Pfizer’s ADCETRIS combination regimen secures FDA approval for relapsed large B-cell lymphoma

The U.S. Food and Drug Administration (FDA) has approved Pfizer Inc.’s supplemental Biologics License Application (sBLA) for ADCETRIS (brentuximab vedotin) in combination with lenalidomide and rituximab. This combination therapy is designed for adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL), who have undergone at least two prior lines of systemic therapy and are not candidates for autologous stem cell transplantation or CAR T-cell therapy. The FDA’s decision is based on compelling data from the Phase 3 ECHELON-3 trial, which demonstrated a 37% reduction in the risk of death with the ADCETRIS combination regimen compared to lenalidomide and rituximab plus placebo. This marks a significant advancement for patients facing aggressive lymphoma subtypes with limited treatment options.

What makes the ADCETRIS combination regimen a breakthrough for relapsed large B-cell lymphoma?

The ECHELON-3 trial represents a pivotal development in lymphoma treatment, being the first Phase 3 study to show a statistically significant and clinically meaningful overall survival improvement in patients with relapsed or refractory DLBCL after two or more prior lines of therapy. This patient population traditionally faces poor outcomes, especially when ineligible for stem cell transplantation or CAR T-cell therapy. Roger Dansey, M.D., Chief Oncology Officer at Pfizer, highlighted the impact of this approval, noting that more than 3,500 patients in the U.S. experience treatment failure or relapse annually after multiple lines of therapy. He stated that the FDA’s approval reinforces the role of ADCETRIS as a standard of care, providing physicians with an option beyond chemotherapy and CAR T-cell therapies for patients with relapsed or refractory large B-cell lymphoma.

The ADCETRIS combination regimen offers new hope for patients with aggressive forms of lymphoma, particularly those who have exhausted existing treatment options. Its ability to deliver survival benefits without the complexities associated with CAR T-cell therapy—such as manufacturing delays, hospitalisation requirements, and high costs—positions it as a more accessible therapy that can be administered on an outpatient basis. This approval expands the landscape of available treatments and provides a crucial option for patients with few alternatives.

How did the ECHELON-3 trial demonstrate overall survival improvement?

The ECHELON-3 trial was a global, randomised, double-blind, multicentre Phase 3 study that enrolled 230 patients across North America, Europe, and the Asia-Pacific region. The trial compared the efficacy and safety of the ADCETRIS combination regimen, consisting of brentuximab vedotin plus lenalidomide and rituximab, against lenalidomide and rituximab with placebo. Participants were adults with relapsed or refractory DLBCL, regardless of CD30 expression, who had received at least two prior lines of therapy and were ineligible for stem cell transplantation or CAR T-cell therapy.

The trial’s primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), overall response rate (ORR), complete response rate, duration of response, and safety. The results were compelling, demonstrating a 37% reduction in the risk of death compared to the control group. This survival benefit was consistent across all patient subgroups, irrespective of CD30 expression levels. In addition to the primary endpoint, positive outcomes were observed in key secondary measures, including improved progression-free survival and overall response rates, confirming the regimen’s efficacy in heavily pre-treated patients.

Dr. Craig Portell, Associate Professor at the University of Virginia and principal investigator of the ECHELON-3 trial, remarked that for patients who have faced multiple rounds of chemotherapy and even CAR T-cell therapy with limited success, ADCETRIS provides a new therapeutic option with proven safety and efficacy. He added that its outpatient administration offers added convenience without compromising treatment outcomes, making it an attractive option for both patients and healthcare providers.

What is ADCETRIS and how does it work in treating lymphoma?

ADCETRIS is an antibody-drug conjugate (ADC) specifically designed to target CD30-positive tumour cells. It consists of a CD30-directed monoclonal antibody linked to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable linker. This targeted approach allows ADCETRIS to selectively deliver the cytotoxic agent to cancer cells while minimising damage to healthy tissue. The drug’s unique design enables it to remain stable in the bloodstream until it reaches CD30-expressing tumour cells, where it is internalised, and the linker releases MMAE to induce cell death.

Interestingly, the ADCETRIS combination regimen demonstrated survival benefits in the ECHELON-3 trial even among patients with low or undetectable CD30 expression, suggesting broader efficacy beyond its initial design parameters. This characteristic differentiates ADCETRIS from other targeted therapies that rely solely on biomarker expression for effectiveness, expanding its potential patient population and therapeutic impact.

What are the safety considerations for the ADCETRIS combination regimen?

The safety profile of ADCETRIS in the ECHELON-3 trial was consistent with previously reported data. The most commonly reported treatment-emergent adverse events (TEAEs) of Grade 3 or higher included neutropenia, thrombocytopenia, and anaemia. Neutropenia was observed in 43% of patients receiving the ADCETRIS combination compared to 28% in the placebo group. Thrombocytopenia occurred in 25% of ADCETRIS-treated patients versus 19% in the control group, while anaemia was reported in 22% and 21% of patients, respectively.

Peripheral sensory neuropathy was infrequent, with low-grade presentations in both treatment groups. Grade 3 neuropathy occurred in 4% of ADCETRIS-treated patients, compared to none in the placebo group. Despite these risks, the manageable safety profile and the potential for overall survival improvement position the ADCETRIS regimen as a promising option for patients with relapsed or refractory LBCL. The outpatient administration and relatively predictable safety profile make it a practical choice for healthcare providers seeking effective treatments with manageable adverse events.

What does this FDA approval mean for the future of lymphoma treatment?

This approval represents the eighth FDA-approved indication for ADCETRIS, further solidifying its role as a cornerstone in the treatment of various lymphomas. For patients with relapsed large B-cell lymphoma, this development offers renewed hope, especially for those who are ineligible for intensive treatments like CAR T-cell therapy or stem cell transplantation.

The ECHELON-3 trial results were published in JCO Oncology Practice and presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, underscoring the robustness of the data and the growing recognition of ADCETRIS in the oncology community. As researchers continue to explore new combinations and indications for ADCETRIS, its role in the evolving landscape of lymphoma treatment will likely expand, offering more personalised and effective options for patients facing aggressive blood cancers.

This FDA approval not only enhances the therapeutic arsenal available to oncologists but also represents a shift towards more targeted, less invasive treatment strategies that can be administered in outpatient settings. The success of the ADCETRIS combination regimen could pave the way for future studies investigating similar approaches in other difficult-to-treat cancers, ultimately improving patient outcomes and quality of life.