CD19-Directed Antibody-Drug Conjugates for DLBCL
During a live virtual event with other physicians, Bijal Shah, MD, MS, discussed treatment options for patients with diffuse large B-cell lymphoma and the data that backs up the efficacy for these options.
A 75-year-old man presented with fever, a 7-lb unintentional weight loss, and occasional chest pain.
What would you most likely recommend for this patient in the third-line setting after chemoimmunotherapy?
Targeted OncologyTM: What do you think of the treatment choices for this patient?
Loncastuximab tesirine-lpyl [(Zynlonta) may be a good choice of therapy for this patient]. I participated in the trials of the first iteration of CD19 antibody-drug conjugate [therapy for diffuse large B-cell lymphoma (DLBCL)]. We initially used the monomethyl auristatin analog, the same cytotoxic agent used in brentuximab vedotin [Adcetris]; however, the analog we used had the ability to diffuse out so that it [not only] killed the cancer cells but also affected other [cells] around it.
[With this approach], we were seeing some thrombocytopenia [and bone] marrow toxicity, so we eventually moved to using the pyrrolobenzodiazepine [PBD] linker, [which is what is used in] loncastuximab. I don’t know if [Seagen Inc] purchased the PBD linker from Seattle Genetics or if they developed their own PBD linker with their own CD19 antibody. [But, based on my experience] using loncastuximab and [its good] safety and tolerability profile, I would consider it a good choice for this patient. Tafasitamab [Monjuvi] plus lenalidomide [Revlimid] would be equally relevant. I've certainly used lenalidomide a lot in relapsed/refractory [R/R] DLBCL. I don’t know whether tafasitamab/lenalidomide plus rituximab [Rituxan] would be better than tafasitamab/lenalidomide dual therapy.
There are data published in Blood 10 or more years ago suggesting that tumor responses to lenalidomide weren’t [based] simply on [activated B-cell or germinal center B-cell (GCB) subtype]. Rather, it seemed to be those patients with interferon regulatory factor 4 [IRF4]- or multiple myeloma oncogene 1 [MUM1]-positive [tumors] derived a greater benefit from lenalidomide in terms of direct cytotoxicity, so I tend to use lenalidomide in patients with MUM1- or IRF4-positive tumors.
How could selinexor (Xpovio) be used for this patient’s treatment?
Selinexor [Xpovio] is a great drug, but [patients experience] a lot of nausea and fatigue with it. It’s a potent histone deacetylase [inhibitor], and it works to bring about stable disease and sometimes partial responses [PRs], but [it can be challenging] to manage the fatigue and nausea associated with it. In some cases, I’ve used atypical antipsychotics to help patients through. I think if selinexor were partnered with another drug, such as bortezomib [Velcade], or one of the newer proteosome inhibitors, or [perhaps a kinase inhibitor, such as] ibrutinib, the dose could be reduced, and it would be better tolerated.
Polatuzumab vedotin [Polivy] plus bendamustine [Treanda] and rituximab [pola-BR] is another good treatment choice for relapsed DLBCL. [However,] the challenge with using loncastuximab or polatuzumab, [particularly in the setting of relapsed disease], is that multidrug efflux pumps [push the drug out]. We often see this with inotuzumab [Besponsa], used to treat acute lymphocytic lymphoma. The more heavily pretreated someone is, the more you run into difficulty with drug efflux pumps pumping the drug out and [thereby reducing its] antilymphoma activity.
What are the data behind using loncastuximab for treatment of R/R DLBCL?
Loncastuximab is a CD19-directed antibody drug conjugate, which uses the PBD linker as its [cytotoxic] payload. Loncastuximab binds to the CD19 [antigen and] then is internalized within the tumor cell where it releases the drug. [Thus], loncastuximab is [essentially] a cytotoxic chemotherapy.1
The phase 2 LOTIS-2 trial [NCT03589469] evaluated loncastuximab for treatment of R/R DLBCL.2,3 Trial patients received 150 μg/kg per body weight [on day 1] of the initial two 21-day cycles, and then the dose was [halved to] 75 μg/kg on subsequent cycles for up to a year.2,3 Patients who had a remission [could go on to maintenance therapy], administered every 12 weeks for up to another 3 years. Loncastuximab is a drug that [can be used as] maintenance therapy.
What were the results of the LOTIS-2 trial?
