DP066 | UPDATED SAFETY RUN-IN RESULTS FROM LOTIS-5: A PHASE 3, RANDOMIZED TRIAL OF LONCASTUXIMAB TESIRINE WITH RITUXIMAB VERSUS IMMUNOCHEMOTHERAPY IN PATIENTS WITH R/R DLBCL/HGBL

CONTEXT: Loncastuximab tesirine (Lonca) is a CD19-targeted, antibody-drug conjugate FDA/EMA-approved for R/R DLBCL/HGBL after ≥2 therapies. OBJECTIVES: Describe safety/efficacy of Lonca-rituximab (Lonca-R) and explore tumor/blood biomarkers. DESIGN: LOTIS-5 (NCT04384484) evaluates Lonca-R vs R-GemOx in transplant-ineligible patients with R/R DLBCL/HGBL. Patients received Lonca 150 μg/kg and R 375 mg/m² Q3W for 2 cycles, then Lonca 75 μg/kg and R 375 mg/m² Q3W for ≤6 cycles. Primary endpoint is PFS. RESULTS: Safety run-in included 20 patients (18 DLBCL/2 HGBL), median age: 74.5 years, median 1 prior therapy (4 refractory to last line). As of 4Oct2024, patients received median 5 Lonca-R cycles. All patients had ≥1 TEAE. Eleven patients had grade ≥3 TEAEs; most common were increased GGT in 5 patients, neutropenia in 4. Nine patients had SAEs. ORR (central review) was achieved in 80% of patients, CR in 50%. Median follow-up was 10.8 months (range 1.9-39.7); mPFS: 8.3 months (95%CI 4.5-NE); mDOR: 8.0 months (95%CI 3.2-NE) for responders and NR for CRs. Response was sustained beyond end of treatment (EOT) in 5 patients; 1 went to SCT, 4 maintained CR 28.5+ months beyond EOT. Median C_max and C_trough were lower in C1 vs C2 for total and conjugated antibodies. Lonca-R resulted in lower median C_max at C1 vs monotherapy; C_through remained comparable. No ADA positivity observed. Of 16 tumors examined for CD19 IHC expression, 12 had H-scores ≥150. No correlation observed between CD19 H-score and BOR/PFS. In 8 patients with ctDNA measurements, 7 (3 CR/4 PR) had ctDNA results at baseline and C3D1. ctDNA decrease from baseline was noted at C3D1 in all 7 patients. All 3 CRs reached MRD negativity at C3D1. CONCLUSION: Fixed duration Lonca-R showed no new safety signals and demonstrated encouraging antitumor activity, with signs of durable response in 4 patients who maintained CR for >28 months after EOT. Lonca-R resulted in lower median C_max than monotherapy in C1. CD19 staining was not predictive of efficacy. Response was associated with early ctDNA decrease.