Part 2: LOTIS-2 Trial Includes High-Risk Patients and CAR T Sequencing in R/R DLBCL

Philippe Armand, MD, PhD

Chief of Division of Lymphoma

Senior Physician

Associate Professor of Medicine

Dana-Farber Cancer Institute

Boston, Massachusetts

Targeted Oncology^TM: What led to the approval of loncastuximab tesirine (Zynlonta) for relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?

PHILIPPE ARMAND, MD, PHD: Loncastuximab is an antibody-drug conjugate, but it's conjugated to pyrrolobenzodiazepine, which is a DNA-toxic agent, and it targets CD19 like tafasitamab [Monjuvi]. It was approved in 2021 for relapsed/refractory DLBCL, after at least 2 lines of prior therapy, so a similar approval to pola-BR [polatuzumab (Polivy) with bendamustine and rituximab (Rituxin)].^1,2

Please describe the patient population and study design of the LOTIS-2 trial (NCT03589469).

The approval [of loncastuximab for relapsed/refractory DLBCL] is based on the LOTIS-2 study, which was a single-arm trial, and enrolled patients pretty broadly; they just had to have 2 or more prior lines of therapy.^1,3

They were treated with loncastuximab up to 1 year of treatment. The results were time-limited therapy, although it was 1 year. For the first 2 cycles, they received 150 µg/kg and then it’s given every 3 weeks at 75 µg/kg.

This trial did have some patients with double-hit lymphoma. There weren't a lot of them, but they made up about 10% of the population. The median number of previous lines of therapy was 3, so they were more pre-treated, and the number of patients who had 2, 3, and greater than 3 previous therapies is probably similar to the population of the pola-BR trial. They're not super heavily pre-treated, but certainly more than the L-MIND trial [NCT02399085] of tafasitamab and lenalidomide [Revlimid]. The other thing is this is a trial where they did have patients who had prior chimeric antigen receptor [CAR] T-cell therapy, so there were 13 patients who had prior CAR T-cell therapy.

What was the efficacy observed in the LOTIS-2 trial overall and in subgroups?

Although the overall response rate was 48%, which included about half complete responses [CRs] and half partial responses [PRs]. Of the CRs, the duration of response [DOR] was fairly durable, like with tafasitamab/lenalidomide.^3,4 Over half of them were maintained at the time of data cutoff, and there is not a lot of long-term follow-up on this trial yet.

Because there were some patients with double-hit lymphoma, we can see their response rate. It is lower for those patients, 33% versus 50%, so even though this is a favorable response in these high-risk patients, it does seem lower.³ There was no effect of having transformed disease versus not. The other interesting result is those patients with prior CAR T-cell therapy. In this case, it doesn't seem to have any bearing on the response rate of loncastuximab. It does seem to be a regimen that can have activity, even in patients with prior CAR T-cell therapy, which we don’t know as much for pola/BR or for tafasitamab/lenalidomide, because they didn't have those patients on those trials.

The [Kaplan-Meier] curve for patients with a CR is pretty durable. It's hard to say what happens [beyond the median DOR] after a year or so, but when you're looking at 10 months, about 90% of patients with a CR [continue to respond], which seems quite good. Not surprisingly, patients with a PR have much shorter DOR. Overall, for the entire population, at the time of last data cutoff, the median DOR was just over a year, 13 months.

There was a median of 5 months for progression-free survival [PFS], and a median 10 months for overall survival [OS]. Of course, if a regimen has less than 50% response rate, the median PFS and OS are probably always going to look pretty poor.

The other part that I think is worth noting on this is for patients who received CAR T-cell therapy after loncastuximab. [We discussed] patients who received CAR T-cell therapy before loncastuximab, and now this goes to the question of whether we can give CD19-directed therapy prior to CAR T cell. Here, the 15 patients that went on to receive CAR T cell had a response rate of 47%, mostly CRs, which is not so different from what we expect from CAR T-cell therapy generally.

What toxicities were observed in the LOTIS-2 trial?

In terms of adverse events [AEs], it's broken down [based on patient age of below or above 65 years old,] but if you look at the total for all patients, you can see that [similar to tafasitamab/lenalidomide], there are mostly hematologic toxicities, and specific to loncastuximab is peripheral edema, including pleural effusions. In terms of grade 3 and above AEs, it was [mainly] hematologic: neutropenia and thrombocytopenia.³

There was increased GGT [gamma-glutamyl transferase], which is an AE particular to loncastuximab, and as best as anybody can tell, it is of no clinical relevance. They measured it on the trial [and found that] it's commonly elevated, but it doesn't seem like it causes significant liver toxicity beyond elevation of GGT.

The treatment discontinuation rate was 18%. You'll see that some of these related to elevated GGT, which is unfortunate, because it probably didn't matter that much.

What special considerations are there for administering loncastuximab?

Loncastuximab is a little bit different, because you have to give dexamethasone premedication. It is given the day before, the day of, and the day after giving loncastuximab.⁵ You have to counsel patients on sun exposure, and if they gain weight, the label recommends initiation of spironolactone. I'm not sure the spironolactone is necessarily the best drug for this, even though it's what's recommended. I think other diuretics probably work well, too.

If you're going to use the drug, it is worth remembering those few idiosyncrasies in terms of how it's given, how the AEs are managed, or how the dose is reduced.

_References:

_{1. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. FDA. Published April 23, 2021. Accessed March 3, 2022. https://bit.ly/3vGStNf}

_{2. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. Published June 10, 2019. Accessed March 3, 2022. https://bit.ly/3sDHphN}

_{3. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X}

_{4. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172}

_{5. Loncastuximab tesirine-lpyl (Zynlonta). Prescribing information. ADC Therapeutics SA; 2021. Accessed March 3, 2022. https://bit.ly/3py4OiA}