Most of the patients enrolled [in LOTIS-2] had DLBCL histology. Some patients were categorized as having high-grade BCL [HGBCL], which is part of the DLBCL categorization. HGBCL is that what we used to call B-cell lymphoma, not otherwise specified with features indeterminate between [Burkitt] lymphoma and DLBCL. A small percentage of patients in LOTIS-2 were categorized as having primary mediastinal B cell lymphoma.
Approximately 10% of patients had double- or triple-hit lymphoma, and 14% had double- or triple-expressor lymphoma. The trial included patients with transformed follicular lymphomas; overall, two-thirds of patients had advanced stage disease. Most [trial patients had] relapsed disease [68%], some had refractory disease [20%], and a few had had prior autologous stem cell transplant [14%] or allogenic stem cell transplant [1%], but most patients had received only chemotherapy.2,3
The overall response rate [ORR] to loncastuximab was 48%. Among patients who responded, most had a response after 41 days, which would be after 2 cycles of loncastuximab. The mean number of loncastuximab cycles was around 4 [and a half], which provides some insight into the duration of remission [we might expect with loncastuximab].2-4 Response to loncastuximab was consistent across patient subsets [defined by age, tumor subtype, and prior therapy]. No group seemed to do considerably better or worse [than any other], and even prior transplant patients seemed to do well, although few were included in the trial.3,5 [Notably], 6 of 13 patients who had had prior chimeric antigen receptor [CAR]-T cell immunotherapy had a preserved response to loncastuximab, [which has implications for the] concept of CD19 antigen loss.
Among the 24% of patients who had a complete remission [CR], remission tended to be of long duration [median duration of remission (DOR), 12.6 months]. Among patients who had a PR, the DOR was much shorter [5.7 months]. The overall median DOR was approximately 10 months.3,4
Trends in median progression-free survival [PFS] closely mirrored those of DOR. The first dip in PFS occurred after the second cycle of loncastuximab,3,4 [which may be because the trial conducted its] first response assessment at that time. The next dip in PFS occurred [approximately] 2 cycles after that, after which patients tended to do well because they were responding to therapy. Median overall survival [OS] in LOTIS-2 was 9.9 months,3 which is consistent with our expectations. Loncastuximab was associated with a CR in [approximately one-fourth of] patients, and half of patients had at least a PR to loncastuximab. So, data from this trial are quite encouraging. [Fifteen] patients received CAR T-cell therapy after [the trial], with an ORR of 46.7%; 9 patients went on to receive a stem cell transplant after [response to] loncastuximab.3,5
What adverse events (AEs) are important to highlight from this treatment?
It's important to talk about AEs associated with loncastuximab. Peripheral edemas are a notable AE because it's something unique and it occurred in 20% of patients.3,5 Localized edema can also occur with loncastuximab but it is not as common as a peripheral edema. To manage edema, patients with a weight gain of 1 kg from day 1 received spironolactone. Elevated γ-glutamyl transferase occurred in some patients [17.2%], as did liver toxicity [20%]. As with any antibody drug conjugate, cytopenias [can occur with loncastuximab]. High-grade neutropenia [occurred in approximately one-fourth] of the patients, high-grade thrombocytopenia in [17.9%], and high-grade anemia in [10.3%]. Older patients did not experience greater toxicity to loncastuximab compared with younger patients, so it may be an option for older patients who don’t want or are not eligible to proceed to CAR T-cell or stem cell therapy.
1. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131(10):1094-1105. doi:10.1182/blood-2017-10-813493
2. Carlo-Stella C, Zinzani PL, Kahl B, et al. Initial results of a phase 2 study of loncastuximab tesirine, a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory diffuse large b-cell lymphoma. Presented at: European Hematology Association meeting; June 12, 2020; virtual. Accessed September 10, 2021. https://bit.ly/2VJiPhQ
3. 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
4. Caimi P, 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 Onc. 2021;39(suppl 15):7546. doi:10.1200/JCO.2021.39.15_suppl.7546
5. Caimi P, Ai WZ, Alderuccio JP, et al. Efficacy and safety of loncastuximab tesirine (ADCT-402) in relapsed/refractory diffuse large b-cell lymphoma. Presented at: 62nd American Society of Hematology Annual Meeting and Symposium; December 5, 2020; virtual. Accessed September 10, 2021. https://bit.ly/3EiZCF