ICML 2025 | ctDNA-directed epcoritamab ± R2 in LBCL at high risk of relapse post-CAR-T: Phase II EpLCART trial

The work I’ll be talking about today is our abstract entitled Circulating Tumour DNA Directed Intervention with Epcoritamab Alone or in Combination with Lenalidomide and Rituximab is Feasible in the Early Post-CAR-T Population at High Risk of Relapse. Preliminary Data from EpLCART. So this is our in-house investigator-initiated trial sponsored by the Peter MacCallum Cancer Centre that I’m running in collaboration with Michael Dickinson and with support from AbbVie and GenMab. So in this abstract, we report the preliminary results up to the interim response assessment post-cycle two of epcoritamab-based therapy for the first 10 patients enrolled in EpLCART from three sites in Australia. 

The study monitors circulating tumour DNA through CAR T-cell therapy in an attempt to identify those patients at risk of relapse post-CAR T-cell therapy using the approved products for large cell lymphoma in second or third line. The area of need that we are addressing is patients that initially respond by conventional PET criteria to CAR T-cell therapy, but then subsequently relapse. We know that of patients that achieve a complete remission or a partial remission post-axi-cel or tisa-cel, have at least a one-third to one-half chance of relapsing. We aim to identify these patients early with an in-house ctDNA based assay. The assay is based on the Kappa NHL panel, which is commercially available from Roche Diagnostics and is run in-house together with a custom bioinformatics pipeline under the direction of Piers Blombery and our molecular hematology department here at the Peter MacCallum Cancer Centre. 

The study itself is a Phase II open label multi-centre multi-arm study It’s for patients that have achieved a complete or a partial remission on their early post-CAR-T PET scan between day 25 and day 100 post the CAR-T infusion, that maintain a performance status of 0 and 2, have adequate organ function and blood counts, and have complete resolution of any CAR-T associated toxicities, including cytokine release syndrome and immune effector cell associated neurotoxicity syndrome. They also must be free from active infection and have no active secondary CNS lymphoma. 

The primary endpoint of the study is complete response at month 12 post-CAR T-cell infusion. And our hypothesis is that bispecific antibodies may prevent progression in post-CAR T ctDNA MRD positive patients, and that a low burden disease state may lead to favourable disease control and safety profile from a fixed course of bispecific antibody. The null hypothesis is that the 12-month complete remission rate in the absence of intervention for this high-risk population is less than 0.3. And our alternative hypothesis is that patients treated with epcoritamab-based therapy will have a 12-month complete remission rate post-CAR-T infusion of more than 0.6. 

The sample size is 40 patients, and patients are randomized between arm A, which is epcoritamab alone for six cycles or epcoritamab, lenalidomide and rituximab for six cycles. Note that this is a fixed duration treatment as opposed to the approved schedule of epcoritamab which is until progression. 

We are excited to report that the monitoring of ctDNA and subsequent intervention post-CAR T-cell therapy appears feasible across multiple sites. This study is now open at six sites across Australia with disparate geography and yet we’re able to receive the samples efficiently and turn around the test in 12 days from receipt. This allows for intervention in the majority of patients before frank progression on PET scan occurs. 

In the data presented in this poster, we monitored ctDNA in 42 patients undergoing CAR T-cell therapy between February and November 2024. 14 patients, or 33%, were identified as MRD-positive in the required window between day 25 and day 100 post infusion. Of those, three had progressive disease by PET criteria and were therefore ineligible. One patient declined enrolment, and 10 patients enrolled in EpLCART. 

The early data suggests that the treatment is well tolerated. Of the 10 patients, only one patient developed CRS following epcoritamab-based treatment, and that was grade 1. There were no cases of ICANs post-epcoritamab-based treatment. Cytopenias and infections were the most significant adverse events that were observed. Severe neutropenia grade 3 to 4 was observed in 6 of the 10 patients, and severe thrombocytopenia grade 3 to 4 was observed in 4 of the 10 patients. 7 out of the 10 patients developed infections, which were mostly grade 1 and 2, including various viral infections, including COVID-19. There was one case of bronchopulmonary aspergillosis, which was successfully treated. 

The early efficacy signal is encouraging. At the interim response assessment post cycle 2, 8 out of 10 patients had converted their ctDNA MRD status to negative. And so in conclusion, monitoring of ctDNA after CAR T-cell infusion appears feasible in the real-world setting with a turnaround time that allows intervention prior to clinical progression in most cases to date. Epcoritamab-based therapy appears to be deliverable with a favourable toxicity profile and encouraging MRD responses. Enrolment is ongoing with a target of 40 patients across six sites, six commercial CAR T-cell centres in Australia.

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