Investigational bispecific antibody shows durable responses in phase 2 follicular lymphoma study, but no head-to-head data yet

Evidence before this study

We searched PubMed on Feb 4, 2022, for articles published in the past 10 years containing combinations of the following terms or phrases in the title or abstract only: “(relapsed OR refractory) AND (indolent lymphoma OR indolent non-Hodgkin lymphoma OR follicular lymphoma) AND (two or more OR at least 2 OR ≥2) AND (lines of therapy / treatment OR prior therapies / treatments OR previous therapies / treatments OR therapy / treatment lines OR systemic therapies / treatments) AND (Phase II OR Phase 2 OR Phase III OR Phase 3)”. Review articles and editorials (or similar) were excluded. We identified ten publications on clinical studies investigating the safety and efficacy of Bruton's tyrosine kinase, PD-1, PI3K, and EZH2 inhibitors and chimeric antigen receptor (CAR) T-cell therapies in patients with relapsed or refractory indolent non-Hodgkin lymphoma or follicular lymphoma who had received two or more previous lines of therapy. As a result of these studies, four PI3K inhibitors (idelalisib, copanlisib, duvelisib, and umbralisib), one EZH2 inhibitor (tazemetostat), and one CAR T-cell therapy (axicabtagene ciloleucel) have been approved for clinical use in patients with relapsed or refractory follicular lymphoma and two or more previous lines of therapy in the USA and in Europe, although recently the sponsors of idelalisib and duvelisib have voluntarily withdrawn the accelerated approval of these agents for relapsed or refractory follicular lymphoma in the USA. In the supporting pivotal studies of the approved PI3K and EZH2 inhibitors, objective response rates were reasonably high in the primary analyses (42–69%), but complete response rates were low (1–14%) and the duration of response was relatively short (median ≤12 months in patients with relapsed or refractory follicular lymphoma or indolent non-Hodgkin lymphoma). In the corresponding pivotal study of the approved CAR T-cell therapy, response rates were high (objective response rate of 94% and complete response rate of 79%) and the median duration of response was not reached at data cutoff, although early adverse events, such as high-grade cytokine release syndrome and neurological adverse events, were also reported. Complex procedures and an extended manufacturing lead time were noted. In addition to the above therapies approved for relapsed or refractory follicular lymphoma and two or more previous lines of therapy, other therapies approved in earlier lines such as obinutuzumab plus bendamustine or rituximab plus lenalidomide might be used, noting that non-cross-resistant regimens are preferred for patients with early relapse.

Added value of this study

Mosunetuzumab is a T-cell engaging CD20 × CD3 bispecific monoclonal antibody that is in development as an off-the-shelf immunotherapy for the treatment of relapsed or refractory non-Hodgkin lymphoma. To our knowledge, this study is the first to report positive data from a phase 2 expansion for a CD20 × CD3 bispecific antibody in patients with relapsed or refractory follicular lymphoma and is also the largest dataset in such patients. A high rate of durable responses was observed in the overall patient population, which was heavily pretreated. With a fixed duration of treatment, more than half of all responders had ongoing responses at 18 months after the first response. In subgroup analyses, consistent response rates were observed among patients who had high-risk disease characteristics. In addition, mosunetuzumab demonstrated a favourable safety profile, with a low rate of treatment discontinuation. Step-up dosing in the first cycle provided effective cytokine release syndrome mitigation, allowing administration as an outpatient regimen.

Implications of all the available evidence

Mosunetuzumab represents an active and well tolerated treatment option for patients with relapsed or refractory follicular lymphoma and two or more previous therapies that appears to be an advance in terms of anticancer activity, safety, and accessibility over the currently available therapies, although no head-to-head studies exist. Several other CD20 × CD3 bispecific antibodies are in clinical development, although pivotal data in relapsed or refractory follicular lymphoma for such agents are not yet available. The overall benefit-to-risk ratio of mosunetuzumab in patients with relapsed or refractory follicular lymphoma and two or more previous therapies appears favourable and will be further validated in ongoing studies, including a phase 3 trial comparing mosunetuzumab plus lenalidomide with rituximab plus lenalidomide in patients with relapsed or refractory follicular lymphoma and one or more previous therapy ().

Source: The Lancet Oncology