The DALY 2-EU study has investigated the role of zamto-cel, a  novel tandem CD20/CD19 targeting CAR T-cell therapy, in the second-line treatment of refractory or relapsed diffuse large B-cell lymphoma patients who are ineligible for high-dose chemotherapy and autologous transplant.

The question was if this intervention, this novel tandem dual-targeting CAR is superior to the standard of care for those patients with a high unmet medical need. The standard of care is R-GemOx, it’s a combination of an antibody and chemotherapy, and this was the comparator in the DALY 2-EU trial.

What was the methodology?

This is a randomised trial, so patients were selected based on transplant ineligibility, as defined by organ dysfunctions and age, but also based on the histology, so diffuse large B-cell lymphoma or related entities, and then randomised in a 1:1 fashion into the comparator group with the standard immunochemotherapy R-GemOx or to treatment with zamto-cel. Both groups would receive a leukapheresis procedure before treatment started and in the zamto-cel group there was no bridging therapy allowed, which is different from approved products, because the turnaround time, the vein-to-vein time of zamto-cel is very brief, it’s only 14-16 days.

What were your findings?

The primary endpoint of this trial was event free survival. Event free survival means no progression of disease, no relapsed disease, no death or/and no other treatment in combination with no response to treatment. So this is a combined endpoint indicating insufficient efficacy of the treatment.

This endpoint, primary endpoint, event free survival, was significantly superior for zamto-cel over R-GemOx. The median event-free survival in the zamto-cel group was 6.2 months whereas it was only 2.5 months in the R-GemOx group. This corresponds to a hazard ratio of 0.39 which obviously is highly significant with a p-value below 0.0001.

Importantly, we had enrolled very old patients in this trial so the median age was 74-75 years. 80% of the patients enrolled to the zamto-cel treatment group were 70 years or older and many of them, 31%, were in poor general condition with an ECOG performance status of 2. Most of them had comorbidities. So this is a truly elderly patient population that was treated within this trial.

Subgroup analyses indicated that the benefit of treatment with zamto-cel was maintained for all risk groups, especially for the older patients, being older than 75 years for example. But also, and this is very different from any trial reported so far, also for patients with poor general condition, so with an ECOG performance status of 2. Surprisingly, the benefit increased with increasing baseline tumour volume, so the higher the tumour volume at baseline it’s usually the poorer the outcome is, the greater the benefit in this trial was for treatment with zamto-cel.

In brief, all different subgroups at different risk for treatment failure in this trial had the same and significant benefit from treatment with zamto-cel.

Could you give us some detail on adverse events?

Treatment emergent adverse events occurred in both treatment groups, so with zamto-cel or with R-GemOx and they were grade 3 or higher in 82% with zamto-cel and 85% with R-GemOx, so this is equally distributed. However, there are treatment emergent adverse events which are typically only seen with CAR T-cell therapies and this is the case also with zamto-cel. For example, focussing of delayed cytopenias, which is after day 29 of treatment up to day 90, 9.8% of the patients had persisting cytopenia which is a comparatively relatively low number and is reflected also by the low incidence of hypergammaglobulinemia with 5.3%.

When going to the typical adverse events CRS and ICANS, the numbers were as follows: grade 3 or higher CRS was observed only in 5.3% of the patients, in other words, this is four out of the 82 enrolled patients. Grade 3 or higher ICANS, so relevant neurological symptoms, were observed only in one patient. So this very good tolerability profile is also reflected by the use of medication for these adverse events, the CRS and ICANS. Usually the adverse events could be managed just with a single drug administration – tocilizumab in 29 patients or corticosteroids in 14 patients. Only 13 patients in the zamto-cel group needed tocilizumab and corticosteroids and only one patient an [??].

What could be the implications of these findings?

The DALY 2-EU trial was done in a very difficult to treat patient population. These elderly and comorbid patients are not very resilient and treatment outcomes, whatever you do, are usually very poor. In this trial we have observed a rather unique risk-to-benefit profile – we have a large benefit in terms of efficacy over the standard treatment with immunochemotherapy for zamto-cel, again, so the hazard ratio was 0.39, reflecting the magnitude of this benefit. And on the other hand we have a very low incidence of grade 3 or higher, so severe, typical CAR T-cell-associated side effects like CRS and ICANS. In numbers in this trial there was only one patient with one grade 3, not even grade 4, ICANS. So this is a risk-to-benefit ratio for zamto-cel which makes it clearly very much superior to the standard group in this trial, which was R-GemOx.

The favourable risk-benefit profile of zamto-cel supports its use as a preferred second-line treatment option for patients with either de novo or transformed refractory or relapsed large B-cell lymphoma.

Is there anything else you would like to add?

This trial is a relevant step forward for the treatment of refractory or relapsed patients with diffuse large B-cell lymphoma. I’d like to thank the patients and their families, the investigators of this European trial conducted in 12 countries and 45 study sites, the study teams involved in the DALY 2-EU trial, for their participation.