Refining Role of Brentuximab Vedotin and Immunotherapy in Hodgkin Lymphoma

Craig Moskowitz, MD

As clinicians’ understanding of the disease pathobiology associated with Hodgkin lymphoma (HL) has increased, novel treatments have emerged, including the anti-CD30 antibody—drug conjugate brentuximab vedotin (Adcetris; BV) and the checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo). However, determining how these agents specifically fit into the current armamentarium is still an ongoing debate.

It is estimated that 8700 new patients develop HL in the United States, but for patients over 70 years, there is no standard therapy. Although most patients with HL achieve cure, treatment fails in about 1400 patients on average, according to Craig Moskowitz, MD, who discussed the role of targeted chemotherapy and immunotherapy during his presentation at the 35th Annual CFS^®.

Patients with relapsed/refractory disease undergo 1 to 2 rounds of salvage therapy, which can consist of ifosfamide, carboplatin, and etoposide (ICE); dexamethasone, cytarabine, and cisplatin (DHAP); gemcitabine, vinorelbine, and liposomal doxorubicin (GVD); and ifosfamide, gemcitabine, vinorelbine (IGEV); all are salvage chemotherapies and can be followed by autologous stem cell transplantation (ASCT).

“We cure about 63% of these patients, so very few patients receive either palliative therapy with a novel agent or are considered for allogeneic stem cell transplant,” said Moskowitz.

Focusing on BV, Moskowitz said the agent is used for “palliation in the post-ASCT setting, as a second salvage therapy administered pre-ASCT, and as maintenance therapy post-ASCT.” He noted that, “By far, the most common reason to administer BV in the United States is pre-ASCT salvage therapy.”

Moskowitz summarized a number years’ worth of data that looked at 7 to 8 salvage regimens that either combined these regimens with BV that was given sequentially or concomitantly. “In general, the results are about the same for whatever you do. I would argue that nearly two-thirds of patients achieve a complete response and all these treatments are nearly equivalent, whether you give BV or not.”

When BV was combined with nivolumab in 55 patients with relapsed or refractory HL, Herrera and colleagues reported an 85% objective response rate with a 63% complete response.

“The complete response rate of 63% suggests that this combination is a bridge to ASCT,” said Moskowitz. “Whether we find patients who do not need to undergo ASCT is a platform for further research.”

“So how should BV be used in the future?” asked Moskowitz. He noted the creation of a new endpoint—a modified progression-free survival (PFS). Modified PFS is a superior endpoint for the evaluation of chemotherapy effectiveness compared with PFS, said Moskowitz.

The phase III open-label ECHELON-1 study (NCT01712490) compared the modified PFS obtained with BV plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine) with that obtained with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical HL.

Moskowitz noted that the study demonstrated a 2-year modified PFS of 81% for patients in the BV plus AVD treatment group versus 73% for patients in the ABVD treatment group (HR, 0.67, assuming an emergent plateau in the PFS event rate after 2 years). “Does this mean that we should treat 100 patients with BV + AVD to help 5 patients? You can make your own decision about this, but we should see further subset analysis data at the American Society of Hematology meeting.”

The BV plus AVD regimen could become the standard of care, said Moskowitz, with private oncologists adopting its use; lymphoma specialists will use it as well by proxy. “If this is true, then the way we use BV will dramatically change. We’ll be giving it as primary therapy for advanced-stage disease. I don’t think we’ll be giving it as a pretransplantation or posttransplantation regimen, and I don’t think we’ll be giving it for palliation. It will be used as upfront management.”

Summarizing longer term results with antibodies blocking PD-1 signaling, Moskowitz noted that more than 500 patients have undergone treatment in phase I and II either pembrolizumab and nivolumab clinical trials, PFS is approximately 12 months, and many patients are still on study after 1 year, the response rate is 70%, with complete response rate by investigator in the 22% to 25% range, and the dosing schedule with pembrolizumab may be easier than nivolumab.

“I have some reservations, however, about the pembrolizumab label,” said Moskowitz. “There is an implication that patients with primary refractory, transplant-eligible disease can receive this therapy prior to salvage chemotherapy—this would be a mistake in clinical judgment.”

Soon, Moskowitz sees checkpoint inhibitors used as part of second-line therapy and not for palliation in first relapse. He sees the agents combined with other therapies—ibrutinib, BV, chemotherapy, and radiotherapy.

Herrera AF, Bartlett NL, Ramchandren R, et al. Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. American Society of Hematology, San Diego, California, December 3—6, 2016, Abstract No. 1105