Assessing the Durability, Tolerability of Loncastuximab in R/R 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 exam: palpable bilateral cervical lymphadenopathy​
• Laboratory results: lactate dehydrogenase, 265 U/L (280 U/L upper limit); Hemoglobulin, 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: CD10+, CD20+, 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 score 2; low-intermediate risk​
• Patient received 6 cycles of R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate), 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, and rituximab (Pola-BR).
• Had stable disease for 6 to 8 months before progression​
• Current treatment:​ loncastuximab tesirine-lpyl (Zynlonta)

Targeted Oncology: How has data from the LOTIS-2 trial (NCT03589469) impacted your long-term outlook on the use of loncastuximab for patients with DLBCL?

MATTHEW MATASAR, MD, MS​: When getting a closer look at the durability [of loncastuximab], the results aren't a surprise.¹ This is a theme in [treating patients with] large cell lymphoma, where the quality of responses does indeed drive outcomes in treatment with this antibody-drug conjugate. While there's relatively few patients who are being followed [after having a complete response], we see that those patients can enjoy what appears to be a quite durable response, [even as patients with partial response have a median duration of response of 5.68 months (95% CI, 1.64-9.26)].¹ As these data continue to mature, we look forward to future updates to see how these patients [receiving loncastuximab] perform over time.

Matthew Matasar, MD, MS​

Chief, Division of Blood Disorders

Rutgers Cancer Institute

Hematologist/Oncologist

Professor of Medicine

Rutgers Robert Wood Johnson Medical School​

Rutgers University​

New Brunswick, NJ

What other efficacy data from LOTIS-2 are important to note?

When you look at the subgroup analysis [from LOTIS-2], you're trying to get a sense for whether there are there patients who derive incremental benefit from treatment with loncastuximab. Indeed, this is a drug that we think has good activity even in the highest-risk subset of patients. There are few data for any of these treatments for patients with relapsed double-hit lymphoma in the third-line setting, but there were responses even for the patients with double- or triple-hit lymphoma. [In this trial], 5 out of 15 patients did respond to loncastuximab, while some patients with early refractory disease also seemed to do well.²

The response rate and activity was similar for those [patients] post chimeric antigen receptor [CAR] T-cell therapy or who didn't have it, and the number of prior lines of therapy, which usually is the most predictive factor for response to a next line of therapy, did not predict response to loncastuximab [in this study].² The theme that I would draw from here...is that this drug is active even in the patients with highest risk.

What was the safety profile for this therapy for the relapsed/refractory DLBCL population?

Loncastuximab does have some toxicities of note, including some cytopenias. There was also asymptomatic gamma-glutamyltransferase [GGT] elevation, which was limiting in the context of a clinical trial.³ I do not routinely check for GGT when I'm giving loncastuximab in practice, and I'm not sure I would encourage other people to check it either. A toxicity that I do want to call attention to is peripheral edema.

[This is because], for reasons that aren't entirely clear, this therapy’s payload is associated with fluid accumulation that can be peripheral edema, or it could even be pleural effusions.3 So being sensitive to your patient's weight, monitoring them for fluid accumulation, and intervening early with diuretics, should they develop edema or effusions early in the course [of treatment], is important when helping them avoid worsening of that toxicity. In terms of the overall tolerability [of loncastuximab], there were several treatment-emergent adverse events but few of these led to treatment discontinuation—fewer than 20%. GGT elevation was a major [reason for treatment discontinuation], and non-GGT toxicity leading to treatment discontinuation was thankfully [not as high].³

^References:

^{1. 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}

^{2. 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}

^{3. 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}