Part 2: Loncastuximab Provides Potential Bridge Therapy for R/R DLBCL

Justin Kline, MD​

Associate Professor of Medicine​

Director, Lymphoma Program​

University of Chicago Medicine​

Chicago, IL​

CASE

• A 75-year-old man presented with fever, 7-lb unintentional weight loss and occasional chest pain.
• Prior medical history included medically controlled hypertension.
• Physical exam: tired-appearing man; palpable bilateral cervical lymphadenopathy​
• Laboratory results: lactate dehydrogenase, 300 U/L (280 U/L upper limit); hemoglobin, 10.8 g/dL; bilirubin, 1.3 mg/dL (1.2 mg/dL upper limit); creatinine 1.7 mg/dL (1.2 mg/dL upper limit); all others within normal limit​
• Hepatitis B, C and HIV negative​
• Lymph node biopsy; immunohistochemistry panel: CD 10+, CD 20+ diffuse large B-cell lymphoma (DLBCL), germinal center B-cell subtype; Fluorescence in situ hybridization: negative for rearrangements of BCL6, BCL2 and C-MYC​
• Whole body PET/CT scan showed activity in multiple lymph nodes above and below the diaphragm, largest node 3.9 cm; evidence of subcutaneous tissue involvement​
• MRI of the brain showed no evidence lesions​.
• Stage: IV; International Prognostic Index: high-intermediate risk; ECOG performance status: 1​
• Patient received 6 cycles of rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP); well-tolerated
• PET/CT scan at end of treatment showed complete remission.
• One year later patient presents with diffuse lymphadenopathy, confirmed by PET CT scan.
• Biopsy shows relapse of the same DLBCL.
• The patient is considered ineligible for transplant.
• He completed second-line gemcitabine-oxaliplatin plus rituximab, with partial response.
• Five months later, he presented with overt disease progression.
• Chimeric antigen receptor (CAR) T-cell therapy was discussed as an option, but the patient declined due to distance to nearest transplant center.

In a live, virtual roundtable discussion, Justin Kline, MD, looked at a case of a patient with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in the third-line setting and how loncastuximab tesirine-lpyl (Zynlonta) might benefit this patient. Moreover, he discussed how it can be used as a bridge therapy to subsequent treatments for this patient population.

What was the newest treatment approval for patients with R/R DLBCL?

KLINE: [Loncastuximab] is an antibody drug conjugate that targets CD19 which is a popular antigen in DLBCL, which was approved in April of this year.¹

The approval was based on the single arm, phase 2 study called LOTIS-2 [NCT03589469].² [The study] included adults with R/R DLBCL after they had 2 or more lines of systemic therapy and patients that had prior anti–CD19 directed therapy, either tafasitamab [Monjuvi] or CAR T-cell therapy, and they had to have a biopsy showing CD19-positive lymphoma cells. They also had to have a respectable performance status and be 60 days from a potential transplant.

What was the design of LOTIS-2 and what were the characteristics of the patients on the trial?

For 2 cycles, patients get 150 µg/kg and then 75 µg/kg given every 3 weeks for up to a year. Moreover, the primary end point of the study was overall response rate [ORR].²

Median age [of patients on the trial] was 66 years old but 90% of patients had DLBCL, while a few had high-grade B-cell lymphoma, or primary mediastinal B-cell lymphoma. About 10% of patients had double or triple hit lymphomas, 14% had double-expressor lymphomas, and 20% had a large cell lymphoma transformed from indolent disease. Most [patients on the trial] were stage III or stage IV.

The median number of prior treatments was 3, so this was a [relatively heavily treated patient population]. Twenty percent were primary refractory to their first line therapy, so primary refractory to R-CHOP, for example, and most had relapsed. About 60% were refractory to their last line of systemic therapy, and about 17% of patients were refractory to all prior therapies, and about 15% had received a prior autologous stem cell transplant. So, this was a difficult population of patients here.

What were the efficacy results of the trial?

Twenty-four percent of patients had a partial response, and 24% of patients had a complete response, for an ORR of 84%.² The median time to first response was about 40-days, and in other words, most patients responded after 2-cycles of treatment. The median number of cycles received [by the patients] was 4.5, but the maximum was 18 cycles.

This is underpowered, but you get a sense that even in patients with double or triple hit lymphomas there was some clear efficacy. Similarly, in patients who had received a prior stem cell transplant there, was also [promising efficacy results].

However, for patients who achieved a complete response, their median duration of response [DOR] was not reached. The median DOR for all responding patients was about 10-months and DOR, depending on how the data was cut off, increased at 13.4 months when the data were cut off on March 21, so a little bit mature data.³ [Ultimately], a reasonably effective treatment option for patients in the third line and beyond with R/R DLBCL.

Median PFS is about 5 months, and the median overall survival [OS] is about 9.5 to 10 months. [This does really highlight] the poor outcomes in general for patients with R/R DLBCL, and these are patients who do not do well. I think we sometimes think of DLBCL as an easily managed disease, and I think in the frontline setting it is. But I think for folks with R/R disease it’s a different story.

Did any patients go on to receive subsequent treatments?

Fifteen patients went on to receive CD19-directed CAR T-cell therapy, with an ORR of about 45% [for the patients on the CAR-T treatment], which I think is relatively impressive given that loncastuximab targets CD19.²

Physicians might worry about CD19 antigen loss like a clinician might see with rituximab [Rituxian], and 9 patients proceeded to transplant as consolidation treatment. [Ultimately], I don’t think loncastuximab is curing anyone, but it can be used as an effective [bridge therapy] either to CAR T-cell therapy or to allogeneic stem cell transplantation, or for a patient ineligible for both its perhaps an option to keep them surviving a little bit longer, hopefully with a reasonable quality of life.

Are there any toxicities that clinicians should be aware of?

This is an interesting drug-related toxicity. Certainly, there are treatment-emergent toxicities [a physician might] expect with any chemotherapy-based drug. Unique toxicities include adverse events [AEs] like skin rash, fluid retention, and pleural effusions that have to be monitored very carefully.²

I’ve used [loncastuximab] a couple of times and it requires some vigilance regarding monitoring patients, particularly [using liver function tests to monitor for AEs]. Patients are all taking dexamethasone 4 mg twice a day on the day before, day of, and the day following treatment, which seems to mitigate some of the AEs including fluid retention and skin rash as well.

_References

_{1. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. News release. April 23, 2021. Accessed November 9, 2021. https://bit.ly/3CdZ7tI}

_{2. 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 Jun;22(6):790-800. doi: 10.1016/S1470-2045(21)00139-X}

_{3. Caimi PF, Ai W, 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. Lancet Oncol. 2021 May;39(15):7546-7456. doi: 10.1200/JCO.2021.39.15_suppl.7546}