Antibody-Drug Conjugates in Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Episode 2

Loncastuximab Tesirine for Relapsed/Refractory DLBCL

Potential implications for treating patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with loncastuximab tesirine, an antibody-drug conjugate, based on early results demonstrated by the LOTIS-2 study.

Tycel Jovelle Phillips, MD: Loncastuximab tesirine was studied in LOTIS-2, so this was in a relapsed/refractory DLBCL [diffuse large B-cell lymphoma] population. The drug was given in 150 micrograms every 3 weeks times 2 doses, then the dose was reduced to 75 micrograms until a year of therapy or until intolerance. From our data, we have an overall response rate of around 45% with around 24% of the patients getting a complete remission. The study is early compared to some of the other studies as far as long-term response, but as we would expect, the patients who obtain a complete remission have a longer duration of response. Overall, the response rate and duration of response for a heavily pretreated population such as this, caveat being that there were few patients who had been exposed to CAR T [chimeric antigen receptor T-cell therapy], is impressive in this situation.

A lot of people will compare this to some of the other approvals, like pola-BR [polatuzumab vedotin in combination with bendamustine and rituximab], lenalidomide and tafasitamab. If you look at the patient populations and overall response rate, this one is competitive with those two. The time to response is quick, generally occurring within the first 6 weeks with the higher dose, and they’re apt to being able to maintain those responses with the loncastuximab with the lower dose and minimize some of the toxicity. The biggest toxicities being a rash, which was partly related to sun exposure in these patients; a capillary leak syndrome or edema, which can be mitigated with the use of steroids and with Aldactone to remove fluid from these patients. There was a bit of neutropenia; there was a fair amount of anemia reported on the study, but again, based on the inclusion criteria of the trial, a lot of the anemia may have been related to disease and prior treatments, and not the treatment itself. Thus, the drug itself was well tolerated. The treatment schedule itself is appealing in this situation, given that the patients can come every 3 weeks, and the fact that it’s not considered to be an indefinite therapy is also a benefit to this patient population.

As far as patients that fare better or worse with loncastuximab, we tend to suspect that younger patients respond better than older patients, especially in this situation because of the tolerance issue. As younger patients will typically have less comorbidities going into a study than what we see with older patients who have more comorbidities, especially related to chronic illnesses that they encounter, such as heart disease and things of that nature. If you look at the differences between the patient population, the median duration of response in this study was a bit longer for the older patients than the younger patients, which is different from what we would expect. Part of this may be related to the lines of therapy, as the younger patients can tolerate more lines of therapy before succumbing to a disease than older patients. As time goes on, this will be something we can pull out more versus where we are now with the readout of the study.

Looking at other patient populations, such as those who were refractory to frontline therapy, there was no real difference between patients who were considered primary refractory versus those who weren't. This is important because those who are primary refractory tend to have worse outcomes than those who are relapse. In this case, it seems this was fairly agnostic to that situation. There were also responses noted in these patients who had double-hit lymphoma and more advanced-stage disease. Overall, the response rate from loncastuximab indicated that the drug can be used irrespective of the patient characteristics. If it's going to work, it's going to work, and what the patient presents with is not necessarily going to be a true determinant of how things are going to respond.

The response rate in itself, being that it was a more heavily pretreated patient population, has to evaluate this in an earlier line setting. This may be something we look into to see if we can get improved outcomes, and maybe there would be more of a difference based on the patient characteristics at that point. However, at least in the current study with LOTIS-2, we’ve seen good response rates across some of the other ways that we try to segregate these patients. It did not seem that a lot of things stood out as being overly detrimental to patient outcome.