Discussion
LBCL, toxicities, aggressive R/R LBCL
DISEASE, REMISSIONS
Primary analysis results from this phase 1b/2 dose-escalation and dose-expansion study demonstrated that mosun-pola is an effective therapy with durable responses and a manageable safety profile in patients with R/R LBCL. The MTD was not reached, and the RP2D of mosunetuzumab was established as 1/2/60/30 mg in combination with polatuzumab vedotin.Patients with R/R LBCL in the dose-expansion cohort treated at the RP2D were observed to have responses of 59.2%, including complete response in 45.9% of patients. With a follow-up of almost 2 years, median PFS was 11.4 months, and median DoCR was not reached. Patients who had received prior CAR-T cell therapy and other high-risk subpopulations (DH/THL, HGBCL and primary refractory disease) demonstrated promising efficacy, which is clinically meaningful given the aggressive nature of the disease.Although comparing across different patient populations and small sample sizes, previous studies showed that single-agent mosunetuzumab achieved a complete response rate of 24%The overall safety profile of mosun-pola was consistent between the overall safety cohort and the dose-expansion cohort treated at the RP2D; was comparable to those of the individual agents in patients with R/R B-NHLThe addition of polatuzumab vedotin to mosunetuzumab had minimal impact on T cell activation by mosunetuzumab, as measured by CD69Previous studies exploring regimens in the second-line or later settings reported a best ORR of 62% and a median PFS of 5.4 months for polatuzumab plus bendamustine and rituximabIn the current study, cell of origin (COO) was assessed by investigators. A numerically greater response was observed in patients with R/R non-germinal center B cell-like (GCB) LBCL compared to those with R/R GCB-LBCL. However, there remains a benefit in patients with GCB-LBCL; the ORR and complete response rates were 55% and 36%, respectively. Comparatively, complete remissions with single-agent mosunetuzumab in third-line and later R/R LBCL were 24% in GCB and 28% in non-GCBThe migration of polatuzumab vedotin to the front-line setting identifies a need to understand the ability to retreat with polatuzumab vedotin. Similar to repeated CD20 targeting, polatuzumab vedotin retreatment may be possible if CD79B expression is retained and polatuzumab vedotin–associated toxicities are limited. In this study, two patients were retreated with mosun-pola while still on study, and five patients were retreated with polatuzumab vedotin as a component of next anti-lymphoma therapy. However, a larger cohort of patients is necessary to further guide clinical practice. In patients treated with polatuzumab vedotin–based therapy in the front-line setting, mosun-pola may be suited for patients who are not refractory to polatuzumab vedotin and have no substantial polatuzumab vedotin–specific contraindications or persistent AEs.The rapidly evolving treatment landscape for R/R LBCL offers patients multiple options. In the second-line transplant-ineligible space, treatment options may include tafa-len, CAR-T cell therapy and traditional chemotherapy, with selection dependent upon potential for cure. Acknowledging differences in study design, patient populations and caveats of cross-trial comparisons, the clinical outcomes and safety profile of mosun-pola are encouraging. The benefits of mosun-pola lie in its relatively high activity, durable responses and ease of administration as a fixed-duration regimen applicable to community oncology practices. Additionally, mosun-pola is distinguished as a bispecific antibody combination with a non-traditional chemotherapy partner. Despite transplant eligibility being an exclusion criterion, some patients were able to receive ASCT, allogeneic SCT and CAR-T cell therapy after mosun-pola, suggesting that disease status and/or disease-associated comorbidities were contributory features for transplant ineligibility at the time of enrollment. In particular, some patients were resistant to salvage therapy yet achieved a response to mosun-pola, which facilitated subsequent eligibility for consolidation with ASCT, allogeneic SCT or CAR-T cell therapy.Our study is limited by its single-arm design and the potential for selection bias. Furthermore, although the responses in high-risk subgroups are promising, the study is underpowered to assess efficacy in these subgroups. Additional translational studies are needed to fully understand mechanisms of resistance to this combination regimen. CD20 loss has been observed as a mechanism of acquired resistance to treatment regimens targeting CD20, including mosunetuzumabIn conclusion, this phase 1b/2 study demonstrated that mosun-pola, a combination regimen targeting two biologically relevant B cell targets using a T-cell-engaging bispecific antibody and an antibody–drug conjugate, induced durable responses in patients with R/R LBCL, including patients with poor clinical and pathologic prognostic features, such as relapse after CAR-T cell therapy. Despite enrolling patients with poor prognostic features, the regimen has a safety profile that is manageable in an outpatient setting. Based on the observed efficacy and safety profile, mosun-pola holds promise for patients with aggressive R/R LBCL ineligible for ASCT or aggressive intense immunochemotherapy.