Adding Epcoritamab to R2 in R/R Follicular Lymphoma Meets Cost-Effectiveness Tests

In November 2025, FDA approved the use of the bispecific antibody epcoritamab (Epkinly; AbbVie/Genmab) with the combination lenalidomide plus rituximab, known as R2, to treat relapsed or refractory (R/R) follicular lymphoma.¹

But will US insurers cover this chemotherapy-free, fixed-duration regimen for patients seeking treatment at their first relapse of follicular lymphoma? This indolent blood cancer accounts for 20% of non-Hodgkin lymphoma (NHL) cases and is well-known for its pattern of relapses and remissions,² making therapy selection in earlier lines of treatment a crucial choice.

A recent analysis in Hematological Oncology suggests the odds of payer coverage are favorable.³ Authors of the analysis evaluated the cost-effectiveness of adding epcoritamab, a CD20×CD3 bispecific antibody, along with R2 for with R/R follicular lymphoma from a US payer perspective. Prior to the analysis, the phase 3 EPCORE FL-1 trial had shown that epcoritamab plus R2 substantially outperformed R2 alone, with a 95% vs. 79% overall response rate and a hazard ratio of 0.21 for progression-free survival (PFS),⁴ which supported the FDA approval.

Because bispecific antibodies add considerable cost to an already resource-intensive treatment pathway, the authors sought to determine whether the clinical benefit justified the added expense. With this regimen, epcoritamab is typically administered for up to 2 years via subcutaneous injection, with rituximab plus lenalidomide administered for up to 12 cycles, with each cycle lasting 28 days.

Study Process and Assumptions

The study used a 3-state Markov model that covered PFS, progressed disease (PD), and death with a 30-year time horizon and 28-day cycles, discounting costs and outcomes at 3% annually. Transition probabilities were derived by extrapolating EPCORE FL-1 Kaplan-Meier curves using parametric survival distributions (exponential for overall survival in both arms; exponential for PFS with epcoritamab plus R2 versus log-logistic for R2 alone). Costs, drawn from wholesale acquisition pricing, CMS fee schedules, and published claims data, included drug acquisition, administration, routine follow-up, adverse event (AE) management, post-progression treatment, and end-of-life care. Health-state utilities came from external published sources rather than the trial itself, since EPCORE FL-1 did not report utility data.

In the base case, epcoritamab plus R2 produced 13.16 life-years and 10.47 quality-adjusted life-years (QALYs), compared with 8.40 life-years and 6.53 QALYs for R2 alone— an incremental gain of 4.76 life-years and 3.94 QALYs. This benefit came at an incremental cost of $267,721, yielding an incremental cost-effectiveness ratio (ICER) of $67,974.64 per QALY gained, well under the $150,000/QALY willingness-to-pay threshold commonly used in US analyses.^4,5

The $150,000/QALY threshold is an established benchmark used in health economics evaluations to determine if a medical treatment is cost-effective. It represents the maximum amount that society or a health system is willing to pay for a QALY, which measures a full year of perfect health.⁵

Authors demonstrated how sensitivity analyses supported the robustness of this finding. One-way sensitivity analysis identified the acquisition cost of epcoritamab as by far the most influential driver of the Incremental Cost-Effectiveness Ratio (ICER), which ranged from about $53,820 to $82,129 per QALY as that cost varied plus or minus 20%; no other parameter pushed the ICER above roughly $70,275. In probabilistic sensitivity analysis (1000 Monte Carlo simulations), epcoritamab plus R2 had a 100% probability of being cost-effective at the $150,000/QALY threshold, and a 2-way sensitivity analysis that varied PFS utilities between arms did not change the conclusion.

Three scenario analyses tested structural assumptions. Refitting overall survival with a probability tool known as a Weibull distribution lowered the ICER to $56,218/QALY, while PFS with a Weibull distribution raised it to $75,595/QALY. Assuming that patients whose disease progressed would be treated someday with CAR T-cell therapy lowered the ICER to $49,311/QALY.

Time horizon mattered most: shortening it to 20 years raised the ICER to $89,810/QALY (still under threshold) but shortening it to 10 years pushed the ICER to $176,730/QALY—the only scenario exceeding the willingness-to-pay threshold.

As the authors explained, this reflects that epcoritamab's economic value depends heavily on long-term accrual of survival gains offsetting high upfront drug costs.

“Given the long disease course of follicular lymphoma and the need for multiple lines of therapy, disease progression is likely to increase subsequent healthcare resource use. Published evidence likewise suggests that costs are markedly higher among patients with disease progression than among those without progression,” the authors wrote. “In our analysis, although costs accrued in the progressed disease state remained substantial, drug acquisition costs during the treatment phase accounted for the largest share of total costs in both arms, and differences in drug acquisition costs between strategies contributed most directly to the incremental cost.

“This also explains why drug acquisition cost remained the most influential parameter in the one‐way sensitivity analysis,” they continued. “Notably, costs of PD state were lower in the epcoritamab plus R2 arm than in the R2 arm, reflecting the ability of more effective disease control to delay progression and thereby reduce the economic burden associated with the progressed disease.”

Cost analyses showed that treatment-phase drug costs were the largest component in both arms ($518,555 for epcoritamab plus R2 vs $217,574 for R2), while cumulative PD costs were actually lower with epcoritamab plus R2 ($174,982 vs. $199,458), reflecting delayed progression under more effective disease control.

The authors cited several limitations. Cost and utility inputs came from external sources rather than the trial itself. Costs following disease progression were modeled generically rather than for a specific treatment regimen. Long-term survival was extrapolated well beyond the trial's follow-up period, introducing uncertainty; not all AEs were captured, potentially understating costs and disutility; and identical utilities were assumed for both arms due to lack of trial-reported data. The authors argue these limitations are unlikely to reverse the overall conclusion, given the consistency shown across sensitivity and scenario analyses.

“In conclusion,” the authors write, “adding epcoritamab to standard R2 for patients with relapsed or refractory follicular lymphoma increased health care costs but also generated meaningful gains in [life years] and QALYs. At a [willingness to pay] threshold of $150,000/QALY, epcoritamab plus R2 is likely to be a cost‐effective treatment option.”

References

1. FDA approves epcoritamab-bysp for follicular lymphoma indications. FDA newsroom. November 18, 2025. Accessed July 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-epcoritamab-bysp-follicular-lymphoma-indications
2. American Cancer Society. Types of B‐cell lymphoma. Accessed July 20, 2026. https://www.cancer.org/cancer/types/non‐hodgkin‐lymphoma/about/ b‐cell‐lymphoma.html.
3. He Y, Wu M, Li A, Yi Y, Wan X. Cost-effectiveness of epcoritamab plus lenalidomide and rituximab versus lenalidomide and rituximab for relapsed/refractory follicular lymphoma: a US payer perspective. Hematol Oncol. 2026;44(4):e70221. doi: 10.1002/hon.70221
4. L. Falchi, M. Nijland, H. Huang, et al. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL‐1): A global, open-label, randomised, phase 3 trial. Lancet 2026;407(10524):161–173. doi: 10.1016/S0140‐6736(25)02360‐8.
5. Rand LZ, Paulden M, Raymakers AJN. Cost-effectiveness thresholds: overvaluing innovation, undervaluing health. Health Aff Forefront. Published online May 28, 2026. doi: 10.1377/forefront.20260522.557564