Background: Brentuximab vedotin (BV) is an antibody-drug conjugate and is highly 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 (Ibr) is a Bruton tyrosine kinase (BTK) inhibitor active in multiple subtypes of non-Hodgkin lymphoma. Limited data exist regarding its use in HL, but malignant Reed-Sternberg cells can express BTK. Ibr also inhibits IL-2-inducible kinase (ITK) with Th1 based responses which may promote immunogenic cell death in combination with BV. As we previously observed preclinical synergy between Ibr and BV, we hypothesized Ibr may enhance the antitumor activity of BV in HL. We conducted a phase II trial of Ibr plus BV in patients with r/r HL and report here the final primary analysis of safety and efficacy.
Methods: This was a multicenter phase II trial with a 6 patient safety lead-in cohort of BV and Ibr in patients with r/r HL. Eligibility included age > 15 years with r/r HL after at least one prior line of therapy. Prior BV was allowed if patients were not refractory. Treatment consisted of 1.8 mg/kg BV intravenously every 3 weeks and Ibr 560 mg oral daily (420 mg in the lead-in cohort). The primary endpoint was CR rate according to Lugano 2014. Secondary endpoints included toxicity, overall response rate (ORR), and duration of response (DOR).
Results: 39 patients were enrolled; 67% were male and median age was 33. At initial diagnosis 40% had stage III-IV disease and 38% had extranodal disease. 51% were refractory to most recent therapy, and 21% had prior BV. Of 36 evaluable patients, CR rate was 33%, ORR 64%, and median DOR 25.5 months (range); median number of cycles received was 5. Most common adverse events of any grade were nausea (67%), diarrhea (59%), peripheral neuropathy (62%), fatigue (46%), thrombocytopenia (46%), headache (41%), rash (41%), elevated ALT (38%), anemia (36%), vomiting (36%), abdominal pain (33%), fever (33%), and hypertension (33%). 6 (%) 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 sepsis during cycle 1.
Discussion: The combination of BV and Ibr had similar efficacy to BV monotherapy in patients with r/r HL, but with additional toxicity compared to BV alone.