Treatment Duration and Risk of Fatal Infections in Patients with B-Cell Non-Hodgkin Lymphoma Achieving Complete Response with Odronextamab

Introduction

The optimal duration of treatment with bispecfic antibodies in the setting of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) has not been prospectively determined. In the Phase 2 ELM-2 study (NCT03888105), odronextamab, a CD20×CD3 bispecific antibody, was evaluated in patients with R/R follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of systemic therapy. Patients received intravenous (IV) odronextamab in 21-day cycles with step-up dosing in Cycle 1, 80 mg (FL)/160 mg (DLBCL) QW in Cycles 2-4, then 160 mg (FL)/320 mg (DLBCL) Q2W post-Cycle 4 until disease progression or unacceptable toxicity (as described previously). During step-up dosing, patients received premedication with dexamethasone (10 mg orally [or equivalent] prior to the first split infusion, and 20 mg IV on each day of split infusion).

Serious infections, including fatal infections, are an important risk with B-cell-depleting therapies, including odronextamab. Given the risks of persistent B-cell depletion with continued odronextamab therapy, a retrospective analysis was performed to evaluate the risk of fatal infections and the probability of progression-free survival (PFS) based on the duration of odronextamab treatment, specifically in patients with R/R FL and DLBCL obtaining a complete response (CR) in the ELM-2 study.

Methods

Patients with a CR in the ELM-2 study were grouped based on different observed durations of odronextamab treatment: Analysis 1, odronextamab treatment duration of <6 months, 6-<12 months, and ≥12 months; and Analysis 2, odronextamab treatment duration of <12 months, 12-<18 months, and ≥18 months. Fatal infection incidence and PFS were analyzed in all patient subgroups.

Results

In ELM-2, 94/128 patients with FL and 40/127 patients with DLBCL achieved a CR and were available for analysis. Overall, 13.4% of patients (8/94 FL and 10/40 DLBCL) with a CR experienced fatal infections. The majority (72.2%, 13/18; 5 FL and 8 DLBCL) of fatal infections occurred early (within 12 months) in odronextamab treatment; 44.4% (8/18 patients) occurred within 6 months, 27.8% (5/18) occurred within 6-<12 months, 22.2% (4/18) occurred within 12-<18 months, and 5.6% (1/18) occurred after ≥18 months of treatment. Median time to fatal infection from first dose was 8.8 months (range 2.5-22.9).

In Analysis 1, 31 patients were treated with odronextamab for <6 months, 29 patients were treated for 6-<12 months, and 74 patients were treated for ≥12 months. The rates of fatal infections in these subgroups were 25.8% (8/31 patients), 17.2% (5/29), and 6.8% (5/74), respectively. The Kaplan-Meier (KM) estimate of PFS showed a higher probability of PFS in patients treated for ≥12 months, compared with those treated for <6 months or 6-<12 months.

In Analysis 2, 60 patients were treated with odronextamab for <12 months, 41 patients were treated for 12-<18 months, and 33 patients were treated for ≥18 months. The rates of fatal infections in these subgroups were 21.7% (13/60 patients), 9.8% (4/41), and 3.0% (1/33), respectively. The KM estimate of PFS showed a higher probability of PFS in patients treated for ≥18 months compared with those treated for <12 months or for 12-<18 months.

Conclusions

In the setting of FL and DLBCL in the third line and beyond, achieving and maintaining a CR is an important treatment goal, as it consistently translates into long-term survival benefit. In ELM-2, odronextamab monotherapy resulted in high rates of CR with associated durability; however, serious and fatal infections were observed. The risk of fatal infections was higher in patients treated for less than 6 or 12 months, likely due to increased susceptibility from prior treatments in the R/R setting. This analysis indicates that longer treatment duration was not associated with an increased risk of fatal infections but was associated with an increased probability of PFS. This suggests that patients who achieve a CR and continue receiving treatment for longer periods may have a different underlying susceptibility to infection compared with those on treatment for shorter periods. Prospective trials are warranted to investigate the optimal duration of treatment with bispecific antibodies in the setting of R/R B-NHL.

von Keudell:AbbVie: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Regeneron Pharmaceuticals, Inc.: Consultancy. Hawkes:Merck KGaA: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Research Funding, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe and Dohme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Antengene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carpio:AstraZeneca: Honoraria; Regeneron Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria. Topp:AbbVie: Consultancy; Autolus Therapeutics: Consultancy; Incyte: Consultancy; Universitatsklinikum Wurzburg: Current Employment; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Roche: Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding. Shen:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Li:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Hearnden:Regeneron Ireland Ltd.: Current Employment, Current holder of stock options in a privately-held company. Shariff:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Ayyappan:TotalCME: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Genmab: Speakers Bureau; Iowa Oncology Society: Speakers Bureau; Peerview: Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Odronextamab, an investigational CD20xCD3 bispecific antibody, for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma