The hypothesis is that we can use an antibody-drug conjugate to target the tumor cells to increase cytotoxicity and antigen release and then use an immune-modulating agent to activate cells of the microenvironment.— Catherine S. Diefenbach, MD
Response rates of 90% to 100% were achieved in early studies evaluating the combination of brentuximab vedotin (Adcetris) and nivolumab (Opdivo) in relapsed or refractory classical Hodgkin lymphoma. The findings were presented at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition by Catherine S. Diefenbach, MD, of New York University Perlmutter Cancer Center,1 and Alex F. Herrera, MD, of City of Hope National Medical Center, Duarte, California.2
Brentuximab vedotin is an antibody-drug conjugate directed against the CD30 receptor that is expressed on Hodgkin/Reed-Sternberg tumor cells. The interaction between Reed-Sternberg cells and immune cells in the tumor microenvironment promote tumor growth. Nivolumab, a monoclonal antibody against programmed cell death protein 1 (PD-1), restores antitumor immune response and prevents tumor-immune evasion. Both agents have high single-agent activity in patients with relapsed or refractory Hodgkin lymphoma and may be synergistic in combination, the investigators explained.
“Hodgkin lymphoma has a unique biology in which a small number of malignant Hodgkin/Reed-Sternberg cells propagate an immunosuppressive microenvironment. Unlike most cancers, which grow in sheets of tumor cells, in Hodgkin lymphoma, you have less than 1% of Reed-Sternberg cells per high-powered field, and they are surrounded by cells of the immune system (macrophages, dendritic cells, T cells). It is this interaction that comprises the tumor itself, not the Reed-Sternberg cells in isolation,” Dr. Diefenbach explained.
“The hypothesis is that we can use an antibody-drug conjugate to target the tumor cells to increase cytotoxicity and antigen release and then use an immune-modulating agent to activate cells of the microenvironment. Doing this, we can turn the cells of the microenvironment from tumor-tolerant to tumor-cytotoxic,” she said.
Phase I E4412 Trial
Dr. Diefenbach presented preliminary findings from two arms of the phase I dose escalation and expansion E4412 trial evaluating the combination of brentuximab vedotin and nivolumab in patients with relapsed/refractory Hodgkin lymphoma. Patients were treated with nivolumab at 3 mg/kg and brentuximab vedotin at 1.2 mg/kg or 1.8 mg/kg. The two drugs were given together every 21 days for 16 cycles; nivolumab could be continued for an additional year.
Dr. Diefenbach reported on 19 patients, who had received a mean of 3 prior systemic therapies; 43% had received prior autologous (32%) or allogeneic (11%) transplant, and 21% had received brentuximab vedotin.
Twelve patients were evaluable for response. All 12 (100%) responded to the combination, and 8 (66%) achieved a complete response, including patients with prior brentuximab vedotin treatment, Dr. Diefenbach reported.
In a heavily pretreated patient population, 20% of whom had had prior brentuximab vedotin and 42% of whom had a stem cell transplant, the response rate of 100% and the complete response rate of 66% suggest the combination is “highly active” and produces “a deepening of response compared to either therapy alone,” she commented.
Dr. Diefenbach acknowledged that the follow-up time is very short. At a median follow-up of 4.7 months, median progression-free survival is 8.5 months and only two patients have disease progression (the analysis includes one death from pneumonitis and another treatment discontinuation unrelated to treatment or disease). Median overall survival has not been reached. “Obviously, longer follow-up is required to evaluate the durability of progression-free survival in the partial and complete responders,” she added.
The concurrent administration of the drugs was well tolerated. Immune-related toxicities were primarily grades 1 and 2; elevation of hepatic enzymes was most common (> 50%) but transient, and peripheral neuropathy was also common (> 40%). Two patients, however, developed pneumonitis, one of which was grade 5 in a heavily pretreated elderly patient, and the other grade 3 (along with typhlitis and dyspnea) in a second elderly patient, who made a full recovery. These observations emphasize the need to proceed cautiously in older patients, noted Dr. Diefenbach.
Dr. Diefenbach called E4412 a “proof-of-concept study, for the optimization of checkpoint inhibition and antibody-drug conjugate strategies.” She and her team believe that this approach may be further optimized by the addition of ipilimumab (Yervoy), and one arm of the ongoing E4412 study is currently accruing patients to that triplet therapy.
