Over the past 5 years, the treatment landscape of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) has evolved dramatically with the introduction of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and other novel agents. CAR T-cell therapy has become the preferred treatment choice for eligible patients in the second-line setting based on the results of the ZUMA-7 and TRANSFORM trials. Despite the promise of CAR T-cell therapy, patient eligibility, access to care, and treatment logistics continue to be barriers for many patients.
For patients who recur beyond 12 months of initial therapy, second-line chemotherapy and hematopoietic stem-cell transplant (HSCT) are curative in a subset although treatment remains restricted to younger, fit patients. Tafasitamab plus lenalidomide (Len) is approved by the US Food and Drug Administration (FDA) in the second-line setting for more frail patients who are not candidates for HSCT. In the third line and beyond, the CD3 × CD20 bispecific antibodies glofitamab and epcoritamab and antibody drug conjugates (ADCs) including loncastuximab and polatuzumab in combination with bendamustine and rituximab are also available.
Brentuximab vedotin (BV), an ADC that binds to CD30, is currently FDA-approved for the treatment of Hodgkin lymphoma and T-cell lymphoma. While CD30 is positive in only 14%-25% of patients with DLBCL, a phase II trial of single-agent BV yielded responses in 44% of patients with R/R DLBCL across a range of CD30 expression levels. A phase I trial also demonstrated tolerability of BV in combination with Len.
In the article that accompanies this editorial, Bartlett et al present the results of ECHELON-3, a randomized, double-blind, placebo-controlled, multicenter phase III trial comparing BV + Len + R with placebo + Len + R in patients with R/R DLBCL. The trial was restricted to patients who had received at least two previous lines of therapy and were considered ineligible for HSCT or CAR T-cell therapy. After the median follow-up of 15.5 and 18.9 months, respectively, BV + Len + R resulted in an improvement in median OS of 13.8 months as compared with 8.5 months with placebo + Len + R and reduced the risk of death by 37%.
Interestingly, the improvement in OS and PFS was maintained independent of cell of origin and CD30 expression. The low rates of CD30 expression in DLBCL beg the question as to why BV is active in this disease without clear differential activity across cell of origin–defined subtypes.
Treatment-emergent adverse events (TEAEs) were common in both arms, and 76% and 48% of patients required dose modifications, respectively. The most common TEAEs of any grade were neutropenia, thrombocytopenia, and diarrhea. Lenalidomide was dosed on a continuous basis, rather than the more typical 21-day-on, 7-day-off schedule, likely contributing to the high rates of hematologic toxicity.
The authors should be lauded for performing a large, randomized, placebo-controlled, international study across 83 sites. Unlike some other trials in this space, ECHELON-3 included patients with primary refractory disease and a subset of patients who had received previous CAR T-cell therapy (30%). The study also included older patients, up to age 89 years. The regimen does not require inpatient administration or intensive observation for acute toxicities.
While an improvement in OS was seen among patients receiving BV + Len + R, a number of factors aside from the efficacy of the regimen contribute to the outcome. First, the comparator arm, Len + R, sets a low bar for comparison. Len + R is not an approved option for patients with R/R DLBCL, and previous studies of the combination in R/R DLBCL have demonstrated poor outcomes. Second, the median follow-up of the experimental arm was 3 months shorter than the control arm and might have contributed to the observed difference in PFS. In addition, the BV + Len + R arm was less heavily pretreated with a median of two previous lines of therapy for DLBCL compared with three in the placebo + Len + R arm.
Another important consideration for many clinical trials in R/R DLBCL is the definition of CAR T-cell and HSCT ineligibility. As comfort with CAR T-cell therapy improves, use has expanded to older and more frail patients. Similarly, CD3 × CD20 bispecific antibodies, which have been associated with durable responses in a subset of patients with R/R DLBCL, generally have a more favorable toxicity profile as compared with CAR T-cell therapy.
While the options for patients with R/R DLBCL continue to expand, the optimal sequencing of therapies has not been clearly defined. In addition, while T-cell–engaging therapies are associated with impressive outcomes, they are still not widely available across treatment locations. ECHELON-3 has demonstrated improvement in OS with the addition of BV, independent of CD30 status, to Len + R compared with placebo + Len + R, providing another potential treatment option for patients with R/R DLBCL.
