The phase 3 EPCOR FL-1 trial showed that adding epcoritamab to the lenalidomide/rituximab (R-squared) backbone profoundly improved progression-free survival in relapsed follicular lymphoma. Presented as the most important FL abstract at ASH, this result is expected to establish a new standard of care in this setting.

Combining polatuzumab vedotin with bispecific antibodies appears particularly effective for patients with double-hit lymphoma. This is significant because these high-risk patients, who have poor prognoses, were notably excluded from pivotal trials like STAR GLOW, suggesting a potential new standard for this specific subgroup.

An exploratory strategy for DLBCL patients involves using ctDNA to detect minimal residual disease after CAR T-cell therapy. This allows for early intervention with bispecific antibodies when the disease burden is low, potentially preventing full clinical progression, a shift from reactive to proactive treatment.

Beyond approving the triplet combination, the positive Epcor FL1 trial data had a significant ripple effect. It solidified the drug's overall profile, leading to the conversion of its prior provisional (accelerated) approvals for monotherapy in follicular lymphoma and DLBCL into full, traditional approvals.

The traditional "germinal center" (GC) classification for DLBCL is overly simplistic. Molecular analysis reveals distinct subtypes within GC, such as "dark zone" and "light zone" signatures, which have different prognoses and responses to targeted therapies like polatuzumab.

In follicular lymphoma, the treatment goal is durable remission with manageable toxicity, not necessarily a cure. Therefore, clinicians frequently prefer using a bispecific antibody first, reserving the more complex and toxic CAR-T cell therapy for transformed disease or after a bispecific fails.

Not all CD20-targeting bispecifics can be combined with rituximab. Mosunetuzumab binds the same epitope, causing competition. However, glofitamab and epcoritamab bind different epitopes, allowing for logical and potentially synergistic combinations with rituximab-based regimens.

The regimen's profound success in relapsed/refractory patients is not an endpoint, but a launchpad. It provides the rationale for the ongoing Epcor FL2 trial, which directly challenges standard chemoimmunotherapy and could establish a chemotherapy-free, bispecific-based combination as the new first-line standard of care.

The dramatic efficacy boost from adding epcoritamab suggests it's the primary driver of patient benefit, not just an adjunct. This shifts the conceptual framework, positioning the bispecific antibody as the new therapeutic backbone, with rituximab and lenalidomide as supportive agents.