A Phase II Study of Brentuximab Vedotin for Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas Other Than Anaplastic Large Cell Lymphoma

Introduction

Brentuximab vedotin is an antibody-drug conjugate targeting CD30 that is a transmembrane glycoprotein of the tumor necrosis factor receptor superfamily. CD30 is involved in signal transduction via the activation of the NF-κB pathway and mitogen-activated protein kinases. CD30 is a non-lineage-specific activation marker expressed by B and T cells. Thus, a subset of T-cell lymphomas such as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) as well as B-cell lymphomas such as EB virus positive diffuse large B-cell lymphoma (DLBCL) may also express CD30. Therefore, brentuximab vedotin may have therapeutic activities against CD30-positive non-Hodgkin lymphoma (NHL) like the previously reported promising outcome of Hodgkin and anaplastic large cell lymphoma (ALCL). In this study, we explored the efficacy of brentuximab vedotin as a salvage treatment in CD30-positive NHL other than ALCL. Considering previous studies did not apply the exact definition of CD30 positivity, we enrolled patients only with more than 30% of tumor cells expressing CD30.

Methods

This is a multi-center, phase II study of brentuximab vedotin for relapsed or refractory CD30-positive NHL. All subtypes of NHL could be enrolled into this study except ALCL. The definition of CD30 positivity was CD30 expression in more than 30% of tumor cells by the immunohistochemistry. Brentuximab vedotin was intravenously administered at the dosage of 1.8mg/kg every 3 weeks. Treatment was repeated until documented disease progression or unacceptable toxicity (maximum of 16 cycles). Prior to the enrollment, patients should have relapsed or refractory NHL and measureable disease that was FDG-PET positive. The primary objective was to assess the overall rate of disease control that was defined as the achievement of complete response (CR), partial response (PR) and stable disease (SD). Response evaluation was done after the 2^nd, 4^th, 8^th, 12^th and 16^th cycles according to the 2007 Cheson criteria. The planned number of patients was 33, and the target rate of overall disease control was 40% (α=0.05, β=0.20). In the first stage, the rate should be more than 22% (4/18), and the study was registered at ClinicalTrials.gov (NCT02280785).

Results

33 patients (median age: 56, range: 27 - 73) were enrolled between March 2015 and January 2017. The subtypes were B-cell lymphomas (n=14) and T-cell lymphomas (n=19). B-cell lymphomas consisted of diffuse large B-cell lymphoma (DLBCL, n=11), and primary mediastinal B-cell lymphoma (PMBCL, n=3). T-cell lymphomas included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS, n=8), extranodal NK/T-cell lymphoma (n=7, ENKTL), angioimmunoblastic T-cell lymphoma (AITL, n=2) and Mycosis fungoides (MF, n=2). All patients were heavily pre-treated after relapse or progression, thus, the median number of prior therapies was three (2 - 10). Seven patients relapsed even after autologous stem cell transplantation. At the time of enrollment, 23 patients were refractory to previous salvage treatments and 10 patients had relapsed disease. 79% of patients (26/33) had stage III/IV and the median percentage of CD30 expression was 50% (range: 30-100%). Based on the best response, five and seven patients achieved CR and PR, respectively, thus, the overall response rate was 36% (12/33). As four patients showed SD, the overall rate of disease control was 48% (16/33). Among five patients with CR, four patients completed the 16 cycles of treatment whereas only one patient progressed after 6^th cycle. The overall rate of disease control was different according to subtypes: DLBCL (1CR, 3PR, 2SD; 6/11, 55%), PTCL-NOS (2CR, 1PR, 2SD, 5/8, 63%), ENKTL (1CR, 1PR, 2/7, 29%), PMBCL (1CR, 1/3, 33%), MF (2PR, 2/2, 100%) and AITL (0/0, 0%). The extent of CD30 expression was not significantly between responders and non-responders, thus, there was no significant correlation. The hematologic toxicity profile was manageable, thus, most hematologic toxicities were grade 1 or 2 except two cases of grade 3 febrile neutropenia.

Conclusions

Our study demonstrated that brentuximab vedotin could have a significant antitumor activity with acceptable safety profiles in heavily pretreated patients with relapsed or refractory CD30-poitive NHL other than ALCL. Given the significant single agent activity, brentuximab vedotin could be used in combination with chemotherapeutic agents as a salvage treatment.