AUTHORS
Mehdi Hamadani, MD, Michal Kwiatek, MD, PhD2, Sebastian Grosicki, MD PhD3, Laura Maria Fogliatto4, Juraj Duraš, MD5, Xiuhua Sun, MD6, Gabriela Cesarman-Maus, MD7, A. Burhan Ferhanoglu, MD8, Juliana Pereira Sr, MD, PhD9, Guilherme Fleury Fleury Perini I, MD10, Pam McKay11, Heidi Mocikova, MD12, Sujun Gao13, Eva Gonzalez Barca, MD PhD14, Wei Liu15, Jie Jin, MD16, Gilles Crochet17, Zsolt Nagy18, Maxim Norkin19, Joseph Maly, MD20, Junichiro Yuda, MD, PhD21, Andrew Niewarowski22, Andrea Donnelly23, Luqiang Wang24, Carmelo Carlo-Stella, MD25
AFFILIATIONS
1 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Aidport Clinical Trials Hospital, Skorzewo (Poznan), Poland
3 Medical University of Silesia, Katowice, Poland
4 Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
5 University Hospital Ostrava, Ostrava, Czech Republic
6 Second Affiliated Hospital of Dalian Medical University, Dalian, China
7 National Cancer Institute, Mexico City, Mexico
8 VKV American Hospital, Istanbul, Turkey
9 Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
10 Hospital Israelita Albert Einstein, São Paulo, Brazil
11 Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
12 Department of Haematology, Fakultni nemocnice Kralovske, Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic
13 The First Hospital of Jilin University, Changchun, China
14 Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain, Catalan Institute of Oncology Hospital, Barcelona, Spain, Faculty of Medicine, University of Barcelona, Barcelona, Spain
15 Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
16 The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
17 Hematology Department, Centre Hospitalier Universitaire UCL Namur, Yvoir, Belgium
18 Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
19 Baptist MD Anderson Cancer Center, Jacksonville, Florida, United States
20 Norton Cancer Institute, Saint Matthews, Kentucky, United States
21 National Cancer Center Hospital East, Kashiwa, Japan
22 ADC Therapeutics America, Inc., New Providence, New Jersey, United States
23 ADC Therapeutics America, Inc., New Providence, New Jersey, United States
24 ADC Therapeutics America, Inc., New Providence, New Jersey, United States
25 Humanitas University and IRCCS Humanitas Research Hospital, Milan, Italy
ABSTRACT
Background: Patients with R/R diffuse large B-cell lymphoma (DLBCL) who are not candidates for autologous stem cell transplant (ASCT) have poor outcomes with standard therapies. Loncastuximab tesirine-lpyl (Lonca), an anti-CD19 antibody-drug conjugate (ADC), has shown clinical activity and durable responses in R/R DLBCL and is approved for R/R DLBCL and high-grade B-cell lymphoma (HGBCL) after ≥2 systemic therapies. Combining rituximab with an anti-CD19 ADC may enhance tumor control.
Methods: LOTIS-5 (NCT04384484) is a global, open-label, randomized phase 3 trial evaluating Lonca plus rituximab (Lonca-R) vs standard immunochemotherapy in patients with R/R DLBCL who received ≥1 prior lines of therapy and were not candidates for ASCT. Patients were randomized to receive fixed duration Lonca-R (Lonca 150 µg/kg + rituximab 375 mg/m2 Q3W for 2 cycles, then Lonca 75 µg/kg + rituximab 375 mg/m2) Q3W for up to 6 additional cycles versus R-GemOx (rituximab 375 mg/m2 + gemcitabine 1000 mg/m2 + oxaliplatin 100 mg/m2) Q2W for up to 8 cycles. The primary endpoint was progression-free survival (PFS) by independent review committee (IRC). Secondary endpoints included overall survival (OS; key secondary), objective response rate (ORR), complete response rate (CRR), duration of response (DoR), duration of complete response (DOCR), and frequency/severity of adverse events. The treatment emergent adverse event (TEAE) reporting window was defined as the time from the first dose to 105 days from the last dose or start of new anti-lymphoma therapy (NALT), whichever occurred first.
Results: A total of 420 patients were randomized (210 per arm; median age 72 years, 65.2% White) between February 2022 and January 2025. 63.3% of patients had 1 prior line of therapy, 61.7% of patients had primary refractory disease, and 11.0% of patients had HGBCL. Median follow up was 25.94 months. Lonca-R significantly improved PFS by IRC compared with R-GemOx (HR 0.73, 95% CI 0.57-0.92; P=0.0083, two-sided; median 6.14 vs 4.73 months). Investigator-assessed PFS demonstrated an HR of 0.65 (95% CI 0.51-0.81; nominal P=0.0002; median 5.49 vs 3.02 months). No statistically significant difference in OS was observed (HR 0.96, 95% CI 0.75-1.23; P=0.7387; median 12.19 vs 12.16 months). Of note, there was an earlier and higher rate of switching to subsequent NALT in the R-GemOx arm compared with the Lonca-R arm (57.6% vs 42.4%). Response outcomes also favored Lonca-R compared with R-GemOx, with higher ORR (58.1% vs 45.2%; 95% CI 1.16-2.58) and CRR (39.5% vs 26.7%; 95% CI 1.22-2.86), as well as longer median DoR (9.20 vs 7.66 months; HR 0.71, 95% CI 0.50-1.02) and DOCR (16.82 vs 12.25 months; HR 0.57, 95% CI 0.35-0.94). At 24 months, 48.5% of patients who achieved complete response (CR) remained in CR with Lonca-R vs 16.7% with R-GemOx. Among patients with primary refractory disease, those treated with Lonca-R had improved ORR and CRR relative to those treated with R-GemOx (45% vs 33.6%, and 27.5% vs 15.6%, respectively).
The most common all-grade TEAEs with Lonca-R were neutropenia (36.8%), thrombocytopenia (27.5%), anemia (25.0%), increased gamma-glutamyltransferase (23.5%), and pleural effusion (19.1%), compared with thrombocytopenia (57.9%), anemia (45.7%), neutropenia (44.7%), nausea (25.9%), and diarrhea (20.8%) with R-GemOx. Based on the protocol-defined 105-day TEAE window, grade ≥3 TEAEs occurred in 74.0% vs 76.1% of patients, while grade 5 TEAEs occurred in 13.2% (primarily in those ≥75 years) vs 4.6% with Lonca-R and R-GemOx, respectively. When observing patients in a standard 30-day window after treatment, rates of grade 5 events were 3% in the R-GemOx arm compared with 1.5% in the Lonca-R arm. Notably, TEAE follow-up time differed between treatment arms (median 3.9 months for Lonca-R vs 2.5 months for R-GemOx).
Conclusions: Lonca-R demonstrated a statistically significant improvement in PFS compared with standard immunochemotherapy in patients with R/R DLBCL, with favorable and durable responses, including high-risk patients with primary refractory disease. Overall TEAEs were manageable. Differences in TEAEs between arms were affected by varying rates of NALT, treatment exposure, and a longer TEAE window. These findings establish Lonca-R as a standard treatment option in the second-line or later setting.
DISCLOSURES
Mehdi Hamadani, MD: AstraZeneca, ADC Therapeutics, BeiGene, Kite, Sobi - Honoraria; ADC Therapeutics, Spectrum Pharmaceuticals, Astellas Pharma - Research Funding; Autolus, Forte Biosciences, Byondis, Daiichi Sankyo, BMS, Caribou, Kite, Abbvie, Incyte, ADC Therapeutics, Takeda - Consultancy (Includes expert testimony)