TP53-mutant disease: BOVen
Patients with TP53-mutant MCL constitute a high-risk subset that shows poor survival when treated with intensive chemoimmunotherapy . Given the lack of a standard frontline regimen, the combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen) was hypothesized to be well tolerated and efficacious in this setting. It has already been demonstrated that the combination of a BTK inhibitor with a BCL2 inhibitor is synergistic and active in relapsed/refractory MCL, including patients with TP53 mutation . Ibrutinib, obinutuzumab, and venetoclax has given rise to high response rates in relapsed and untreated MCL .
The preliminary analysis of a multicenter, investigator-initiated phase II study presented at ASH 2021 by Kumar et al. showed promising efficacy and good tolerability of BOVen in 17 patients with previously untreated MCL and TP53 mutation . Fourteen patients were evaluable for efficacy. After a median follow-up of 4 months, the ORR was 86 %, with a CR rate of 64 %. At cycle 3, peripheral blood flow cytometry became negative in all patients. Grade ≥ 3 AEs occurred in 11 %. Serious AEs included grade 3 lung infection, grade 4 tumor lysis syndrome, and grade 1 non-neutropenic fever. No events resulted in drug discontinuation. Longer follow-up is required to further assess the outcomes over time.
Step-up dosing of glofitamab
The bispecific antibody glofitamab redirects T cells to eliminate malignant B cells by targeting both CD20 and CD3 . Glofitamab has shown promising efficacy and manageable safety as monotherapy and in combination with obinutuzumab in patients with heavily pretreated relapsed/refractory B-NHL [9, 10]. Obinutuzumab pretreatment and/or cycle 1 step-up dosing enabled effective mitigation of cytokine release syndrome (CRS). At ASH 2021, Phillips et al. reported data on obinutuzumab followed by glofitamab monotherapy in patients with relapsed/refractory MCL who were treated in the phase I dose escalation setting . The study contained 3 arms. Glofitamab was assessed with fixed dosing after obinutuzumab 1,000 (n = 3), and with step-up dosing over 12 cycles (2.5 mg up to 30 mg) after obinutuzumab administered at doses of either 1,000 mg (n = 7) or 2,000 mg (n = 19) (Figure 2).
This approach gave rise to high response rates, with activity observed across the dosing regimens. For fixed dosing of glofitamab after obinutuzumab 1,000 mg, responses occurred in 67 %, and for step-up dosing after obinutuzumab 1,000 mg and 2,000 mg, this was 71 % and 91 %, respectively. Prior BTK inhibitor therapy did not affect the results; response rates in patients with and without prior BTK inhibition amounted to 83 % and 75 %, respectively. Overall, 81 % of patients in the entire group responded, and complete metabolic responses arose in 67 %. At the time of the data cutoff, most patients had ongoing responses, and 85.7 % of those with a CR remained in remission.
The treatment demonstrated favorable safety. Glofitamab-related grade 3/4 AEs occurred in 24.1 % of all patients. No fatal AEs or AEs leading to treatment discontinuation were reported. CRS represented the most common all-grade AE (58.6 %). Most CRS events were observed during cycle 1, were grade 1 or 2, and resolved. Immune effector cell-associated neurotoxicity syndrome (ICANS) grade 1 emerged in one patient (3.4 %) in the 1.000 mg obinutuzumab plus glofitamab step-up dosing cohort. No grade ≥ 2 ICANS or grade ≥ 3 tumor flare events were noted.
The authors pointed out that these results support a future confirmatory trial. Glofitamab, which is a fixed-duration regimen with off-the-shelf availability, continues to be evaluated in patients with relapsed/refractory MCL after BTK inhibitor treatment.