Next Steps With Loncastuximab Tesirine in LBCL Involve Exploring Novel Combo Regimens

Paolo F. Caimi, MD

Following the FDA accelerated approval, loncastuximab tesirine-lpyl (Zynlonta) has joined the treatment arsenal for patients with relapsed or refractory large B-cell lymphoma (LBCL), and represents a safe active option that has potential to be utilized in future combination regimens, according to Paolo F. Caimi, MD.

On April 2021, the FDA approved loncastuximab tesirine for use in adult patients with relapsed or refractory LBCL following 2 or more lines of systemic therapy, including DLBCL not otherwise specified, diffuse large B-cell lymphoma (DLBCL) arising from low-grade lymphoma, and high-grade B-cell lymphoma.¹

The regulatory decision was supported by data from the phase 2 LOTIS-2 trial, which showed that the antibody-drug conjugate (ADC) elicited an overall response rate of 48.3% (n = 70/145) in adult patients with relapsed/refractory DLBCL after 2 or more previous systemic therapies; this included a complete response (CR) rate of 24.1% (n = 35) and partial response rate of 24.1% (n = 35).

“This opens up the armamentarium of agents that target CD19, and it allows patients to have another drug that is active against their disease,” Caimi said. “More importantly, it is a single agent drug that is active and has a different toxicity profile than other drugs that are approved in this line of therapy. For patients for whom neuropathy is a problem, loncastuximab tesirine does not have the complication.”

Because the agent is so active as a monotherapy, it is hypothesized that it will have even stronger efficacy when paired with chemotherapy or other targeted agents, according to Caimi. To this end, the agent is now under evaluation in combination with agents like with ibrutinib (Imbruvica) and with rituximab (Rituxan).

In an interview with OncLive®, Caimi, an associate professor in the Department of Medicine of the Division of Hematology and Oncology, School of Medicine, and member of the Immune Oncology Program at Case Comprehensive Cancer Center, discussed the FDA approval of loncastuximab tesirine, results from the phase 2 LOTIS-2 trial, and future research directions with the agent.

OncLive®: What are the clinical implications of the FDA approval of loncastuximab tesirine in DLBCL?

Caimi: Loncastuximabtesirineis a new ADC targeting CD19, [and is yet another option] available to patients. It is beneficial for patients with DLBCL to have multiple agents that can target the same antigen because they work in different ways. Loncastuximab tesirine is able to control disease as a single agent because it carries itself as a chemotherapy warhead; it is also an off-the-shelf agent, which is [beneficial for patients in terms of having something] immediately available compared with CAR T-cell therapy that requires time to manufacture.

Could you speak to the LOTIS-2 trial? What were the eligibility criteria?

LOTUS-2 was a multicenter, multinational, single-arm phase 2 study that included adult patients with relapsed or refractory DLBCL. Patients had to have received 2 or more prior systemic therapies and measurable disease. [Notably, patients eligible for enrollment on this trial included those with] primary refractory disease, double-hit lymphoma, and those who had [progressed on CAR T-cell therapy]. Patients with bulky disease were excluded, however, those with other high-risk [features] were included.

What efficacy data were reported with the ADC?

Seventy out of 145 patients [on the trial] experienced a response [to treatment], for an ORR of approximately 48%; 35 [patients] achieved a CR, for a CR rate of about 24%. The median time to first response was 41 days or approximately 2 cycles, and the median duration of response [DOR] for the whole cohort of responding patients was 10.3 months. For patients who achieved a CR, the median DOR was 13.4 months at data cutoff, prior to the publication of the study.

What were some of the key safety findings with the agent?

The toxicity profile of loncastuximab tesirine is somewhat different than other agents. [The ADC] does have some degree of hematologic toxicity, with approximately one-quarter of patients [reporting] neutropenia, [and 20% of patients experiencing] thrombocytopenia. Additionally, 17% of patients had increased gamma glutamyltransferase, as well as foot sensitivity. A small number of patients also developed edema or pleural effusion, and required management with diuretics, such as spironolactone, and premedication with corticosteroids to decrease the incidence of this adverse effect [AE].

What are some future research directions for this agent?

Loncastuximabtesirine’s activity as a single agent, as well as its well-tolerated profile of AEs, [provide rationale for its use in] combination with other agents. This is already being studied with ibrutinib and with rituximab. Other studies [evaluating the ADC] in combination are ongoing; [the agent] will likely be a part of a combination regimen [that will hopefully] improve responses and DOR. The fact that it is a very active single agent raises the expectation that we will have very good activity in combination with either chemotherapy drugs or other targeted drugs that are not just limited to ibrutinib.

[In DLBCL, loncastuximab tesirine could also] be considered for [use in] early lines. It would be interesting to see how well tolerated and active [the agent] is in combination with chemotherapy, and to see whether it has the potential to be used in the first-line setting with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. In this setting, it could be a relatively subtype-agnostic and risk-agnostic drug.

Beyond DLBCL, [it remains to be seen] whether this can be used [in place of] other CD19-targeting drugs. In the phase 1 LOTIS trial, data showed activity against other lymphoma subtypes. Further expansion of the label will be because other subtypes, such as follicular lymphoma and mantle cell lymphoma, are also areas of need for treatment.

Reference

1. ADC Therapeutics SA (ADCT) announces FDA approval of ZYNLONTA (loncastuximab tesirine-lpyl) in relapsed or refractory diffuse large B-cell lymphoma. News release. ADC Therapeutics. April 23, 2021. Accessed August 23, 2021. https://bit.ly/3gr0Wf1