Brentuximab Vedotin Studies Explore Novel Combinations, Pretransplant Settings

Alison J. Moskowitz, MD

Alison J. Moskowitz, MD, is among researchers at Memorial Sloan-Kettering Cancer Center and elsewhere who are investigating an expanded role for the CD30-targeting brentuximab vedotin (Adcetris) in hematologic malignancies. Moskowitz specializes in the treatment of patients with lymphoma and her research focuses on evaluating novel treatments for Hodgkin lymphoma.

1. Please briefly describe your research as it relates to CD30 signaling in cancer.

Along with my colleagues at Memorial Sloan-Kettering Cancer Center, I am investigating the role of brentuximab vedotin in the second-line (or pretransplant) setting for Hodgkin lymphoma. In addition, I am evaluating the safety and efficacy of novel brentuximab vedotin combinations. The role of brentuximab vedotin in the pretransplant setting for Hodgkin lymphoma remains investigational. In our current pretransplant study, patients with relapsed or refractory Hodgkin lymphoma who have failed only one line of therapy receive weekly brentuximab vedotin alone for 2-3 cycles. Those with normalization of their FDG-PET (PET) scan proceed directly to autologous stem cell transplant and those with persistent abnormalities on PET receive additional therapy with augmented-ICE (ifosfamide, carboplatin, etoposide) chemotherapy prior to consideration for transplant. We recently completed the first part of this study in which patients received 2 cycles of brentuximab vedotin and we are currently enrolling patients onto the expanded portion of this study in which patients receive 3 cycles of brentuximab vedotin.

There are currently limited data regarding the safety of combining brentuximab vedotin with other agents. Phase I studies have established its safety in combination with AVD (adriamycin, vinblastine, dacarbazine) and CHP (cyclophosphamide, doxorubicin, prednisone). Ongoing studies are evaluating its safety and efficacy in combination with bendamustine, gemcitabine, and other standard chemotherapy agents. The mTOR inhibitors are a class of drugs with established activity in Hodgkin lymphoma. Everolimus, a member of this class, produced an overall response rate of 42% in HL patients and preclinical data suggest synergy between brentuximab vedotin and temsirolimus, a closely related mTOR inhibitor. We are conducting a Cancer Therapy Evaluation Program (CTEP)-sponsored phase I study evaluating the safety of brentuximab vedotin in combination with temsirolimus.

2. Besides brentuximab vedotin, are there any other CD30-targeting agents in development?

Given the success of brentuximab vedotin, other approaches to targeting CD30 are certainly warranted, though these are currently limited. One example is the CD30 chimeric-receptor activated T cells (CARTCD30) currently under evaluation in a phase I trial (NCT01316146). CART-CD30 cells are autologous T-cells that have been genetically engineered to express an anti-CD30 receptor, and thus potentially exert antitumor effects on CD30-positive cancers.

3 What do you think the future holds for the development of brentuximab vedotin?

There are two ongoing international phase III studies evaluating brentuximab vedotin in the frontline setting. The ECHELON-1 study is evaluating brentuximab vedotin plus AVD compared with ABVD in advanced-stage Hodgkin lymphoma. The ECHELON-2 study is studying brentuximab vedotin plus CHP compared with CHOP in CD30 positive non-Hodgkin lymphomas. These studies may change the frontline treatment for these diseases. A phase III study evaluating brentuximab vedotin as posttransplant maintenance for Hodgkin lymphoma is complete (the AETHERA study) and the results from this study are expected soon. This may lead to the use of brentuximab vedotin in the posttransplant setting to reduce relapse rates.

As described above, brentuximab vedotin is also being investigated in the second-line setting for Hodgkin lymphoma and multiple brentuximab vedotin combination studies are ongoing. While brentuximab vedotin is very effective as a single agent, novel brentuximab vedotin combinations likely have the most promise for replacing or altering our currently frontline and second-line therapies for these diseases.

4. What is the most exciting recent finding relating to CD30-targeting in cancer?

The significant single-agent activity of an anti-CD30 antibody- drug conjugate in Hodgkin lymphoma and anaplastic large cell lymphoma is certainly the most exciting finding related to CD30 targeting in cancer. It is interesting that, unlike the results seen with rituximab in CD20 lymphomas, an unconjugated anti-CD30 monoclonal antibody has little to no activity in CD30-positive lymphomas. On the contrary, conjugating a chemotherapy agent to the monoclonal anti-CD30 antibody leads to significant clinical activity, greater than ever seen with a single agent in Hodgkin lymphoma or anaplastic large cell lymphoma.

5 What are the most significant hurdles to the development of CD30-targaeted agents?

First, determining mechanisms of resistance is vital. Some patients with Hodgkin lymphoma or anaplastic large cell lymphoma do not respond to brentuximab vedotin despite the presence of CD30 on their tumor cells. Determining the mechanism of resistance or identifying biomarkers that predict resistance will help determine which patients are most appropriate to receive brentuximab vedotin, particularly if it becomes incorporated into frontline treatments. Secondly, determining the spectrum of activity of CD30-targeted drugs is also an important hurdle. Studies are currently evaluating the role of brentuximab vedotin in other CD30-positive lymphomas, and emerging data indicate that the degree of tumor cell CD30 positivity does not necessarily predict response to brentuximab vedotin. Identifying markers that predict response, perhaps other than CD30 expression, will be important for determining the full spectrum of activity of this agent.