New Data Solidify Benefit of Loncastuximab Tesirine for Relapsed/Refractory DLBCL

Brad S. Kahl, MD

Substantial anti-tumor activity and tolerable safety was observed with loncastuximab tesirine (lonca; Zynlonta) in the phase 2 LOTIS-2 clinical trial ultimately leading to the FDA approval of the chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

In the study, 145 adult patients were treated with lonca. The objective response rate observed was 48.3% (95% CI, 39.9%-56.7%) with complete responses (CRs) in 24.1% (95% CI, 17.4%-31.9%). Furthermore, partial responses were achieved in 24% of patients, stable disease was seen in 15%, and progressive disease was observed in 21%. Response lasted for a median duration of 10.3 months (95% CI 6.9–not estimable) in the overall population. In patients who had a CR to lonca, the median duration of response was 13.4 months (95% CI, 10.3-NE).

The survival analysis in the LOTIS-2 study (NCT03589469) showed that the median progression-free survival was 4.9 months (95% CI, 2.9-8.3) and the median overall survival was 9.9 months (95% CI 6.7-11.5).

In an interview with Targeted Oncology™, Brad S. Kahl, MD, a professor in the Department of Medicine, Division of Medical Oncology at Washington University School of Medicine in St. Louis, provided an efficacy update from the LOTUS-2 study and discussed multiple agents showing promise for the treatment of relapsed/refractory DLBCL.

TARGETED ONCOLOGY™ How has it been to treat DLBCL since the newest drug approvals?

Kahl: The management of relapsed diffuse large B-cell lymphoma has changed considerably in the past few years. We've had the approval now of 3 CAR T-cell products for relapsed diffuse large B-cell lymphoma. So certainly, if one is envisioning treating a patient with curative intent, then that should be your choice. Now, there are a number of patients who relapse after CAR T-cell therapy or maybe aren't candidates for CAR T-cell therapy because of age or comorbidities, or because their disease just isn't under good enough control. There still is a huge need for novel therapies, even if they don't have curative potential, just things that have good activity, high response rates, and that can relieve symptoms. That’s where we've had a number of new agents and the most recent approval is this novel, antibody-drug conjugate loncastuximab tesirine, which targets CD-19, and the toxic payload is this PBD dimer. It's a very potent cytotoxic agent that is a DNA-damaging agent. It's far too potent and toxic to be administered as intravenously, but when you give it conjugated to an antibody and delivered in a targeted fashion, suddenly you have a novel chemotherapy drug that you can give in this targeted way. So, loncastuximab tesirine has been a very nice new addition to the toolbox. For patients with relapsed diffuse large B-cell lymphoma.

What was shown in the primary analysis of lonca?

The study that led to approval of lonca was called LOTUS-2 and this was a single-arm, phase 2 study done in a number of centers in the United States and in Europe, where the agent was administered to patients with relapsed diffuse large B-cell lymphoma. The way the treatment is administered in LOTUS-2 is patients receive a dose of 150 micrograms per kilogram, and that's repeated 3 weeks later, so you just give that dose for the first 2 cycles. Then, the dose drops in half to 75 micrograms per kilogram administered every 3 weeks for up to a year. So that's just an important detail to know about the dosing strategy.

In this particular phase 2 study that was published in Lancet Oncology recently, there were 145 patients, they received an average of 4 cycles of lonca. But a third of the patients received more than 7 cycles. The response rate was impressive at 48%, with a complete response rate of 24%. And the median progression-free survival was right around 5 months in the original paper. There are a number of patients who relapse shortly after finishing the drug. Although if patients achieve a complete response, they're much more likely to get a durable remission.

Can you discuss the update from the LOTUS-II study presented during the SOHO meeting?

At the SOHO meeting we presented updated data on the durability. So, there were 70 responding patients, and if you just look at the patients who achieved a partial remission, the median duration of response is right around 6 months. But if you look at the patients who achieved a complete remission, about one-quarter of the patients, the median duration is not reached. Finally, if you look out at a year, about 70% of the complete responding patients are still in their first remission. So, there is a significant proportion of patients who can achieve very durable disease control with this agent.

What can you tell other oncologists about how to manage toxicities from lonca?

There’s a little bit of a learning curve to using this agent because it's a brand-new cytotoxic agent that we don't really have a lot of experience with. The cytopenias are modest, I wouldn't say they're extreme, and we don't see a ton of neutropenia. Only a quarter of patients had grade 3 or worse neutropenia. Only 20% of patients had grade 3 or worse thrombocytopenia. So, I think the myelosuppression is quite manageable. One thing that I think investigators need to be aware of is it can cause an isolated increase in the GGT levels. We don't really see alterations in the transaminase or the bilirubin. So, the clinical significance of these increased GGT levels is not completely clear yet. But I think that is something that people should be aware of and monitor.

I think the type of toxicity that can be a little more problematic for the patients is for example, a photosensitivity type rash. Patients can get a significant skin rash in sun-exposed areas. So, I think it's important to advise your patients to be very careful about sun exposure while they're on this agent. Then, there's some sort of nonspecific vascular injury that can occur with his agent, and we do see some patients getting significant third spacing of fluids with edema, or effusions, and that could be pleural effusions, or pericardial effusions. It can be a bit challenging to manage, and it doesn't respond all that well to loop diuretics but responds a little bit better to things like spironolactone. If a physician is seeing that, they may want to back off on the dose or just discontinue the treatment if their patient is having a great response because the third space can go on for weeks or even months. So, it can be a problematic toxicity to deal with.

What key advice can you provide about treating DLBCL today?

Well, I think for those of us who take care of patients with diffuse large B-cell lymphoma and manage people with relapsed diffuse large B-cell lymphoma, lonca is a great new tool to have in the toolbox. It's a very potent agent. It works very quickly if you have patients who are suffering with symptoms from their relapse. Administering lonca can get them relief within days and so it works very quickly like other cytotoxic agents, and I've personally seen the drug work when they're completely refractory to traditional chemotherapeutic agents, so it can work even in chemotherapy-resistant disease. I do think this is a very nice option to have for our relapsed diffuse large B-cell lymphoma population.

Aside from the LOTUS-2 study, are there any other drugs coming down the pipeline for this patient population?

We've had other drugs recently approved in relapsed diffuse large B-cell lymphoma. Polatuzumab vedotin [Polivy] given with bendamustine plus rituximab [Rituxan] is a nice option too. Tafasitamab [Monjuvi] with lenalidomide [Revlimid] is another nice option, and then we have Selinexor [Xpovio] that was approved in this space. So, there are definitely some newer options that weren't available a few years ago.

The agents I'm most excited about that seem like they're just around the corner would be some of the bispecific monoclonal antibodies. Not to single any out in particular, but just as a class, the bispecific monoclonal antibodies are having impressive activity in relapse diffuse large B-cell lymphoma, and these things typically target CD-20 and CD-3. There's a little bit of risk for cytokine release syndrome, but it seems manageable. So, the toxicity profile seems reasonable and it's not excessive. Also, response rates are coming in at 60% to 70% with complete responses in 30%, 40%, and even 50%, in some of the studies.

The drugs are pretty new, so I don't think we know the full picture on durability yet. But my prediction is we'll have some approvals of bispecific monoclonal antibodies and in relapse diffuse large B-cell lymphoma within the next year or 2.

_Reference:

_{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}