Early data from a phase I/II study suggest that the combination of brentuximab vedotin and nivolumab may be an active and well-tolerated outpatient regimen in patients with relapsed/refractory classical Hodgkin lymphoma after failure of standard frontline chemotherapy.
Alex Herrera, MD
Early data from a phase I/II study suggest that the combination of brentuximab vedotin (Adcetris) and nivolumab (Opdivo) may be an active and well-tolerated outpatient regimen in patients with relapsed/refractory classical Hodgkin lymphoma (HL) after failure of standard frontline chemotherapy.
The findings were reported by Alex Herrera, MD, assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation and a hematologist/oncologist at City of Hope, at the 2016 ASH Annual Meeting.
“The overall response rate to the combination of brentuximab vedotin and nivolumab as a second-line therapy for Hodgkin lymphoma was 90%,” Herrera said. “The complete response rate was 62%, and the partial response rate was 28%.”
To date, 42 patients have been enrolled in the study; 60% are women, and the median age of all participants is 32 (range, 18-69 years). Eligible patients had an ECOG performance status of 0 or 1, and patients were excluded if they received more than 1 line of anticancer therapy, autologous stem cell transplant (ASCT), or had prior treatment with brentuximab vedotin or any immuno-oncology therapy affecting the PD-1, CTLA4, or CD137 pathways.
At study entry, 40% of patients were primary refractory, 33% relapsed after a remission lasting ≤1 year, and 26% of the cohort relapsed after a remission lasting more than 1 year. The majority (88%) of the cohort’s prior chemotherapy regimens were ABVD (adriamycin or doxorubicin, bleomycin, vinblastine, and dacarbazine).
Patients were treated in 21-day cycles for up to 4 cycles. During the first cycle, 1.8 mg/kg brentuximab vedotin was given on day 1, followed by 3 mg/kg nivolumab on day 8. In the subsequent 3 cycles, both drugs were administered at the same doses on day 1. After cycle 4, treatment response and progression were assessed using the Lugano Classification Revised Staging System for malignant lymphoma, at which time patients were eligible to undergo ASCT.
At the September 15, 2016, data cutoff for this presentation, all of the 42 patients in the study had received at least 1 dose of the study drugs, 12 remained on treatment, 28 patients had completed the regimen, and 2 had discontinued, but not as a result of an adverse event (AE), Herrera noted.
A median of 4 doses of the brentuximab vedotin plus nivolumab regimen were administered; no patients had dose reductions, but 3 doses of brentuximab vedotin were delayed, and 4 nivolumab delays were reported. Herrera attributed these delays to uticaria, chills, hypoxia, thrombosis, and elevated lipase. All dose interruptions11 for brentuximab vedotin and 3 for nivolumab—were due to infusion-related reactions (IRRs). Patients were managed with supportive care, and the infusions could be reinitiated and completed.
IRRs, largely grade 1 or 2, occurred in 38% of patients. The researchers initiated a prophylactic safety protocol involving premedication with low-dose corticosteroids and antihistamines, and Herrera explained that although this measure did not impact the rate or severity of IRRs, no patients discontinued treatment as a result of them. Fatigue (37%), nausea (26%), pruritis (17%), and rash (22%) were the most common AEs; very few grade 3 AEs were reported.
Among the immune-related AEs (irAEs), there was 1 grade 3 transaminase elevation. “Other irAEs were grade 1 and 2 and occurred in a minority of patients,” said Herrera. These include hypothyroidism, transaminase elevation, diarrhea, rash, and infusion-related reaction. No occurrences of pneumonitis or colitis were reported.
Preliminary biomarker data were also collected and suggest a brentuximab vedotin-induced decrease in the percentage of CD4+ T regulatory (Treg) cells at C1D8, the researchers reported. Herrera said that the preliminary biomarker findings suggest that there didn’t appear to be any antagonism between brentuximab vedotin and nivolumab. Additional tissue-based biomarkers and immune assays are planned, Herrera said.
“The promising activity of [brentuximab vedotin] and nivo in combination supports further exploration of this chemotherapy-free regiment for relapsed/refractory patients,” concluded Herrera. “The overall safety profile is manageable with no dose reductions or discontinuations due to AEs; the incidence of immune-related AEs is also low.”
Part 2 of the study will further characterize safety and evaluate the antitumor activity of brentuximab vedotin combined with nivolumab and is currently recruiting patients (NCT02572167).
Herrera AF, Bartlett NL, Ramchandren R, et al. Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 1105.