Brentuximab Vedotin Plus Ibrutinib in Relapsed and Refractory Hodgkin Lymphoma

Introduction Brentuximab vedotin (BV) is an antibody-drug conjugate that delivers monomethyl auristatin E (MMAE) to CD30+ cells and is safe and effective in relapsed/refractory (r/r) Hodgkin lymphoma (HL). Although most patients respond to BV, only a minority will obtain a complete response (CR), and almost all patients eventually progress.Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor highly active in multiple subtypes of non-Hodgkin lymphoma; limited data exist regarding its use in HL. It irreversibly inhibits interleukin-2-inducible kinase (ITK) with Th1 based immune responses. As we previously observed preclinical synergy between ibrutinib and BV, we hypothesized ibrutinib may enhance the antitumor activity of BV in HL. We designed and conducted a phase II trial of ibrutinib plus BV in patients with R/R HL, and herein report the final primary analysis of safety and efficacy. Methods This was a multicenter phase II trial with a lead-in cohort in patients with r/r HL. Eligibility criteria included age ≥ 15 years with r/r HL after at least one prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Prior BV was allowed if patients were not refractory. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints included toxicities, overall response rate (ORR), and duration of response (DOR). Results 39 patients were enrolled onto the study, of which 67% were male; the median age was 33 (range: 17-71). 38% had extranodal disease at baseline, 51% had advanced stage disease, 51% were refractory to the prior therapy, and 21% had prior BV. Of 36 patients who were evaluable for response, the CR rate was 33% and ORR 64%; median DOR was 25.5 months. 13 patients proceeded to autologous transplant and 3 patients proceeded to allogeneic transplant for consolidation after response. The most common adverse events were nausea (67%), peripheral neuropathy (62%), diarrhea (59%), fatigue (46%), thrombocytopenia (46%), headache (41%), rash (41%), elevated ALT (38%), anemia (36%), vomiting (36%), abdominal pain (33%), fever (33%), and hypertension (33%). Six patients experienced unacceptable toxicity, defined as Gr 3/4 non-hematologic toxicity or non-resolving Gr 3/4 hematologic toxicity including one patient who died of multiorgan failure from suspected COVID-19 infection during cycle 1. Discussion The combination of BV and ibrutinib was active in r/r HL; however, given significant toxicity, it cannot be recommended for future development. MicroAbstract Brentuximab vedotin (BV) is highly active in Hodgkin lymphoma (HL) and is approved as monotherapy for relapsed/refractory (r/r) disease; nonetheless, depth and duration of response to BV monotherapy are limited. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor but also inhibits other tyrosine kinases including interleukin-2-inducible kinase (ITK) and has multiple immunomodulatory effects. We conducted a phase II trial (NCT02744612) of BV with ibrutinib in patients with r/r HL and enrolled 39 patients, 36 of whom were evaluable for response. The primary endpoint was CR with a promising rate considered to be 50%. The median follow-up time was 29.4 months, and the CR rate was 33% and ORR 64%; 2-year OS and PFS were 92% and 36%, respectively while the 2-year CIR was 64%. 6 patients experienced unacceptable toxicity defined as grade 3+ non-hematologic toxicity or grade 3+ hematologic toxicity not resolving to grade 1-2 within 7 days. Ultimately, combination therapy did not appear to be more effective than BV monotherapy but conferred additional toxicity.