Bispecific antibody mosunetuzumab: phase II expansion
Mosunetuzumab is a bispecific antibody that redirects T cells to eliminate malignant B cells by binding to CD3 on T cells and CD20 on B cells . In patients with relapsed/refractory follicular lymphoma (FL) and ≥ 2 prior therapies, mosunetuzumab has shown encouraging efficacy and manageable safety in the phase I setting . Findings obtained in the international, single-arm, pivotal phase II expansion study were presented by Budde et al. at ASH 2021 .
This analysis included 90 patients with FL grade 1-3a after ≥ 2 prior regimens including ≥ 1 anti-CD20 antibody and ≥ 1 alkylating agent. They received fixed-duration treatment with 3-weekly mosunetuzumab; those who achieved CR after 8 cycles discontinued their treatment at that time, while those who showed partial response or disease stabilization after 8 cycles went on to receive a total of 17 cycles. Step-up dosing was performed in cycle 1 to mitigate cytokine release syndrome (CRS) and to allow for a higher targeted dose. Hospitalization was not mandatory. CR as best response by independent review facility constituted the primary endpoint and was assessed against the 14 % historical control CR rate . After a median number of 3 prior treatment lines, approximately 50 % of patients were double refractory to any prior anti-CD20/alkylator therapy. Likewise, more than 50 % had experienced disease progression within 24 months (POD24). These are indicators for advanced disease and elevated risk commonly associated with poor prognosis.
Deep responses in heavily pretreated FL patients
After a median follow-up of 18.3 months, 60 % of patients had completed treatment. Eight and 17 cycles had been administered in 58.9 % and 12.2 %, respectively. The study met its primary endpoint, with the 60 % CR rate being significantly greater than the historical control rate (p < 0.0001). Overall, 80 % of patients responded to treatment. Subgroup analyses demonstrated that high-risk groups including those with double-refractory disease and POD24, as compared to other groups, obtained similar response rates. Median duration of response was 22.8 months both in all responders and complete responders. At 18 months, 70 % of complete responders were event-free. Median PFS amounted to 17.9 months.
Mosunetuzumab showed a favorable tolerability profile. Treatment-related grade 3/4 AEs and AEs necessitating discontinuation occurred in 51.1 % and 2.2 %, respectively. No patient died due to mosunetuzumab-related AEs. CRS was the predominant AE, with an any-grade incidence rate of 44.4 %. Most events were low-grade and were confined to cycle 1. CRS management required the administration of corticosteroids and tocilizumab in 11.1 % and 7.8 %, respectively. All events eventually resolved. Immune effector cell-associated neurotoxicity syndrome events were infrequent (4.4 %) and confined to grade 1 and 2. No cases of aphasia, seizures, encephalopathy, or cerebral edema occurred. As the authors noted in their conclusion, mosunetuzumab is the first T-cell–engaging bispecific antibody to demonstrate clinically meaningful outcomes for patients with relapsed/refractory FL in the pivotal phase II setting.
Naratuximab emtansine plus rituximab
A medical need for new treatment options is evident in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), particularly relapsed/refractory DLBCL, who are no candidates for stem cell transplant or CAR-T cell therapy. The CD37-targeting antibody-drug conjugate naratuximab emtansine was tested in combination with rituximab in an open-label, multicenter, adaptive phase II study conducted in patients with DLBCL and other NHL B-cell lymphomas after 1-6 treatment lines . The study consisted of two parts. Patients included in Part 1 had a confirmed diagnosis of relapsed/refractory NHL including DLBCL, FL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). These were treated 3-weekly (Q3W). Part 2 was limited to patients with relapsed/refractory DLBCL ineligible for stem cell transplantation; here, two dosing strategies were evaluated. Cohort A was dosed Q3W, while Cohort B received weekly treatment (QW). Overall, 50 and 30 DLBCL patients received Q3W and QW treatment with naratuximab emtansine, respectively. Another 20 had other types of NHL and were treated Q3W (Table 1).
This study enrolled patients who are often excluded from DLBCL trials due to double- or triple-hit morphologies, bulky disease, transformed lymphoma, and primary refractory disease or disease refractory to the last treatment. Thus, the population mirrored the difficult-to-treat patients seen in everyday practice. The overall response rate was defined as the primary endpoint.
Efficacy across lines and treatment schemas
Substantial proportions of patients in the three groups managed to complete ≥ 6 cycles (Table 1). In the efficacy-evaluable DLBCL population (n = 76), 44.7 % of patients responded, and 31.6 % achieved complete responses. CR rates were 43.3 % and 33.3 % for Cohorts A (Q3W) and Cohort B (QW). The objective response rate (ORR) was 50 % for both cohorts. Similar rates resulted in patients treated in the third and later lines who were non-primary refractory (ORR, 46.4 %; CR, 32.1 %). Patients with relapsed/refractory FL obtained an ORR of 57.1 %. Median duration of response had not been reached for either DLBCL or FL. Sixty-six percent of patients with DLBCL showed a duration of response > 12 months.
The most frequently observed grade 3/4 treatment-emergent AEs (TEAEs) were hematological in nature and manageable. G-CSF prophylaxis was offered to 22 % of patients. Three liver TEAEs grade ≥ 3 occurred, as well as 2 cases of non-serious neuropathy grade ≥ 3. Most of the patients discontinued treatment because of disease progression rather than AEs (Table 1). Ten patients died due to TEAEs; 2 of these were considered related to the treatment. According to the assessment of health-related quality of life, the administration of naratuximab emtansine was associated with a significant increase in well-being in 38 % of responders. The vast majority of patients reported that they were not or hardly bothered by the side effects of treatment. In their summary, the authors noted that naratuximab emtansine plus rituximab might represent a new option for patients with relapsed/refractory NHL, especially DLBCL, including heavily pretreated patients.