Within the past few years, many targeted therapies have emerged to address the poor outcomes faced by patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL), including chimeric antigen receptor (CAR) T-cell therapy, antibody drug conjugates (ADC), and bispecific antibodies. This rapid expansion in the treatment landscape has introduced several targeted options but has also led to more questions regarding the preferred sequencing among the various options.
Despite advances in R/R LBCL therapy, a large portion of patients will either relapse following CAR T-cell therapy or are not candidates, emphasizing the need for accessible, well-tolerated, and effective therapies. Bispecific antibodies (targeting CD20 and CD3) may offer a solution to some of these challenges. Single-arm phase II studies of epcoritamab and glofitamab demonstrated an objective response rate (ORR) of 52 to 63% (complete response rate [CR]: ~39%), with durable responses.1,2 Cytokine release syndrome (CRS), one of the most frequent adverse events associated with these bispecific antibodies, occurred in 50 to 63% of patients, with most cases being grade 1 or 2 and confined to the first cycle. Both epcoritamab and glofitamab are approved in the U.S. for third-line or later R/R LBCL treatment.
Mosunetuzumab is a CD20xCD3 bispecific antibody approved for R/R follicular lymphoma, but not for LBCL. The reported ORR and CR for mosunetuzumab monotherapy were 42% and 24%, respectively, with a 26% incidence of CRS in R/R LBCL.3 Polatuzumab vedotin is a CD79b-targeting antibody conjugated to a microtubule inhibitor and is approved in combination with chemoimmunotherapy in the frontline and relapsed LBCL settings. Although neither mosunetuzumab nor polatuzumab exhibits high single-agent activity in LBCL, there are no significant overlapping toxicities, suggesting they can be combined to improve efficacy.
Lihua Budde, MD, PhD, and colleagues reported on a phase Ib/II study of mosunetuzumab in combination with polatuzumab in 120 patients with second-line or later LBCL.4 Patients received a median of two prior lines of therapy, with 35% previously receiving CAR T-cell therapy. The ORR was 59% (CR: 46%). Over a median follow-up of 23.9 months, median duration of response was not reached, median progression-free survival was 11.4 months, and median overall survival was 23.3 months. CRS was observed in 17% of patients, and most cases were grade 1 or 2. In general, these findings suggest that mosunetuzumab plus polatuzumab is a well-tolerated targeted combination with higher efficacy than that observed for either agent alone or in other settings. The toxicity profile for this combination also appears to be more favorable than those for other R/R LBCL therapies, which may increase access since treatment can be safely administered in the outpatient setting.
In Brief
A randomized study has now launched to explore whether mosunetuzumab plus polatuzumab is more effective than chemoimmunotherapy in patients with R/R LBCL. Several important questions remain, including whether polatuzumab can be used in multiple lines of therapy given the POLARIX study supporting its use in frontline LBCL5 and the risk for peripheral neuropathy, which was 31% in this study (grade 3: 2.5%). Further, is mosunetuzumab the most promising bispecific for combination therapy with polatuzumab in LBCL? Can this combination replace the need for CAR T-cell therapy given its impressive efficacy in recent trials? Despite some unanswered questions, this novel targeted combination appears promising for patients with R/R LBCL and opens the door to additional novel combinations in the future.
Competing Interests
Dr. Nastoupil has received honoraria for participation on advisory boards and research support from Genentech/Roche.
