177Lu Lilotomab Satetraxten Shows Early Activity in Transplant-Ineligible, Relapsed/Refractory DLBCL

The next-generation CD37-directed radioimmunotherapy ¹⁷⁷Lu lilotomab satetraxten (Betalutin) has showcased early clinical activity with favorable tolerability when used in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for stem cell transplantation, according to initial data from the phase 1 LYMRIT 37-05 trial (NCT02658968).¹

Results indicated that activity was observed in 6 evaluable patients who received the product that the highest dosing regimen evaluated, which was 20 MBq/kg, with lilotomab given at 100 mg/m². Among the responders, 1 complete response (CR) and 1 partial response were reported.

Moreover, among the 16 patients who received treatment, ¹⁷⁷Lu lilotomab satetraxten was found to be well tolerated, with a favorable toxicity profile. A single, reversible dose-limiting toxicity was observed in the cohort of patients who received the highest dosing regimen. A review of this event conducted by the International Review Committee (IRC) led to the enrollment of 3 additional patients.

The IRC noted that the antitumor activity and safety observed with the highest dosing regimen could be considered for investigation in combination with other options used in this treatment paradigm. Efforts are focused on identifying combination partners that will not compromise the toxicity profile of ¹⁷⁷Lu lilotomab satetraxten.

“We continue to be very encouraged by the overall safety profile that [¹⁷⁷Lu lilotomab satetraxten] exhibits in even the most fragile and highly pretreated patients with non-Hodgkin lymphoma,” Peter Braun, chief executive officer at Nordic Nanovector, stated in a press release. “We have also seen clinical activity in [patients with] DLBCL from a single administration of [¹⁷⁷Lu lilotomab satetraxten] and we will now consider the next steps for its development in this large patient population potentially in combination with other therapies, as part of our overall strategy to develop [the product] for difficult-to-treat hematological tumors.”

In the open-label, single-arm, dose-escalation phase 1 trial, investigators set out to evaluate the safety and preliminary activity of single-dose ¹⁷⁷Lu lilotomab satetraxten. Participants were enrolled at clinical sites throughout the United States and Europe.

To be eligible for participation, patients needed to be at least 18 years of age, have histologically confirmed DLBCL, and have previously received at least 1 line of therapy, including chemoimmunotherapy.² Moreover, patients had to be in first or subsequent relapse or refractory to the last therapy they received.

Other inclusion criteria included a life expectancy of at least 3 months, an ECOG performance status of 0 to 2, and normal organ and bone marrow function. Patients could not be eligible for, or they must have declined, high-dose chemotherapy and autologous stem cell transplant.

Patients enrolled to cohort 1 received ¹⁷⁷Lu lilotomab satetraxten at a starting dose of 10 MBq/kg with 60 mg of lilotomab (n = 3). Cohort 2 received ¹⁷⁷Lu lilotomab satetraxten at 10 MBq/kg with 100 mg of lilotomab (n = 3). Moreover, cohort 3 was given ¹⁷⁷Lu lilotomab satetraxten at a dose of 15 MBq/kg plus 100 mg of lilotomab (n = 3), and cohort 4 received the 2 agents at 20 MBq/kg and 100 mg, respectively (n = 7).

The primary outcome measure of the trial is to determine the maximum-tolerated dose of the regimen, and secondary measures are focused on best overall tumor response rate and dosimetry. Investigators will also evaluate safety, pharmacokinetics (PK), and biodistribution.

Previously, the phase 1/2a LYMRIT-37-01 trial (NCT01796171), a dose-escalation and expansion study, evaluated the safety, biodistribution, and PK of single-dose radioimmunotherapy with ¹⁷⁷Lu lilotomab satetraxten in patients with relapsed, indolent non-Hodgkin lymphoma.³

Patients needed to be at least 18 years of age and have histologically confirmed, relapsed/refractory indolent non-Hodgkin B-cell lymphoma, which could include follicular grade I to IIIA disease, marginal zone lymphoma, small lymphocytic disease, or lymphoplasmacytic disease. Patients with mantle cell lymphoma were also eligible to participate.

Key eligibility criteria for the trial required that patients have a World Health Organization performance status of 0 or 1, a life expectancy of at least 3 months, less than 25% of tumor cells in bone marrow biopsy, and measurable disease. Patients could not have central nervous system lymphoma, transformed disease, or have previously undergone a stem cell transplant.

The lilotomab satetraxten conjugate was manufactured by conjugating lilotomab with the chelator satetraxten. The conjugate was mixed with noncarrier added ¹⁷⁷Lu for each patient to create the final ¹⁷⁷Lu lilotomab satetraxten product, which was supplied to centers involved in the trial. Doses for the product were calculated based on patient body weight on the day of administration and they were corrected for physical decay of ¹⁷⁷Lu.

The trial was comprised of 5 arms. Arm 1 received pretreatment with rituximab (Rituxan) at a dose of 375 mg/m2 on day -28 and -21, a pre-dose of lilotomab at 40 mg, and ¹⁷⁷Lu lilotomab satetraxten at either 10 MBq (n = 3), 15 MBq/kg (n = 6), or 20 MBq/kg (n = 3). Those enrolled to arm 4 of the trial received pretreatment with rituximab at a dose of 375 mg/m2 on day -14, a pre-dose of lilotomab at 100 mg/m2, and 177Lu lilotomab satetraxten at a dose of either 15 MBq/kg (n = 3) or 20 MBq/kg (n = 7).

In arm 1, the dose of 15 MBq/kg of ¹⁷⁷Lu lilotomab satetraxten was selected for dose expansion (n = 30), and in arm 4, the dose of 20 MBq/kg was selected for dose expansion (n = 12). Arms 2, 3, and 5 have closed.

Most patients in the phase 1 and 2a portions of the trial had follicular lymphoma. Notably, 34% of patients in phase 1 and 44% of those in phase 2a were refractory to rituximab. Participants had received a median of 2 prior lines of therapy, which included rituximab (91%), alkylating agents (81%), and bendamustine (31%). Twenty-eight percent of patients were refractory to the last line of therapy that they had received prior to study entry; 30% of these patients had follicular lymphoma.

Results indicated that the overall response rate (ORR) achieved with this approach was 61%, with 30% of patients experiencing a CR. The ORR was slightly higher in patients with follicular lymphoma, at 65%. Among patients with follicular lymphoma who were refractory to rituximab and had received 2 or more prior therapies (n = 21), the ORR was even higher, at 67%, with a CR rate of 24%. The overall median duration of response with the treatment was 13.6 months; this was 32.0 months in those who achieved a CR.

Regarding safety, the most frequent adverse effects reported with ¹⁷⁷Lu lilotomab satetraxten were found to be reversible and included grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks following radioimmunotherapy. Moreover, the most common nonhematologic toxicity was grade 1/2 nausea, which was reported in 15.8% of patients.

References

1. Nordic Nanovector announces initial results from LYMRIT 37-05 phase 1 trial of Betalutin in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). News release. Nordic Nanovector. June 22, 2021. Accessed June 23, 2021. https://prn.to/3d9lWVL
2. Study of Betalutin for treatment of relapsed or refractory non-Hodgkin lymphoma (LYMRIT-37-05). ClinicalTrials.gov. Updated December 1, 2020. Accessed June 23, 2021. https://clinicaltrials.gov/ct2/show/NCT02658968
3. Kolstad A, Illidge T, Bolstad N, et al. Phase 1/2a study of 177Lu-lilotomab satetraxten in relapsed/refractory indolent non-Hodgkin lymphoma. Blood. 2020;4(17):4091-4101. doi:10.1182/bloodadvances.2020002583