Background: Mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific antibody, combined with polatuzumab vedotin (Pola), a CD79b-directed antibody–drug conjugate, is an effective regimen for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). The primary analysis of Mosun-Pola in a Phase Ib/II study (NCT03671018) demonstrated durable responses and manageable safety in patients (pts) with transplant-ineligible R/R LBCL (Budde et al. Nat Med 2023). We report 3-year follow-up efficacy and safety data, and subgroup analyses for high-risk pts, including those who experienced early relapse or were refractory to primary therapy, or were refractory to their last therapy or prior chimeric antigen receptor T-cell therapy (CAR-T).

Methods: Pts with R/R LBCL (diffuse [D] LBCL not otherwise specified, high-grade B-cell lymphoma [HGBCL], follicular lymphoma [FL] Grade 3b) who received ≥1 prior line of therapy (including an anti-CD20 antibody) were treated with Mosun-Pola in 21-day cycles. Pola (1.8mg/kg) was administered on Day (D) 1 of Cycles (C) 1–6. Mosun was administered with C1 step-up dosing: C1D1 (1mg), C1D8 (2mg), C1D15 (60mg), C2D1 (60mg), and 30mg on D1 of C3+. Pts with a complete response (CR) completed Mosun after C8; pts with stable disease or partial response at the end of C8 continued Mosun for a total of 17 cycles. The primary endpoint was best overall response rate (ORR) by the Independent Review Committee (IRC). Secondary endpoints included CR rate, duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), and safety.

Results: As of November 15, 2024, 98 pts were enrolled, of whom 85 (87%) were based in the US. The mean age was 68 (range: 20–88) and 29% were female (Budde et al. Nat Med 2023). Most pts (n=73, 74%) had DLBCL, 23 (23%) had HGBCL and 2 (2%) had FL Grade 3b. Median number of prior lines of therapy was 2 (range: 1–8); 43% of pts had ≥3 prior therapies and 37% had prior CAR-T. Most pts (77%) were refractory to their last prior therapy, 73% were refractory to or had early relapse after primary therapy, and 27% were refractory to CAR-T. Median follow-up was 38.5 months (range: 0–52).

Overall, the IRC-assessed ORR and CR rate were 62% (95% confidence interval [CI]: 52–72) and 50% (95% CI: 40–60), respectively. Median DOR was 43.7 months (95% CI: 16.2–not evaluable [NE]) and the 36-month DOR rate was 53% (95% CI: 39–68). Median DOCR was 43.7 months (95% CI: 21–NE; range: 0–46 months), and the 36-month DOCR rate was 58% (95% CI: 43–73). Median PFS was 14.1 months (95% CI: 8.8–29) and the 36-month PFS rate was 37% (95% CI: 26–49). Median OS was 26.9 months (95% CI: 15–NE) and the 36-month OS rate was 48% (95% CI: 38–58).

Response rates were generally consistent across high-risk subgroups. In pts with early relapsed or primary refractory LBCL (n=72), ORR was 58% (95% CI: 46–70) and CR rate was 44% (95% CI: 33–57). In pts refractory to last prior therapy (n=75), ORR was 55% (95% CI: 43–66) and CR rate was 41% (95% CI: 30–53). The ORR and CR rate in pts with prior CAR-T (n=36) were 67% (95% CI: 49–81) and 50% (95% CI: 33–67), respectively. In pts refractory to CAR-T (n=26), the ORR was 58% (95% CI: 37–77) and CR rate was 42% (95% CI: 23–63). PFS and OS subgroup data will be presented.

Safety data were consistent with previous analyses; no new cytokine release syndrome events were reported. Following the last data cutoff (July 6, 2023), 2 new adverse events (AE) were reported. Both were Grade 3 serious AEs (COVID-19 and influenza) and occurred in the same patient. Grade 3–5 serious infections occurred in 12 (12%) pts and included Grade 3 COVID-19/COVID-19 pneumonia (n=4), and sepsis (n=1), and Grade 5 COVID-19 pneumonia (n=2) and pneumonia (n=1). The median duration of infections was 16.5 days (n=68; range: 1–499). No additional Grade 5 AEs were reported. Biomarker data will be presented.

Conclusions: With a median follow-up of over 3 years, Mosun-Pola continued to show high, durable, and clinically meaningful responses in pts with highly refractory R/R LBCL, including pts with prior CAR T-cell therapy or primary refractory disease. At 3 years, 37% of pts remained free of progression, and 48% were alive. Consistent with previous analyses, the safety profile remained manageable. Mosun-Pola may be beneficial for transplant-ineligible pts, those with co-morbidities, or pts with limited access to or relapse after CAR-T.

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2025
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