EMA Action Brings Nivolumab Closer to First Hematology Approval

Jean Viallet, MD

The European Medicines Agency (EMA) validated an application for use of nivolumab (Opdivo) for previously treated patients with classical Hodgkin lymphoma (cHL), which officially begins the centralized review process for final approval of the drug in the European Union (EU).

The EMA will be evaluating nivolumab primarily based on data from the phase II CheckMate-205 trial, which is evaluating nivolumab in both newly diagnosed and previously treated patients with cHL. Results from the study will likely be presented at a scientific meeting later this year, according to Bristol-Myers Squibb (BMS), the developer of the drug.

“We are eager to continue to extend the use of Opdivo as a treatment option and potentially provide hematology with its first PD-1 inhibitor, a type of treatment that is designed to work with the PD-1 pathway and leverage the immune system to help fight classical Hodgkin lymphoma,” said Jean Viallet, MD, oncology global clinical research lead at BMS. “We are hopeful to build on expanding our hematology franchise and bring the science of immuno-oncology to these adult relapsed and refractory classical Hodgkin lymphoma patients in Europe who often have limited remaining treatment options.”

The multicohort, open-label phase II CheckMate-205 study has an estimated enrollment of nearly 300 patients with an ECOG performance status of 0 or 1. All previously treated patients must have received prior high-dose conditioning chemotherapy followed by autologous stem cell transplant as a part of salvage therapy for cHL. Prior brentuximab vedotin (Adcetris) treatment is allowed, but not required.

Individuals enrolled in 1 of the study’s 3 pretreated patient cohorts will receive 3 mg/kg of nivolumab as an IV injection every 2 weeks. The treatment-naïve patient cohort will receive 240 mg of nivolumab as an IV injection every 2 weeks plus 25 mg/m² of doxorubicin, 6 mg/m² of vinblastine, and 375 mg/m² of dacarbazine. The primary outcome measures are overall response rate (ORR) and safety.

Phase I data for single-agent nivolumab in cHL were previously reported at the 2015 ASH Annual Meeting. In 1 study (CA209-039), 23 patients with relapsed/refractory cHL received nivolumab at weeks 1 and 4, and then every 2 weeks for up to 2 years or until disease disease progression or unacceptable toxicity.¹

At a median follow-up of 86 weeks (range, 32-107 weeks) the ORR was 87% (n = 20), including 6 complete responses (CR) and 14 partial responses. Fifty percent of the responders had durable responses as defined by the study protocol.

The time to CR ranged from 3 to 88 weeks following initiation of nivolumab therapy, including 2 patients whose PRs converted to a CR. Of the 20 responses, 75% (n = 15) occurred within 16 weeks of starting treatment, including 5 patients who proceeded to stem cell transplant (1 CR, 4 PR). Three patients had a best overall response of stable disease.

Three patients discontinued nivolumab due to adverse events (AEs), including grade 2 peripheral neuropathy, grade 3 myelodysplastic syndrome, and grade 3 pancreatitis. Grade 1 or 2 immune-related AEs (IR-AEs) occurred in 4 of 10 evaluated patients, and resolved without treatment in 2 patients. The researchers noted that there was no correlation between time on treatment and an increased rate of IR-AEs.

A second study presented at the 2015 ASH Annual Meeting² retrospectively evaluated single-agent nivolumab in 12 patients with Hodgkin lymphoma who relapsed following allogeneic stem cell transplantation (allo-SCT). Patients had received a median of 9 (range, 7-11) prior systemic therapies, including allo-SCT. Nivolumab was dosed at 3 mg/kg every 2 weeks.

At a median follow-up of 60 days, 9 patients remained on treatment, 1 patient discontinued therapy due to progressive disease, and 2 patients stopped treatment due to GVHD. Among 8 evaluable patients, the ORR was 87.5% (n = 7), including 3 CRs and 5 PRs.

Nivolumab has regulatory approval in 48 countries, including the United States, the EU, and Japan. In the EU, the PD-1 inhibitor has approved indications in melanoma and non—small cell lung cancer.

References

1. Ansell S, Armand P, Timmerman JM , et al. Nivolumab in patients (Pts) with relapsed or refractory classical hodgkin lymphoma (R/R cHL): clinical outcomes from extended follow-up of a phase 1 study (CA209-039). Blood. 2015;126(23):583.
2. Herbaux C, Gauthier J, Brice P, et al. Nivolumab is effective and reasonably safe in relapsed or refractory hodgkin's lymphoma after allogeneic hematopoietic cell transplantation: a study from the Lysa and SFGM-TC. Blood. 2015;126(23):3979.