The study that we presented summarised data, efficacy and safety, of epcoritamab monotherapy in patients with relapsed/refractory chronic lymphocytic leukaemia. This is an ongoing phase I/II study which enrols patients with relapsed/refractory CLL who have progressed after at least two prior lines of therapy. The study had two cohorts, the expansion cohort and the optimisation cohort and there were some distinctions between the two where during the optimisation cohort there was an additional step-up dose of epcoritamab administered. There was some undated steroid, dexamethasone, use and undated hydration.

The overall goal of the study was response rate for the expansion cohort and certain safety measures for the optimisation cohort.

What were the results of this study?

The results of the study basically come in two groups. First, if we talk about safety, it is important to highlight that epcoritamab was, in general, well tolerated by patients with CLL. As you know, epcoritamab is already approved in patients with relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma who underwent  intensive therapy but this is the first time it has been used in chronic lymphocytic leukaemia. It’s an agent which is administered subcutaneously and, just like other bispecific antibodies, it is associated with certain [?? 1:39] adverse events, particularly cytokine release syndrome. So in this study we have seen some anaemia and thrombocytopenia which are very common in patients with CLL. In fact, the majority of patients who reported these two adverse events had pre-existing anaemia and thrombocytopenia going into the study. But other adverse events were quite tolerable – there was low grade diarrhoea, fatigue, nausea – and most of them were transient. The treatment discontinuation due to adverse events was rare – only five patients discontinued in the expansion cohort and one patient from the optimisation cohort.

What also is important to note is that in the optimisation cohort the grade of CRS was significantly decreased, both the frequency of CRS, which went down from 96% to 82% and, again, the grade. Most cases were grade 1, there were no grade 3 CRS in the optimisation cohort and the use of tocilizumab was significantly less frequent in that cohort. Also there were no cases of ICANS and, as we are used to seeing that, [?? 3:00] cases of CRS occurred with the first full dose of epcoritamab which would be when epcoritamab was administered at a 48mg dose.

The second part of the study is efficacy and that has mostly been so far assessed in the expansion cohort which [?? 3:28] long follow-up of 23 months. In that cohort among response evaluable patients the response rate was 67% and complete response 43%. It’s good to know that responses were maintained in patients with high risk disease, including TP53 aberration, IGHV3 mutated status and patients who were doubly refractory to ibrutinib and venetoclax. In fact, this patient population was highly refractory with four median prior lines of therapy and the vast majority had progressed on ibrutinib and venetoclax. Therefore, in this patient population such a high response rate for a single agent, I believe it is a big success.

The optimisation cohort so far has a fairly short follow-up of 3 months, however, we do see a similar response rate, although complete responses it’s still too early to determine the true frequency of complete responses. So those are the results of the study.

What do you think is the clinical significance of these results?

Patients with CLL who progress on novel agents, ibrutinib and venetoclax or other BTK inhibitors, represent an unmet medical need. So really we don’t have very effective therapies for those patients – chemotherapy doesn’t work. We do have pirtobrutinib which works, however, progression free survival is in the order of one year, a little bit over one year. CAR T-cells also have been approved for this patient population, however, they are associated with high toxicity and high infection rates. 

So far, I’d say, the treatments for these patients are limited and suboptimal in their efficacy. So this is a new state of the art technology, a bispecific T-cell engager approach, which I believe can really eventually change how we treat double refractory CLL.

Also, it is important to note that bispecific antibodies have been shown to exhibit synergy with targeted agents. So I believe that moving this agent into earlier lines of therapy is also something that we should be doing.