Clinical Trial Success Rate in Lymphoma: Fate of Trials and Agents from 2000 to 2023

Introduction:Only 7.5% of investigational agents tested in phase 1 trials resulted in new drug approvals by the FDA for hematologic malignancies from 2011 to 2020 (©BIO 2024). Although approximately half of investigational agents tested in phase 1 trials progress to phase 2 trials, just 27.8% transition to phase 3 trials, illustrating the low success rate transitioning agents from early phase trials. However, comprehensive studies examining development success of agents for patients with lymphoma have not been performed.

Methods: We conducted a retrospective analysis of clinical trials investigating lymphoma treatments between January 1, 2000, and May 25, 2023. Clinical trial data were obtained from the Biomedtracker® database and were supplemented with information from ClinicalTrials.gov to ensure data completeness and accuracy. We identified phase 1, 2, and 3 trials conducted during this period focused on or including patients with lymphoma and reviewed agents approved by FDA for patients with lymphoma from 2006 to 2024. We assessed the numbers of patients enrolled and trial enrollment period and calculated the phase transition success rates for the identified trials to assess the efficiency and success of the clinical development process.

Results: A total of 2,222 phase 1 trials were conducted during the study period of which patients of lymphoma were eligible for participation in 1,868 phase 1 trials that evaluated 858 agents. 1,132 phase 1 trials evaluated single agents and 736 trials evaluated combinations. Overall, 60,809, 68,325 and 53,848 patients were treated in phase 1, 2 and 3 trials. The median duration of opening to closing the trial was 42, 44 and 49 months in phase 1, 2 and 3, respectively. During this period, 1,769 phase 2 trials and 188 phase 3 trials were conducted to further assess the safety and efficacy in lymphoma. From 2006 to 2024, 44 new agents (including rituximab biosimilar) in 91 indications received approval from FDA. and common lymphoma subtypes that received new agent approval were follicular lymphoma (n=15), chronic lymphocytic leukemia (n=16), diffuse large B-cell lymphoma (n=11) while little to no new agents approved for peripheral T-cell lymphoma (n=4), classical Hodgkin lymphoma (n=3), Burkitt lymphoma (n=1), and primary CNS lymphoma (n=0). For 26 agents, FDA granted accelerated approval which requires phase 3 confirmatory trial. The success rate from phase 1 to phase 2, phase 2 to phase 3, and phase 3 to approval for lymphoma were 94.7%, 10.6% and 48.4%, respectively. The overall success rate from agents evaluated in phase 1 to approval was 5.1% (95%CI: 3.7%-6.6%).

Conclusions:Our study defines the clinical development landscape and timelines of new therapies for lymphoma and illustrates the unmet need for further clinical trials focusing on rare subtypes. Success rate in lymphoma is still low suggesting the critical role of better pre-clinical data conducting phase 1 trials.

Luo:Sanofi: Ended employment in the past 24 months. Flowers:Bio Ascend: Consultancy; Bayer: Consultancy, Research Funding; Guardant: Research Funding; Novartis: Research Funding; BostonGene: Research Funding; Seagen: Consultancy; Acerta: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Takeda: Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Bristol Myers Squibb: Consultancy; Nektar: Research Funding; Allogene: Research Funding; TG Therapeutics: Research Funding; Iovance: Research Funding; Ziopharm National Cancer Institute: Research Funding; Pfizer: Research Funding; Morphosys: Research Funding; Kite: Research Funding; Burroughs Wellcome Fund: Research Funding; Janssen Pharmaceuticals: Research Funding; Cellectis: Research Funding; Sanofi: Research Funding; EMD Serono: Research Funding; Xencor: Research Funding; Adaptimmune: Research Funding; Spectrum: Consultancy; 4D: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; BeiGene: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Denovo Biopharma: Consultancy; Karyopharm: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Pharmacyclics / Janssen: Consultancy; Celgene: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding. Chihara:MorPhosys: Research Funding; Ono pharmaceutical: Research Funding; Genmab: Research Funding; BeiGene: Honoraria; SymBio pharmaceutical: Honoraria; BMS: Research Funding.