Carmelo Carlo-Stella, MD, Professor of Hematology, Humanitas University, Section Chief, Lymphoid Malignancies, Humanitas Cancer Center, Humanitas Clinical & Research Center, Milan, Italy, discusses a phase 2 study on loncastuximab tesirine plus ibrutinib for patients with advanced diffuse large B-cell lymphoma (DLBCL). These data were presented at the 2021 ASH Annual Meeting.

Transcript

My name is Carmelo Carlo-Stella. I am Professor of Hematology at Humanitas University in Milano, and I am chief of the section of Lymphoid Malignancies at the Humanitas Cancer Center.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

The big round of the largest 3 span relies on a few points. The first point is that relapse and refractory diffuse large B-cell lymphoma patients still represent an unmet medical need, despite the recent advances that we have observed in this field, including new immunotherapy molecules such as CAR T-cell therapy.

Since the great majority of these patients are not cured by existing therapy, elaborating and investigating new therapies remains an important goal.

Loncastuximab is an antibody-drug conjugated, which has been shown in phase 1 and in phase 2 to be very effective in patients with DLBCL, particularly in patients with high genetic refractory and high genetic risk.

This was the first consideration. However, the phase 2 efficacy data can obviously be improved, and so we hypothesized that the combination of loncastuximab with a molecule with a different mechanism of action could result in an improvement on the efficacy of lonca.

Ibrutinib was selected due to its mechanism of action that is a very general and broad mechanism of action, targeting neoplastic disease. They both discovered that the combination of ABC antibody with ibrutinib could result in an improvement on the efficacy in patients with relapse and refractory DLBCL.

OLN: Can you briefly describe your recent study and the findings? Were you surprised by any of the outcomes?

The LOTUS-3 trial is an open-label, single-arm, phase 1/2 trial combining loncastuximab with ibrutinib. The maximum tolerated dose of both these agents had been identified during the phase 1, and now, we are conducting the phase 2 part of the study.

In particular, at ASH, we reported the planned interim analysis of the phase 2 local trial. The main objective of the phase 2 is to identify the complete remission rate that can be obtained with the combination of lonca plus ibrutinib in relapse and refractory non-GCB, non germinal center B-cell DLBCL.

The objective of the planned interim analysis is to determine if the complete remission rate in the non-GCB DLBCL cohort, warranted the continuation of patient enrollment to study completion. The patients enrolled in phase 2 are DLBCL relapse and refractory, with a minimum of 18-year-old age, measurable disease, and an ECOG ranging from 0 to 2.

Patients receive 2 cycles of lonca, and they achieve a response in terms of complete response, fast response, or stable disease. They can achieve an additional fourth cycles of lonca at day 1 of cycles 5, 6, 9, and 10. Lonca treatment is combined with the oral administration of ibrutinib for up to 1 year.

The main finding in terms of drug efficacy in these population of patients, is composed of patients who are early pretreated. In fact, they have received a median of 3 previous line of therapy. In addition, these are patients with a very high percentage of primary refractory patients. In fact, the primary refractory patients account for about 30 percent of the overall cohort in the patients so far enrolled.

Early pretreated and refractory, these are the main features. The efficacy finding in these patients is a very interesting one, because the overall response rate in the global population of 35 patients is 57 percent, with that 34 percent of patients achieving a complete remission.

The 35 patients so far enrolled in the third objective of this analysis include 22 patients with non-germinal center DLBCL, and 13 patients with germinal center B-cell DLBCL. The overall response rate in the non-germinal center patients is 45 percent, and the overall response rate in germinal center B-cell is 77 percent.

This 77 percent is quite an impressive result, because we were anticipating a better activity on lonca plus ibrutinib in the non-germinal center B-cell patients, while the finding we observed in this, very interesting, is that 77 percent of GCB patients are responding, with a very high percentage of complete remission.

46 percent of the GCB patients achieved a complete remission, as opposed to the 27 percent if the non-germinal center B-cell patient population. The toxicity of some of these patients was manageable, and essentially consisted of hematological toxicity, including thrombocytopenia, neutropenia, and anemia.

However, patients with grade 3 or higher treatment-related adverse events, where in the global population of 45 patients were 51 percent, with 23 percent of the patients experiencing grade 3 or higher neutropenia, and 17 percent experiencing grade 3 or higher thrombocytopenia.

Among non-hematological adverse events, we observed coronavirus infection in 3 patients, febrile neutropenia in 2 patients, and a general physical health decline in 2 patients. These findings support the initial hypothesis of a better efficacy activity of lonca in combination with ibrutinib. Overall, they support the continuation of the study. The study will also be amended, so to be able to use loncastuximab at each cycle the patient will receive.

OLN: What are the possible real-world applications of these findings in clinical practice?

Upon conclusion of the study, I think that the translation in the real world application will be the use of this combination first in elderly patients that could receive this therapy instead of conventional chemotherapy.

Chemotherapy is very difficult to be used in elderly patients with DLBCL. Particularly, with elderly patients with relapse and refractory DLBCL. The use of this specific therapy, lonca plus ibrutinib, which is very effective -- significantly more effective, let me say, than even a non-comparative basis -- is very effective, and more effective than conventional chemo. In addition, it's very manageable in terms of toxicity.

The first real world application will be in the elderly population of relapse refractory DLBCL, but in addition, such a high effective combination of novel agents, 2 novel agents, will need to be applied in young patients, for example, as a bridge therapy prior to CAR T-cell therapy.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be the next steps?

We've learned to translate this specific combination also in patients with indolent lymphoma. For example, follicular lymphoma, so marginal zone lymphomas, where lonca has already been proven to be very effective.

We also plan to make a more detailed biomarker analysis in biosamples from patients who have been enrolled in the DLBCL part of the LOTUS-3 trial. Biomarker analysis can -- such as the analysis of circulating DNA -- may be a great opportunity for identifying predictive markers of response, and can be potentially be used in the future as a driving biomarker for key managing factor of optimizing this therapy.