From September 13th to 17th, the 2024 European Society for Medical Oncology (ESMO) Annual Meeting was held in Barcelona, Spain. As one of the world's top oncology conferences, it brought together experts and scholars from across the globe to share cutting-edge research findings and discuss future directions. At the session dedicated to hematologic malignancies, Dr. Junyuan Qi from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, presented the first-in-human study of the BCL-2 inhibitor TQB3909 in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML), showing promising results. Hematology Frontier invited Professor Qi to provide an in-depth analysis of the study and discuss the future clinical applications and research directions for this novel BCL-2 inhibitor.

Hematology Frontier: At this year’s ESMO meeting, you presented the first-in-human study of the BCL-2 inhibitor TQB3909 in R/R NHL and AML. Could you start by giving us a brief overview of the study’s background and design?

Dr. Junyuan Qi: TQB3909 is a novel, highly selective BCL-2 inhibitor that has shown greater anti-tumor activity and the potential for inducing deeper remissions in preclinical studies. The TQB3909-I-01 study we presented is a Phase I clinical trial consisting of two stages: dose escalation and dose expansion, conducted separately in the NHL and AML cohorts. The primary objectives of the study were to assess the safety and tolerability of TQB3909 in NHL and AML patients, identify the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended Phase II dose (RP2D). Secondary objectives included evaluating the pharmacokinetics (PK) and preliminary efficacy of TQB3909.

Hematology Frontier: Based on the data you presented, how did TQB3909 perform in terms of safety in R/R NHL and AML patients? Were there any significant DLTs or MTDs encountered during dose escalation, and how might these findings impact the design of future clinical trials?

Dr. Junyuan Qi: As of April 24, 2024, the study had enrolled 69 patients, including 52 with NHL (18 of whom had R/R chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL]) and 17 with AML. In NHL patients, TQB3909 doses were escalated from 100 mg to 1200 mg, while in AML patients, doses ranged from 200 mg to 800 mg. No DLTs were observed in either cohort, nor was the MTD reached. The treatment-related adverse events primarily consisted of hematological toxicities, diarrhea, and metabolic abnormalities. The proportion of patients who required dose reductions or discontinued treatment due to adverse events was low, indicating that TQB3909 was generally well-tolerated. To prevent tumor lysis syndrome (TLS), associated with BCL-2 inhibitors, different starting doses and daily incremental increases were used depending on the tumor type. The overall safety profile was favorable, with no clinical TLS observed and only four cases of laboratory TLS in CLL patients, all of whom recovered within three days. These findings provide valuable insights for the upcoming Phase II studies and significantly boost confidence in future research.

Hematology Frontier: You mentioned that TQB3909 showed significant efficacy in R/R B-NHL patients, particularly among CLL/SLL cases. Could you elaborate on the significance of these efficacy results and what new hope TQB3909 offers for patients with BTK inhibitor-resistant disease? What about the preliminary efficacy in AML patients?

Dr. Junyuan Qi: Among the 18 enrolled R/R CLL/SLL patients, the objective response rate (ORR) was 88.9%, and the complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 44.4%. With a median follow-up of 9.5 months, the median duration of response (mDOR) and median progression-free survival (mPFS) had not yet been reached. Although direct comparisons with other studies are not possible, and the current sample size is limited, we observed that TQB3909’s ORR and CR rates in R/R CLL/SLL were relatively high compared to other BCL-2 inhibitors, suggesting that TQB3909 could potentially be the best-in-class BCL-2 inhibitor.

For patients with BTK inhibitor-resistant CLL/SLL, treatment options are limited, and the prognosis is poor, presenting a significant unmet clinical need. In this Phase I study, 12 patients with prior BTK inhibitor-resistant CLL/SLL were included, with an ORR of 83.3% and a CR/CRi rate of 41.7%, similar to those who had not received BTK inhibitors or were not resistant. Moreover, the responses were durable, with mDOR and mPFS still unreached, offering a new treatment option that could potentially extend survival for this patient group.

In the AML cohort, TQB3909 monotherapy also showed some efficacy, with 16 out of 17 evaluable patients, one (6.3%) achieving CR, and four (25.0%) achieving CRi. The patient who achieved CR has been receiving TQB3909 treatment for over a year and remains under study observation. However, BCL-2 inhibitor monotherapy for AML has limited efficacy, indicating a need for further exploration in combination therapies.

Hematology Frontier: Based on the current Phase I results, what are your plans for future clinical trials with TQB3909? How do you view the clinical prospects of this drug in the treatment of relapsed or refractory hematologic malignancies, and what are the potential research directions or challenges?

Dr. Junyuan Qi: BCL-2 inhibitors target the anti-apoptotic action of the BCL-2 protein family to promote cancer cell death. Previous studies have shown that BCL-2 inhibitors are effective in a variety of hematologic malignancies. Our Phase I study has demonstrated that TQB3909 shows promising efficacy in CLL/SLL, providing a great deal of encouragement. We will continue to explore this indication further, including single-agent and first-line combination therapies. Research is also underway to investigate TQB3909 in combination therapies for AML and other hematologic cancers.

As the bar for new drug approvals continues to rise, focusing on clinical value and patient-centered approaches, achieving overall survival (OS) benefits is becoming a key factor for anti-tumor drug approval. In this context, for promising new drugs like TQB3909 that demonstrate outstanding efficacy and manageable safety, the path forward involves precisely identifying target patients, carefully designing clinical trials, collaborating closely with regulatory authorities, and seizing the right “window of opportunity” to secure approval and benefit more patients. This is a shared mission for both clinicians and drug developers.

Dr. Junyuan Qi

• Chief Physician, Director of the GCP Phase I Ward, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
• MD with postdoctoral experience in France and the United States
• Committee Member, Translational Medicine Committee, Chinese Society of Clinical Oncology
• Over 30 years of experience in clinical and basic research in hematologic diseases
• Author of numerous publications and contributor to several medical monographs
• Editorial Board Member, Chinese Journal of Hematology; Reviewer for Chinese Journal of Clinical Oncology and Chinese Journal of General Practice
• Specializes in: Diagnosis and differential diagnosis of hematologic diseases, complex and rare conditions, comprehensive individualized treatment for hematologic malignancies, and clinical trials of new drugs and therapies (including CAR-T).