Phase 2 Study of Brentuximab Vedotin plus Ibrutinib for Patients with Relapsed/Refractory Hodgkin Lymphoma

JHOP - March 2018 Vol 8, No 1 - CLL & Other B-Cell Malignancies - ASH 2017

 

Brentuximab vedotin (BV), an antibody drug conjugate, selectively delivers the antitubulin agent, monomethyl auristatin E, to CD30+ cells.1 In a multicenter phase 2 trial in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months.1 Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, has demonstrated antitumor activity in B-cell lymphomas.2 As a single agent at standard dose, ibrutinib does not have antitumor activity in the HL cell line. However, standard-dose ibrutinib is synergistic with BV in L428, an HL cell line. Based on this preclinical model, it can be hypothesized that ibrutinib may enhance the antitumor activity of BV in patients with HL. At ASH 2017, the authors reported on an interim analysis of efficacy and safety from a phase 2 trial using the combination of ibrutinib plus BV in patients with R/R HL.3

This was a prospective, multicenter phase 2 trial in patients with R/R HL. Patients were treated with 1.8 mg/kg of BV intravenously every 3 weeks and oral ibrutinib 560 mg daily. Patients could have received prior BV. The primary end point was the CR rate. Secondary end points were toxicities, ORR (CR + partial response [PR]), DOR, BTK/IL-2 inducible T-cell kinase receptor occupancy, and changes in T-cell/B-cell/natural killer–cell subsets in peripheral blood.

At the time of the presentation, 16 patients were evaluable for toxicity, and 13 patients were evaluable for efficacy. At baseline, 50% of the patients were stage III/IV at diagnosis, 50% were primary refractory to induction, 37% were refractory to last therapy, and 4 patients had prior BV (25%). The overall best response (CR+PR) rate was 69% (CR rate, 46%). Stable disease (SD) was noted in 31%, resulting in a disease control rate (CR+PR+SD) of 100%. Treatment with ibrutinib plus BV was well-tolerated, and there were no grade 4 adverse events (AEs). Grade 3 possibly related AEs included neutropenia and hypokalemia. Grade 1 AEs included diarrhea, nausea, fatigue, rash, and thrombocytopenia.

The authors concluded that the combination of BV and ibrutinib is well-tolerated. Although the ORR of 69% may be similar to BV alone, the CR of 46% and disease control rate of 100% appear promising. The study has met its interim analysis end point and warrants further accrual to investigate the final CR rate.


References

  1. Younes A, et al. J Clin Oncol. 2012;30:2183-2189.
  2. Aw A, Brown JR. Drugs Aging. 2017;34:509-527.
  3. Chen RW, et al. ASH 2017. Abstract 738.
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Last modified: March 14, 2018