Response-adapted treatment with mosunetuzumab with or without obinutuzumab and polatuzumab vedotin in treatment naïve follicular and marginal zone lymphoma: Final results and phased-seq MRD analysis

Abstract Background: Mosunetuzumab (mosun) is a CD20xCD3 bispecific antibody that is active in relapsed/refractory follicular lymphoma. We designed a PET response adapted study for patients (pts) with untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL) (NCT05169658). Methods This was a single center, open label, investigator-initiated response-adapted clinical trial in untreated pts with FL or MZL with indication for treatment. Pts received subcutaneous mosunetuzumab monotherapy for 8 cycles (Part A) employing step up dosing in cycle 1 (5/45/45 mg). A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. Pts with SD or PR could receive 6 cycles of polatuzumab vedotin and obinutuzumab (Part B), followed by an end of treatment (EOT) PET/CT. The primary endpoint was best response as complete response (CR) rate. A CR rate of ≥80% is considered a promising signal of efficacy, based on retrospective benchmarks from chemoimmunotherapy in indolent lymphoma. Planned sample size of 42 patients. Interim efficacy and safety stopping rules were in place. PhasED-Seq (Kurtz et al. Nature Biotech 2021) was performed on baseline plasma specimens as well as at C3D1, after all mosun treatment, and after obinutuzumab and polatuzumab vedotin for those in PR. Results 42 pts enrolled on study between March 24, 2022, and October 2, 2024, with all pts evaluable for safety and efficacy. This included Grade 1-2 FL (30), Grade 3a FL (7), and MZL (5). All 42 patients have completed Part A mosun therapy, with an ORR and CR rate of 100% and 76%, respectively. 7 patients ultimately proceeded with Part B, with 6/7 (86%) achieving a CR. Two patients did not proceed with Part B due to progression and transformation events, respectively. Another patient elected not to proceed with Part B in PR. One patient who initiated part B was unable to complete cycle 1 of part B due to neutropenia and thrombocytopenia and remains in an improving PR with serial imaging off all study therapy for 6 months. The rate of CR as best response was 90%, exceeding the pre-specified efficacy benchmark. With a median follow-up of 24.7 months, the 2-year PFS for the overall population is 88% (95% CI: 77-100%). By histology, the 2-year PFS for Grade 1-2 FL was 86% (95% CI: 73-100%), Grade 3A was 86% (63%-100%), and MZL was 100% (100-100%). To date, no patient has died during or after study therapy. Four progression events have been observed to date. One transformation and one CD20-negative FL relapse were observed immediately after Part A mosun monotherapy. One transformation was observed about one year after completion of Part A alone. One CD20 negative FL relapse was observed about one year after completion of Part B. Five pts experienced a serious adverse event, (one pt with G3 lung infection followed by G3 shingles, one pt observed inpatient overnight with G1 cytokine release syndrome, and one pt with a G2 URI, one episode of G3 febrile neutropenia, and one patient with G3 abdominal pain/malabsorption). Other notable AEs include CRS (64%, all G1), Headache (60%, G2 7%), Neutropenia (31%, G4 12%), and ALT elevation (40%, G3 4%) Thirty-six patients had baseline and on treatment samples available for MRD analysis. All patients analyzed had detectable ctDNA at baseline. After 2 cycles of mosun, 16/35 (46%) of patients had undetectable MRD. After 8 cycles of mosun, 27/36 (75%) of patients had undetectable MRD. Five pts who proceeded with Part B due to PET+ post Part A had samples available. 4/5 of these patients in PR were ctDNA positive prior to Part B, with rising ctDNA levels observed between the interim and end of Part A timepoints. Despite this finding all 5 patients achieved a CR and undetectable MRD after completion of Part B. In an exploratory analysis, we calculated 2-year PFS by MRD detectable vs. detectable in Part A at C3D1 (75% vs. 100% (p=0.065)) as well as end of Part A (65% vs. 94% (p=0.021)). Summary/Conclusion: Fixed duration mosun monotherapy achieves a high CR rate in untreated pts with follicular and marginal zone lymphoma, with high rates of undetectable MRD. Obinutuzumab and pola appeared to reverse early signs of treatment failure. MRD-adapted approaches warrant further study to determine patients who may benefit from chemo-free treatment or who may require escalated therapy.