Risks and benefits of phase 1 clinical trials for patients with relapsed or refractory lymphoma, from 2008 to 2023

Introduction: Previous reviews of phase 1 trials in oncology have reported a treatment response rate of 4%–6% and a toxicity-related mortality rate of 0.5%. These results may not reflect current Phase 1 trial rates for patients with lymphoma. Methods: All non-pediatric phase 1 trials for relapsed or refractory (R/R) lymphoma approved by the Cancer Therapy Evaluation Program of the Institut Gustave Roussy between 2008 and 2023 (cut-off date 05 January 2023) were reviewed. We reported on overall survival (OS), treatment response rates, treatment-related deaths, and the number of patients who benefit to have received a drug in clinical trial which was further approved by the health authorities (FDA or EMA). Results: We analyzed 50 trials involving 447 participants (pts) with R/R lymphoma who received at least one dose of treatment. All patients were assessed for toxicity and 382/447 (85%) for treatment response. The median (range) age of patients was 64.9 (19.2–88.5) years. The median of treatments received before entering the trial was 3 (1–13). The main types of lymphoma were DLBCL (n = 253; 56.6%), PTCL (n = 45; 10.1%), Hodgkin (n = 40; 8.9%) and FL (n = 39; 8.7%). The overall response rate (i.e complete and partial responses) was 23.6%. Drug classes in trials included epigenetic modifiers (n = 99 pts; 22.1%), Proteolysis Targeting Chimeras (PROTAC) (n = 90; 20.1%), IO (n = 77; 17.2%), anti-apoptotic inhibitor (n = 50; 11.2%), molecular targeted therapy (n = 46; 10.3%), T-Cell Engagers (n = 23; 5.1%), antibody drug conjugated (n = 20; 4.5%), monoclonal antibody (n = 17; 3.8%), cycle cellular inhibitor (n = 8; 1.8%), gamma secretase inhibitor (n = 8; 1.8%), chemotherapy (n = 5; 1.1%), antiangiogenic (n = 4; 0.9%). Trials including drug further approved by health authorities involved 84/447 (18.8%) of patients and had an overall response rate of 32.9% (26/79 evaluable pts). The overall rate of deaths due to toxic events was 0.45% (2/447 pts). The median OS of patients was 14.1 (CI95% 11.7–17.9) months, with significant variation among lymphoma types (p < 0.0001) (Figure 1). Poor OS was observed for patients with relapsed or refractory with peripheral T-cell lymphoma (8.9 months CI95% 6.9–9.6) (Figure 1). Overall survival of patients with relapsed or refractory lymphoma included in phase 1 trials from 2008 to 2023, according to the lymphoma type (CLL = Chronic lymphoid leukemia; DLBCL = Diffuse large B cell lymphoma; FL = Follicular lymphoma; MCL = Mantle cell lymphoma; MZL = Marginal zone lymphoma; WD = Waldenstrom disease; PTCL = Peripheral T cell lymphoma). Conclusion: Overall response rates among phase 1 trials for patients with R/R lymphoma are higher than those reported with phase 1 in oncology. Toxicity-related mortality rates are similar those reported with phase 1 in oncology. The research was funded by: Ideogen (funding for clinical data analysis) Keywords: Aggressive B-cell non-Hodgkin lymphoma, Aggressive T-cell non-Hodgkin lymphoma, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. J. M. Michot Honoraria: Ideogen (clinical data analysis)