMate-238 trial presented at the 2019 ESMO Congress were generally consistent with the 18-month findings. The median recurrence-free survival (RFS) with nivolumab was not reached (95% CI, 38.7—not reached) compared with 24.9 months with ipilimumab (95% CI, 16.6-35.1), leading to a 32% reduction in the risk of recurrence or death with the PD-1 inhibitor (HR, 0.68; 95% CI, 0.56-0.82; P <.0001).³ The 3-year RFS rates were 58% and 45% for nivolumab and ipilimumab, respectively.

The RFS benefit was observed across most prespecified subgroups, except for those with stage IV M1c disease (HR, 1.02; 95% CI, 0.40-2.57). Moreover, data from biomarker analyses showed that high tumor mutational burden and tumor inflammation biomarkers, lower levels of peripheral suppressive immune cells, as well as combinations of these biomarkers, correlated with improved RFS with both nivolumab and ipilimumab.

Furthermore, in April 2018, the European Commission granted an approval to the every-4-week dose of single-agent nivolumab infused over 60 minutes for patients with advanced melanoma and previously treated renal cell carcinoma. At this time, the European Commission also approved the every-2-week 240-mg dosing option that is infused over 30 minutes for all 6 approved monotherapy indications in the European Union.

Additionally, in March 2018, the FDA approved a supplemental biologics license application adding a 4-week dosing schedule for nivolumab across several of the PD-1 inhibitor's indications:

• Metastatic melanoma (monotherapy or monotherapy phase after combination treatment with ipilimumab)
• Previously treated metastatic non—small cell lung cancer (NSCLC)
• Advanced renal cell carcinoma (RCC) following prior antiangiogenic therapy
• Previously treated locally advanced or metastatic urothelial carcinoma following disease progression during or after platinum-based chemotherapy
• Classical Hodgkin lymphoma following relapse/progression after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or three or more lines of systemic therapy that includes autologous HSCT
• Recurrent/metastatic squamous cell carcinoma of the head and neck following platinum-based therapy
• Hepatocellular carcinoma after prior sorafenib therapy
• Adjuvant therapy for patients with completely resected melanoma with lymph node involvement or metastatic disease.

Data that were presented at the 2017 AACR Annual Meeting indicated that safety and efficacy would be similar between a nivolumab dosing schedule of 480 mg every 4 weeks compared with 3 mg/kg every 2 weeks.⁴ Using quantitative clinical pharmacology analyses and safety assessments, the investigators examined the predicted risk/benefit profile of the less frequent 480-mg regimen relative to the 3-mg/kg regimen.

Among the patients with melanoma, NSCLC, or RCC, results showed a <1% difference in the predicted probability of achieving a response. The predicted 1- and 2-year survival probabilities were also similar among patients with these tumor types receiving either of the 2 doses, with differences ranging between 0% to 4.6% at year 1, and 1.9% to 6.9% at year 2.

The FDA first approved nivolumab as a single agent for advanced melanoma in December 2014, as a treatment for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600—positive, a BRAF inhibitor.

References

1. European Commission Approves Opdivo (nivolumab) Four-Week Dosing Schedule for the Adjuvant Treatment of Adult Patients with Melanoma with Involvement of Lymph Nodes or Metastatic Disease Who Have Undergone Complete Resection. Bristol-Myers Squibb. Published October 24, 2019. https://bit.ly/2MI6LpE. Accessed October 24, 2019.
2. 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;377:1824-1835. doi: 10.1056/NEJMoa1709030.
3. Weber J, Del Vecchio M, Mandala M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase 3 CheckMate 238 trial. Ann Oncol. 2019;30(suppl¬_5):v533-v563. doi: 10.1093/annonc/mdz255.
4. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract CT101. doi:10.1158/1538-7445.AM2017-CT101.