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In the past 5 years, 3 chimeric antigen receptor (CAR) T-cell therapies, 2 antibody-drug conjugates (ADCs), 1 CD19-directed monoclonal antibody, and 1 exportin-1 inhibitor have been approved by the Food and Drug Administration for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The noncellular therapies received accelerated approval based on the overall response rate in clinical trials that differ in multiple aspects of the patient populations enrolled, including age, performance status, prior lines of therapy, and inclusion of patients with primary refractory DLBCL, transformed lymphoma, or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. ADCs approved for DLBCL differ in target antigen, antibody structure, linker, and cytotoxin, which results in a different safety and efficacy profile. Here, we comprehensively review the current knowledge of recently approved and emerging strategies for the management of R/R DLBCL with a focus on ADCs.

Context Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who are ineligible for, or relapse after, salvage chemotherapy/stem cell transplant (SCT) have a poor prognosis. Lonca comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. Objective To assess updated efficacy and safety findings from a Phase 2 study evaluating Lonca in patients with R/R DLBCL (LOTIS-2; NCT03589469). Design Multicenter, open-label, single-arm Phase 2 study in adult patients (≥18 years) with pathologically defined R/R DLBCL and ≥2 prior systemic treatments. Intervention Lonca (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter). Main Outcomes Measures Primary efficacy endpoint: Overall response rate (ORR), assessed by central review. Secondary efficacy endpoints: Duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Safety analyses: Treatment-emergent adverse events (TEAEs). Follow-up period: Q12W for ≤3 years after end of treatment. Results 145 patients with R/R DLBCL received ≥1 Lonca dose. Median age was 66 years (range 23–94). Patients received a median of 3 prior therapies (range 2–7). At data cut-off (October 26, 2020, ≥12 months since first dose), 2 patients continued treatment. Patients received a mean of 4.6 Lonca cycles (std 4.1; range 1–22). ORR was 48.3% (complete response [CR]: 24.8%; partial response [PR]: 23.4%). Median DoR was 12.6 months for patients with CR or PR (n=70); not reached for patients with CR. Median PFS and OS were 4.9 and 9.5 months, respectively. Post-Lonca treatment, 15 patients received CD19-directed chimeric antigen receptor T-cell therapy with an investigator-assessed ORR of 46.7%, and 11 patients proceeded to SCT as consolidation after Lonca response. Most common (≥25.0%) all-grade TEAEs were increased gamma-glutamyltransferase (41.4%), neutropenia (40.0%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). Grade ≥3 TEAEs occurred in 107 (73.8%) patients. Treatment-related TEAEs leading to treatment discontinuation and dose delays occurred in 26 (17.9%) and 62 (42.8%) patients, respectively. Conclusions After longer follow-up of patients in LOTIS-2, durable responses to Lonca continue to be observed in heavily pre-treated patients with R/R DLBCL. No new safety concerns occurred. Research funding ADC Therapeutics SA.

G A A b st ra ct s and / or surgery for histological examination and sub-classification of adenocarcinomas according to Lauren into diffuse, intestinal or mixed type. Fasting blood samples were collected preoperatively for determination of serum gastrin by radioimmunoassay (upper normal range 40 pM) and Helicobacter pylori (H pylori) serology. Tumor localization was determined after macroscopic and histological examination and classified as antrum, corpus and overlapping. Results: Patients with localization of the carcinoma in the gastric corpus (n=45) had significantly higher serum gastrin than patients with carcinoma localized to the antrum (n=32) (100.7±27.5 vs. 17.1±2.6 pM, p=0.004). There was no significant difference in serum gastrin between patients with intestinal type (n=49) carcinoma compared to diffuse type (n=46) carcinoma (49.7±16 vs 58.0±21 pM, p=0.33), while patients withmixed histological type (n=7) had gastrin 98.7±50.6 pM, (p=0.29 vs. intestinal type). Among patients with tumor localized to the corpus, those with diffuse type carcinoma tended to have higher serum gastrin than patients with intestinal type (131.6±61 vs. 78.4±37 pM, p =0.29). H pylori positive patients tended to have higher serum gastrin than HP negative patients (69.4±22.4 pM vs. 32.3±11.0 pM, p=0.29), but H pylori status did not differ between diffuse and intestinal type cancers (82.6% vs. 68.7% positive patients, p=0.26). Conclusions: Patients with adenocarcinomas localized to the gastric corpus had higher serum gastrin that patient with localization of carcinoma in the antrum. The histological subtype did not seem to be influenced by serum gastrin concentrations. The findings support the hypothesis that hypergastrinemia, as seen in animal models also promotes carcinogenesis in patients.