Efficacy Data Support Loncastuximab as Third-Line DLBCL Treatment

Matthew Matasar, MD, MS

Chief, Division of Blood Disorders,

Rutgers Cancer Institute

Professor

Rutgers Robert Wood Johnson Medical School

New Brunswick, NJ

Targeted Oncology: What options have become available for patients with diffuse large B-cell lymphoma (DLBCL) who have received 2 prior lines of therapy?

MATTHEW MATASAR, MD, MS: Loncastuximab tesirine [Zynlonta] was approved in 2021 after 2 or more prior lines of therapy, so in the third line and beyond.¹ Selinexor was approved for after 2 or more prior lines as well, although it’s very rarely used in routine practice.² Polatuzumab vedotin [Polivy], even though the trial GO29365 [NCT02257567] used it in second-line therapy, its official label is 2 or more prior lines. In the NCCN [National Comprehensive Cancer Network] compendium listing, it’s listed for 1 or more prior lines.^3,4 Now approved as of [May 19, 2023] is epcoritamab-bysp [Epkinly], the first FDA-approved bispecific antibody in the treatment of relapsed or refractory diffuse large B-cell lymphoma, approved here again in the third line and beyond.⁵

What data led to the approval of loncastuximab in relapsed/refractory DLBCL?

Loncastuximab is an antibody-drug conjugate [ADC] targeting CD19 with a PBD [pyrrolobenzodiazepine] payload, PBD being the intercalating and crosslinking chemotherapy moiety. It’s a fully humanized antibody and it’s been now tested in a number of different contexts in the treatment of B-cell lymphoma.

Its approval for large B-cell lymphoma is on the basis of the LOTIS-2 trial [NCT03589469]. This was a single-arm phase 2 trial looking at loncastuximab monotherapy in patients with relapsed large B-cell lymphoma, given with a loading dose [of 0.15 mg/kg] for the first 2 cycles and then given every 3 weeks for up to a year at the dose of 0.075 mg/kg.⁶ Then there’s a maintenance phase where it can be given every 12 weeks for up to 3 years, with a primary end point of overall response rate [ORR] and secondary end points [including duration of response, complete response (CR) rate, progression-free survival (PFS), and overall survival (OS)].

It was a relatively real-world patient population, including patients with primary refractory and early relapsing disease. This is not a cherry-picked patient population, and is more representative of real-world patients.

The activity of the drug is quite good. There was an ORR of about 50%, CR rate about 25%, and median PFS of approximately a year in this patient population, with an OS that closely matches that as you’d expect from treatments for multiple relapsed large B-cell lymphoma.

Which particular patients show benefit with loncastuximab?

When you look at the subgroup analysis, it’s not clear to me that there’s any patient population that derives specific benefit or alternatively lack specific benefits.⁷ There are a couple of subgroups that do merit attention. I would call out the 13 patients who had prior CD19-directed CAR [chimeric antigen receptor] T-cell therapy, and were still CD19 positive at time of enrollment on LOTIS-2. The ORR of about half of those patients was similar to those who were CAR T-cell therapy naïve, which are encouraging results. Also, we see that the activity of this regimen in patients with high-grade lymphoma. We see that even in the double- or triple-hit, multiple relapsed patients, a third of those patients did respond. That patient population…is very difficult to treat in late lines of therapy. As we’ve seen with other ADCs, patients with bulky disease may not fare as well. Primary mediastinal large cell lymphoma may not fare as well because of that but clearly a drug that is active across patient populations.

How well do patients tolerate loncastuximab?

The toxicity profile of loncastuximab is different than that of other ADCs because the toxicity is driven by the PBD payload. We see that the payload itself is relatively tolerable.⁸ There is some myelosuppression seen. There was some asymptomatic GGT [gamma-glutamyl transferase] elevation in a number of patients that limited their ability to stay on the study drug but didn’t have clinical ramifications. Peripheral edema [can occur]; there can be fluid accumulation, either peripheral edema or pleural effusions with PBD-delivering drugs like loncastuximab. Keep track of patients’ weights, their breathing status, and look on examination for effusions. Importantly, intervening early with the fluid accumulation with early initiation of diuretics can be very effective at preventing clinical progression of fluid accumulation or pleural effusions.

We saw no adverse safety signals with longer-term follow-up.⁹ Myelosuppression seems to be self-limited and manageable, and the most common adverse event leading to discontinuation was that asymptomatic GGT elevation.

_References:

_{1. Zynlonta. Prescribing information. ADC Therapeutics; 2021. Accessed Jun 21, 2023. https://tinyurl.com/yeytwndh}

_{2. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed Jun 21, 2023. https://tinyurl.com/2989n4ua}

_{3. Polivy. Prescribing information. Genentech, Inc.Accessed Jun 21, 2023. https://tinyurl.com/36dnj3yf}

_{4. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphoma, version 4.2023. Accessed June 21, 2023. https://tinyurl.com/4tnnkr68}

_{5. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. News release. FDA. May 19, 2023. Accessed June 21, 2023. https://tinyurl.com/2s47xp26}

_{6. 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}

_{7. Caimi PF, Ai WZ, Alderuccio JP, et al. Efficacy and safety of loncastuximab tesirine (ADCT-402) in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2020;136(suppl 1):35-37. doi:10.1182/blood-2020-137524}

_{8. Caimi PF, Ai WZ, Alderuccio JP, et al. Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: Subgroup analyses from LOTIS 2. J Clin Oncol. 2021;39(15_suppl):7546. doi: 10.1200/JCO.2021.39.15_suppl.7546}

_{9. Zinzani PL, Caimi PF, Carlo-Stella C, et al. LOTIS 2 follow-up analysis: updated results from a phase 2 study of loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma. Hematol Oncol. 2021;39(S2):252-254. doi:10.1002/hon.89_2880}