Two separate studies are investigating brentuximab vedotin plus nivolumab combination therapy for adults with Hodgkin lymphoma: one as first-line therapy and another as salvage therapy for relapsed/refractory classic disease, according to data presented at the 2019 Annual Meeting & Exposition of the American Society of Hematology (ASH).^1,2 The combination seems to be less toxic than commonly used chemotherapy regimens for Hodgkin lymphoma, and experts interviewed at the meeting were enthusiastic about its potential.

First-Line Therapy

Christopher Yasenchak, MD

“Older patients with Hodgkin lymphoma are underrepresented in clinical trials. Brentuximab vedotin and nivolumab have high responses as single agents in relapsed or refractory Hodgkin lymphoma. We studied this combination in adults with Hodgkin lymphoma aged 60 and older,” said lead study author Christopher Yasenchak, MD, of the Willamette Valley Cancer Institute and Research Center, Eugene, Oregon.

“Our findings show that brentuximab vedotin/nivolumab represents a good regimen for treatment-naive older patients with Hodgkin lymphoma who are ineligible for chemotherapy,” Dr. Yasenchak stated.¹ The study was small, just 21 patients, but it suggests this regimen may prove to be an effective option in the first-line treatment of older patients who cannot tolerate or decline chemotherapy.

Study Details: Of patients enrolled in the trial, 95% had am Eastern Cooperative Oncology Group performance score of 0 or 1, measurable disease of various histologic subtypes, no evidence of autoimmune disease, and were ineligible for or declined conventional chemotherapy. The median age of patients was 72. A total of 77% had stage III/IV disease, and 57% presented with B symptoms at baseline. In this elderly population, 48% had bulky disease, and 38% had extranodal disease at diagnosis.

Patients received brentuximab vedotin at 1.8 mg/kg plus nivolumab at 3 mg/kg as well as prophylactic premedication for infusion-related reactions on day 1 of each 3-week cycle for up to 16 cycles. Computed tomography (CT)/positron-emission tomography scans were performed at cycles 2 (CT alone), 4, 8, 12, and 16. The median number of treatment cycles with brentuximab vedotin/nivolumab was 10.

Key Findings: In 18 evaluable patients, the objective response rate was 100%, and the complete response rate was 72%. All evaluable patients experienced some degree of tumor shrinkage. At a median follow-up of 6.8 months, the median duration of response was not reached.

The incidence of grade 3 or higher treatment-related adverse events was 57%; grade 3 peripheral neuropathy was reported in 52%. Immune-related adverse events requiring steroids were reported in 14% and resolved with appropriate therapy.

Matthew Mei, MD

Study Commentary: “The results of this study are compelling,” said Matthew Mei, MD, of City of Hope, Duarte, California. “The toxicity was manageable for brentuximab vedotin plus nivolumab in these older patients. Some older patients can tolerate potentially curative chemotherapy with ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine], but the conundrum is how to treat those who are not good candidates due to toxicity, especially those with cardiac problems. These results are encouraging, but we don’t yet know about survival with brentuximab vedotin/nivolumab.”

Dr. Mei continued: “Ultimately, the optimal way to treat these patients is an unanswered question. However, for older patients who cannot tolerate ABVD-like regimens, there is no question in my mind that a novel therapy–based regimen is preferable as front-line therapy.”

Salvage Therapy

A second presentation focused on longer-term follow-up of a single-arm phase I/II study of adults with relapsed or refractory classic Hodgkin lymphoma after one previous line of therapy.² An interim report of this study was published in 2018 using two different schedules of brentuximab vedotin and nivolumab (staggered and concurrent).³ The overall efficacy and tolerability were similar for both dosing schedules, so results were combined for the longer-term analysis presented at ASH, explained lead study author Alison J. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, New York.

Alison J. Moskowitz, MD

“In my opinion, the high objective response rate and complete response rate support the use of brentuximab vedotin/nivolumab as second-line therapy for relapsed or refractory Hodgkin lymphoma,” Dr. Moskowitz said.

Study Details and Results: The study included 91 patients who were treated with four cycles of brentuximab vedotin/nivolumab before consideration for autologous stem cell transplantation (ASCT). The median age of patients was 34 years (range, 18–69 years). A total of 25% of patients had extranodal sites of disease; 42% were considered primary refractory; 30% relapsed within the first year of treatment.

The objective response rate was 85%, and the complete response rate was 67%. About 75% went on to ASCT after brentuximab vedotin/nivolumab. A total of 22% received salvage therapy, 17 of whom went on to ASCT. Of 91 patients, 84 proceeded to ASCT.

At a median follow-up of 22.6 months, the estimated 2-year progression-free survival was 78% in all treated patients. For patients who underwent ASCT after treatment with brentuximab vedotin/nivolumab, the estimated progression-free survival was 91%. The estimated 2-year overall survival was 94% in all treated patients.

A total of 13 patients experienced immune-related adverse events that required steroids, but no patient discontinued treatment. Infusion-related reactions were common. Most infusion-related reactions were grades 1 and 2, and “premedication did not seem to change this,” added Dr. Moskowitz.

Treatment with brentuximab vedotin/nivolumab was associated with an increase in activating and dividing CD8-positive T cells, regulatory T cells, and circulating plasma blasts in blood. There appeared to be no association between the magnitude of these changes and clinical response.

Additional Study Commentary: Dr. Mei, who had two patients on this trial, provided some thoughts on the use of brentuximab vedotin/nivolumab as salvage therapy. “For patients with Hodgkin lymphoma who are not cured by front-line therapy, the standard of care remains cytotoxic chemotherapy followed by ASCT in responders to chemotherapy. At this point, many patients could be bridged to transplant with brentuximab vedotin alone. However, in this study, there were excellent responses—almost 70% complete responses. Brentuximab vedotin/nivolumab was at least as good as a cytotoxic regimen with less toxicity, in this study. The numbers are small, and we need a phase III study, but with fairly mature follow-up, the toxicity is minimal compared with cytotoxic chemotherapy,” Dr. Mei said. 

DISCLOSURE: Dr. Yasenchak reported financial relationships with Bristol-Myers Squibb and Seattle Genetics. Dr. Mei has served as a consultant for Sanofi Genzyme. Dr. Moskowitz reported financial relationships with Erytech Pharma, Merck, Incyte, Cell Medica, Takeda Pharmaceuticals, ADC Therapeutics, Bristol-Myers Squibb, Kyowa Hakko Kirin Pharma, and Seattle Genetics and has served as a consultant for miRagen Therapeutics.

REFERENCES

1. Yasenchak CA, et al: Phase 2 study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin lymphoma aged ≥ 60 years. 2019 ASH Annual Meeting & Exposition. Abstract 237. Presented December 7, 2019.

2. Moskowitz AJ, et al: Brentuximab vedotin and nivolumab for relapsed or refractory classic Hodgkin lymphoma. 2019 ASH Annual Meeting & Exposition. Abstract 238. Presented December 7, 2019.

3. Herrera AF, et al: Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 131:1183-1194, 2018.