Alex F. Herrera, MD
Dr. Herrera presented the results of an ongoing phase I/II study that is evaluating the safety and antitumor activity of brentuximab vedotin administered in combination with nivolumab as first salvage therapy in patients who relapsed after standard front-line chemotherapy (patients were excluded if they had received more than one line of therapy, prior brentuximab vedotin, or prior stem cell transplant).
Patients were treated in 21-day cycles for up to 4 cycles (12 weeks), receiving 1.8 mg/kg of brentuximab vedotin on day 1 of cycle 1 and 3 mg/kg of nivolumab on day 8 of cycle 1. For cycles 2 through 4, brentuximab vedotin and nivolumab were administered concurrently on day 1. After completion of the cycle 4 response assessment (Lugano Classification Revised Staging System), patients were eligible to undergo autologous stem cell transplant (ASCT).
The current analysis included 42 patients who had received at least 1 dose, of whom 40% had primary refractory disease, 33% had relapsed within 1 year, and 26% had relapsed after 1 year or longer in remission. Treatment was completed by 67%, whereas 29% remained on treatment. Two patients (5%) discontinued therapy prior to the end of treatment, 9 (21%) initiated ASCT, and 2 (5%) received alternative salvage therapy prior to ASCT.
Preliminary efficacy was evaluated in 29 patients, of whom 26 (90%) had an objective response and 18 (62%) had a complete response. The majority of complete responders had a Deauville score of 1 or 2, Dr. Herrera reported.
Peripheral blood immunophenotyping revealed a relatively high proportion of CD30-positive regulatory T cells at baseline. No effect was seen on total CD4-positive cells with single-agent brentuximab vedotin at cycle 1, but after receipt of nivolumab, an increase in activated and dividing CD4-positive cells was observed. There also appeared to be a decrease in immunosuppressive regulatory T cells after brentuximab vedotin alone, during cycle 1. Minimal change was observed in total CD8-positive cells in the peripheral blood after brentuximab vedotin treatment during cycle 1, but after combination therapy, an expansion of dividing CD8-positive cells was observed.
“The effect of these observations on the tumor immune microenvironment is unknown. Functional assays and additional tissue-based correlative studies are planned,” Dr. Herrera revealed. The preliminary biomarker results indicate, however, no antagonism between brentuximab vedotin and nivolumab and a decrease in T regulatory cells with brentuximab vedotin.
The overall safety profile was manageable, with no dose reductions or discontinuations due to adverse events. The incidence of immune-related adverse events was also low, he reported.
Adverse events emerging prior to ASCT were mostly grade 1 or 2. Three patients (7%) experienced peripheral sensory neuropathy, all grade 1. One patient experienced a treatment-related serious adverse event with brentuximab vedotin after cycle 1. No patients developed pneumonitis or colitis.
Infusion-related reactions occurred in 38% overall, most commonly flushing, nausea (14% each); chest discomfort, dyspnea, urticaria (12% each); cough and pruritus (10% each). The protocol was amended to require premedication with low-dose corticosteroids and antihistamine at cycles two and three; however, this change did not impact the rate or severity of infusion-related reactions. “No patients, however, discontinued treatment due to an infusion-related reaction,” noted Dr. Herrera.
Nine patients proceeded to ASCT. In this preliminary analysis, the combination of brentuximab vedotin and nivolumab appeared to have no impact on stem cell mobilization or engraftment of neutrophils or platelets. ■
Disclosure: Dr. Diefenbach has served as a consultant to Seattle Genetics and Bristol-Myers Squibb and has received research funding from Seattle Genetics, Bristol-Myers Squibb, Merck, Genentech, Incyte, LAM Therapeutics, Molecular Templates, and OncoMed. Dr. Herrera has received research funding from Pharmacyclics, Merck, Immune Design, Genentech, Adaptive Biotechnologies, and Seattle Genetics.
1. Diefenbach CS, Hong F, David KA, et al: A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: A trial of the ECOG–ACRIN Cancer Research Group (E4412 Arms D and E). 2016 ASH Annual Meeting. Abstract 1106. Presented December 5, 2016.
2. 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. 2016 ASH Annual Meeting. Abstract 1105. Presented December 5, 2016.