Comparing Results with Loncastuximab in the Clinic and Real-World Settings in DLBCL

CASE

• A 73-year-old woman presented with fever, headaches, and 7-lb unintentional weight loss​.
• Medical history: no family history of cancer, and hyperlipidemia that was well controlled with simvastatin.
• Physical examination: palpable bilateral cervical lymphadenopathy​
• Laboratory results: lactate dehydrogenase (LDH) s265 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+, which confirmed diffuse large B-cell lymphoma (DLBCL).
• Fluorescence in situ hybridization: negative for rearrangements of BCL6, BCL2 and C-MYC​
• Whole body PET/CT scan showed diffuse adenopathy, largest node 3.9 cm.
• MRI of the brain showed no evidence of lesions​.
• ECOG performance status: 1​
• Stage III disease; International Prognostic Index (IPI) score 2: low-intermediate risk​
• Patient received 6 cycles of R-CHOP [rituximab (Rituxan),cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin)], and vincristine sulfate (Oncovin), which was well tolerated​.
• She had a complete response (CR) at the end of treatment, but 1 year later the patient presented with diffuse lymphadenopathy, confirmed by PET CT scan​.
• Biopsy showed relapse of the same DLBCL​.
• Patient received 6 cycles of polatuzumab vedotin (Polivy), bendamustine (Bendeka), and rituximab (Pola-BR).
• She had stable disease for 6 to 8 months before progression​.
• Current treatment:​ loncastuximab tesirine-lpyl (Zynlonta)

Targeted Oncology: What were the efficacy long-term efficacy results for the LOTIS-2 trial (NCT03589469) assessing loncastuximab in this patient population?

EMILY AYERS, MD: The overall response rate [ORR] was 48.3%, with a complete response [CR] rate of 24.8%.^1,2 The event-free survival [EFS] rate at 1-year was 44.0%, and then EFS at 2 years was 31.0%, and the median time to response was 42.0 days or 2 cycles [of treatment].²

The median duration of response [(DOR) for all treated patients] was 13.37 months [95% CI, 6.87-not reached].² When you look at those patients who obtain a CR [with loncastuximab] the median DOR is not reached, but those patients who obtain a CR with this therapy seem to still have a durable response. Then, as seen with other therapies, for the patients who achieve a partial response most of them seem to relapse early with a median DOR of only 5.7 months [95% CI, 1.64-9.26].²

Emily Ayers, MD​

Assistant Professor

Emily Couric Clinical Cancer Center

University of Virginia Health​

Charlottesville, VA

For those patients with a CR...the median progression-free survival [PFS] was not reached...and the median PFS for all comers was 4.9 months [95% CI, 2.89-8.31].² Looking at overall survival [OS], the median was not reached in those patients with a CR and the median OS of 9.5 months [95% CI, 6.74-11.47] was for all patients treated [with loncastuximab].²

Were there any toxicities of concern with this therapy?

[The majority] of patients had an adverse event [AE] of some sort, but something that a lot of people talk about with loncastuximab is the increased [rate of] GGT [(gamma-glutamyl transferase) seen in 42% of patients at any grade].²

This is followed solely based on the payload with this drug, and the concern for hepatotoxicity, but usually patients just see an isolated GGT increase without any decreased hepatic function, so the clinical meaning of this is unclear. We also have some cytopenias [with the use of loncastuximab], and then a unique AE seen in 20% [of patients at] any grade is peripheral edema and fluid accumulation.² [However], there were no new safety signals that were identified in the long-term follow-up.

How does loncastuximab in the real-world setting compare with the outcomes in the clinical setting?

There was a real-world analysis from 21 different sites [in the United States]...that included 187 patients with a median age of 68 years [95% CI, 22-95].³ Compared with the LOTIS-2 study, almost 20% of these patients had double-hit DLBCL, and the majority of patients had prior chimeric antigen receptor [CAR] T-cell therapy at 60%, but the real-world outcomes did not hold up to what we saw on LOTIS-2.3 There was a CR rate of 14% and an ORR of 33% with a median PFS and OS of 2.1 months and 4.6 months, respectively. This analysis did show that those patients with non-bulky [disease] and those patients who had a CR to the most recent therapy prior to loncastuximab still had significantly improved outcomes.³

Did prior CAR T-cell therapy impact these outcomes? How did those patients with a CR to loncastuximab fare overall?

Interestingly, prior CAR T-cell therapy did not impact outcomes [in the real-world setting].³ So, those patients who had prior CAR T-cell therapy did the same as those patients without prior CAR T-cell therapy. Looking at PFS by the response to loncastuximab, as you would expect, those patients with a CR do better. But the median PFS was not reached for those patients achieving a CR, so even though the CR rates are low with this drug, those patients who can achieve a CR seem to have durable responses. On the flip side of that, those patients who progress [do so] early and have very poor outcomes.³

REFERENCES:

1. 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

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 2 LOTIS-2 study. Haematologica. doi:10.3324/haematol.2023.283459

3. Ayers E, Zelikson V, Gurumurthi A, et al. Loncastuximab in high-risk and heavily-pretreated relapsed/refractory diffuse large B-cell lymphoma: A real world analysis from 21 US centers. Blood. 2023;142(Suppl 1):312. doi:10.1182/blood-2023-174257