CD19-Directed Antibody-Drug Conjugates for DLBCL

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

Justin Kline, MD, discusses what makes loncastuximab tesirine-lpyl a good bridge therapy for patients with relapsed/refractory diffuse large B-cell lymphoma to potential CAR T-cell therapy.

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 would you most likely recommend for this patient in the third-line setting after chemoimmunotherapy?

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