Loncastuximab Leads to Responses in DLBCL After Prior CD19 CAR T

Amitkumar Mehta, MD

Director, Lymphoma Program

Assistant Director, Phase I Program

Associate Professor
O’Neal Comprehensive Cancer Center at UAB

Birmingham, AL

Targeted Oncology: In addition to tolerability, what was the efficacy of loncastuximab tesirine (Zynlonta) in the LOTIS-2 trial (NCT03589469) of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)?

Amitkumar Mehta, MD: In LOTIS-2, there was a 48.3% overall response rate [ORR], and approximately one-fourth of patients went into a complete remission [CR].¹ Event-free survival [was 44.0% at 1 year and 31.0% at 2 years]. Median time to response was 42 days [range, 36-247], and that is classic for any clinical trial because that's when they get their first scan. Those patients who are in a CR had the best duration of response on the trial [median, not reached].

[Looking at] progression-free survival and overall survival, especially in those patients who had CR, they do fairly well with loncastuximab.

Is CD19 expression important to predicting response to loncastuximab in DLBCL?

It did not correlate with CD19 expression. They looked at soluble CD19 levels, and they did not show any correlation between any intensity of CD19 and response. Even though the trial mandated it, in a real-life setting, if…a biopsy is not feasible, it's still worth considering treatment with loncastuximab.

What other efficacy data could guide the use of loncastuximab?

There are real-world data for loncastuximab [in DLBCL]. Essentially, they looked at those patients who have been exposed to loncastuximab and especially at the timeline of chimeric antigen receptor [CAR] T-cell therapy and loncastuximab. These patients received CAR T-cell therapy first and then they got loncastuximab…and we saw how these patients fared.

Ninety-five patients received CAR T-cell therapy in the second line and loncastuximab in the third line.² Twenty-three patients received CAR T-cell therapy in the third line and then loncastuximab in the fourth line. The ORR was 73% and CR rate was 34% for those [receiving loncastuximab in the third line] post CAR T-cell therapy in the second line. Similarly, in the fourth-line setting there was a 78% ORR, and 17% CR [rate].

Those patients who had responded to CAR T-cell therapy in the second line and then got loncastuximab [n = 67] had higher responses. They were sensitive to CAR T-cell therapy and they [experienced disease progression], and those patients had higher ORR [82%], as well as CR rate [43%]. For those who are refractory to CAR T-cell therapy, [52%] still responded, but the CR rate dropped to just 11%. Similarly, in those who responded to CAR T-cell therapy in a third-line setting and got loncastuximab afterwards in the fourth line, their ORR was higher compared with those who are refractory to CAR T-cell therapy [83% vs 67%, respectively].

In other words, in those patients who had CAR T-cell therapy and then had progression, this is a reasonable option. Vice versa is also true; if you treat somebody with loncastuximab and they have to get CAR T-cell therapy, there is a high chance that they would respond to CAR T-cell therapy. We’re still learning how much CD19 expression is required to be effective for CD19-directed therapy. Hopefully in the future we'll have more studies with more patients, so we'll be able to predict it better. But so far, the responses in the post CAR T-cell therapy setting are much better with loncastuximab, even though it is the same [target of] CD19-directed therapy.

There are 3 different published [real-world] studies of options post CAR T-cell therapy [including] loncastuximab, and…of course it is not a home run, but there is a decent ORR and a CR rate that you would see in a post CAR T-cell therapy setting.^3-5

REFERENCES:

1. 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 II LOTIS-2 study. Haematologica. 2024;109(4):1184-1193. doi:10.3324/haematol.2023.283459

2. Epperla N, Lucero M, Bailey T, et al. Real-world clinical effectiveness of loncastuximab tesirine monotherapy for the treatment of relapsed/refractory diffuse large B-cell lymphoma following chimeric antigen T cell therapy in the US. Transpl Cell Ther. 2024;30(suppl_2):S353. doi:10.1016/j.jtct.2023.12.493

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

4. Nastoupil LJ, Andersen CR, Ayers A, et al. Effectiveness of chemo-immunotherapy (CIT) and novel therapies in second or later line of therapy (2L+) for patients with relapsed/refractory (R/R) aggressive large B-cell lymphoma (LBCL). Blood. 2024;142(suppl_1):309. doi:10.1182/blood-2023-174497

5. Iqbal M, Jagadeesh D, Chavez J, et al. Efficacy of CD19 directed therapies in patients with relapsed or refractory large b-cell lymphoma relapsing after CD19 directed chimeric antigen receptor T-cell therapy. Bone Marrow Transplant. 2024;59(2):211-216. doi:10.1038/s41409-023-02148-4