Combination Regimen Safe, Effective as Salvage Therapy for Relapsed/Refractory Hodgkin Lymphoma

Alex Herrera, MD

Brentuximab vedotin (Adcetris) plus nivolumab (Opdivo) appeared active and well tolerated for the treatment of patients with relapsed/refractory Hodgkin lymphoma (HL), according to phase I/II study results presented at the 2017 ASH Annual Meeting.

Brentuximab vedotinan antibody-drug conjugate directed against CD30, a receptor expressed by malignant Reed-Sternberg (RS) cells present in the inflammatory/immune cell microenvironment of classical HLhas the potential to prime an antitumor immune response. This is possible through the microtubule disruption of CD30-expressing RS cells.

In conjunction, nivolumab has the ability to block PD-1 receptors, inhibit binding of PD-1 ligands, and restore an antitumor response. Therefore, targeted killing of CD30-expressin RS cells concurrent with the restoration of the immune response may improve outcomes in patients with relapsed/refractory HL. In addition, this combination regimen could elongate durability of responses following autologous stem cell transplantation (ASCT).

“Brentuximab vedotin and nivolumab are effective single-agent treatments for relapsed or refractory HL,” said Alex F. Herrera, MD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope. “We hypothesized brentuximab vedotin in combination with nivolumab may be an active salvage regimen for relapsed or refractory HL, offering patients an alternative to traditional chemotherapy.”

In the open label, multicenter trial, researchers evaluated brentuximab vedotin in combination with nivolumab in 21-day cycles for up to 4 cycles. Patients received 1.8 mg/kg brentuximab vedotin on day 1 of cycle 1 and 3 mg/kg nivolumab on day 8 of cycle 1. They were then given the same dose of both agents on day 1 of cycles 2 through 4. After the cycle 4 assessment, patients were eligible to undergo ASCT.

Safety, adverse event (AE) incidence and severity, and complete response (CR) rate served as the primary endpoints. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) post-ASCT, overall PFS, and biomarker analyses.

In parts 1 and 2 of the trial, 62 patients with classical HL who had relapsed or were refractory to frontline chemotherapy were enrolled. Of those enrolled, 61 patients received the combination regimen; however, only 58 patients completed treatment. Four study discontinuations were caused by patient decision (n = 2), AE (n = 1, peripheral neuropathy), and investigator decision (n = 1). Median age was 36 years, 52% were female, and 90% had received frontline chemotherapy. Overall, 45% of patients had primary refractory disease and 31% experienced relapse within 1 year of chemotherapy.

AEs were recorded from the start of treatment through 100 days after the last dose of the regimen, including the ASCT period. Sixty patients (98%) experienced AEs, including 40 who experienced grade 1/2 AEs and 19 with grade 3/4 AEs.

Infusion-related reactions (IRRs) occurred in 41% of patients during a brentuximab vedotin infusion. These IRRs occurred most frequently during cycle 2 of infusion. However, no patients discontinued treatment due to IRRs. Excluding IRRs, potential immune-related AEs occurred in 82% of patients, but again, no patients discontinued treatment as a result.

Of the 60 patients evaluable for efficacy, ORR was 83% (95% CI, 72-92), including 37 CRs (62%; 95% CI, 48-74) and 13 partial responses (22%; 95% CI, 12-34). Five patients (8%) had stable disease, 4 patients (7%) progressed on treatment, and 1 patient (2%) had clinical improvement.

At the time of analysis, 54 patients initiated ASCT. Treatment with the combination regimen did not appear to impact stem cell mobilization and collection yields or engraftment, and patients did not appear to have increased toxicity during or after the transplant period. Forty-one patients with ASCT plus the combination regimen and 16 patients with salvage therapy plus the combination regimen remain in follow-up. Median follow-up is 8 months and median DOR was not reached. Six-month PFS was 89% (95% CI, 75-95).

The researchers used peripheral blood immunophenotyping, serum cytokine/chemokine analyses, T-cell receptor sequencing, and intracellular cytokine staining to determine the combination’s effect on the immune system.

The combination increased circulating T cell numbers, and increased innate and adaptive immune activating cytokines and chemokines. The regimen also increased the ability of memory T cells to mount an immune response.

Because of this “encouraging activity” from brentuximab vedotin plus nivolumab, the combination will be further studied in multiple settings, including a pivotal phase III trial in patients with advanced HL who are ineligible for ASCT or after failure of ASCT, Herrera said.

Herrera AF, Moskowitz AJ, Bartlett NL, et al. Results from a phase I/II study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory hodgkin lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 649.