Takeaways on Tolerability Challenges With Loncastuximab in DLBCL

Amitkumar Mehta, MD

Director, Lymphoma Program

Assistant Director, Phase I Program

Associate Professor
O’Neal Comprehensive Cancer Center at UAB

Birmingham, AL

TARGETED ONCOLOGY: What is significant about the mechanism of action of loncastuximab tesirine (Zynlonta) in patients with B-cell lymphoma?

AMITKUMAR MEHTA, MD: Loncastuximab is an CD19 antibody-drug conjugate [ADC]. [From] the L-MIND study [NCT02399085], tafasitamab [Monjuvi] is a naked CD19 monoclonal antibody. It's just like rituximab [Rituxan], which targets CD20; tafasitamab targets CD19, but there is no payload. Loncastuximab is a step further; it has a payload attached to it, and it is a PBD payload.¹ Like many other ADCs, it binds to CD19 on the surface of the malignant B cells, gets internalized, and gets degraded to release the PBD toxin, which affects the DNA and causes the apoptosis of the cell.

In the era of bispecific therapies, where we are all worried about cytokine release syndrome [CRS], hospital admission, etc, loncastuximab is a simple infusion every 3 weeks. There is no CRS and no immune effector cell–associated neurotoxicity syndrome.

How was loncastuximab studied, and how did this study design compare with the study of tafasitamab plus lenalidomide (Revlimid)?

Loncastuximab was studied, like tafasitamab, in a single-arm phase 2 study. The LOTIS-2 study [NCT03589469] enrolled patients who had relapsed/refractory disease, but they had at least 2 lines of therapy, so loncastuximab is approved in the third-line setting onwards. The only requirement for them was that if a patient had CD19-directed therapy before, they should have CD19 positivity on the surface of the malignant B cells. They also allowed patients who had prior [autologous stem cell] transplant and allogeneic transplant. There are some patients who also had chimeric antigen receptor T-cell therapy. Importantly, they allowed patients who had double or triple-hit [lymphoma] so the patient population on LOTIS-2 was different than the L-MIND study. These are more high-risk patients compared with what we saw on L-MIND. Loncastuximab was given in a 30-minute infusion every 3 weeks, and on the trial, it was continued for 1 year. For the first 2 cycles the dosage is [doubled]; for the rest, it was half the dose after the first initial higher dose. The primary end point was overall response rate.

The number of patients was higher [than in L-MIND]: 124 patients.² There were 36 patients with a complete response, 16 who were event free for 1 year, and 11 who were event free for more than 2 years. [Investigators reported their] characteristics to give you a glimpse at those patients who remained long term in complete remission. There were 5 patients with double-hit lymphoma who were in complete remission and 16 patients who had more than 3 prior line of therapy who also were in complete remission. Even as later-line therapy, loncastuximab showed activity. Remember that these patients have high risk compared with what we saw on the L-MIND study.

What toxicities are of most concern when using loncastuximab?

Loncastuximab has a toxin, PBD, which has unique adverse events [AEs]. In all the ADCs, the AE is because of the payload. Just to give you an example, if you look at brentuximab vedotin [Adcetris], the payload is MMAE and the AE of the payload is neuropathy. One major AE of PBD is photosensitivity. These patients have extreme sensitivity to the sunlight. Skin rash can potentially happen in this patient. I saw a patient today who had skin rash. He is a [fisherman] and he's on loncastuximab and got skin rash on the sun-exposed area, [although] I've seen worse skin rash. Sun protection is very important for these patients.

This toxin can also give you pleural effusion and ascites. Third spacing [edema] is very common. The way you avoid that is these patients get dexamethasone before and for a few days after the infusion of loncastuximab. That is part of the prescribing information and part of our [management] plan. When we order this, that prescription gets filed automatically. Another thing that is important to remember is diuretics. On the trial, they used spironolactone [Aldactone] as needed for fluid accumulation. These are the 3 specific clinical AEs that you will see. One less clinically meaningful AE is GGT [gamma-glutamyl transferase] elevation, which is also part of the payload. If you monitor GGT, this patient will have elevation of GGT the majority of the time. There are dose adjustments based on the GGT elevation.³

Cytopenias are also one of the AEs for loncastuximab. If you're using loncastuximab, make sure that you closely monitor the blood counts, and if needed, you can always use growth factor support, but that's where the peripheral edema comes in. There is fluid retention, that's where dexamethasone and spironolactone or any diuretic you could use for these patients [are needed].

REFERENCES:

1. Kingsley E, Grosicki S, Kwiatek M, et al. ABCL-320 initial safety run-in results of the phase 3 LOTIS-5 trial: novel combination of loncastuximab tesirine with rituximab (Lonca-R) versus immunochemotherapy in patients with R/R DLBCL. Clin Lymphoma Myeloma Leuk. 2022;22;(suppl_2):S372. doi:10.1016/S2152-2650(22)01527-0

2. Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study. Haematologica. 2024;109(4):1184-1193. doi:10.3324/haematol.2023.283459

3. Zynlonta. Prescribing information. ADC Therapeutics; 2023. Accessed July 30, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf