In recent years, with the emergence of new targeted drugs such as ibrutinib and zanubrutinib, the treatment strategies for chronic lymphocytic leukemia (CLL) patients have been changing, sparking widespread discussions. At the recent 2024 CSCO Hematology Academic Conference, Professor Yang Liang from Sun Yat-sen University Cancer Center shared some thoughts on the classical international phase III clinical trial designs of BTK inhibitors and related issues. “Oncology Frontier – Hematology Frontier” specially invited Professor Yang Liang to discuss the progress in CLL treatment and the design of the ALPINE study.

Oncology Frontier – Hematology Frontier：In recent years, novel targeted drugs have continued to emerge, especially with the advent of BTK inhibitors, which have changed the treatment strategies for CLL. Could you please discuss the significant research progress in the treatment of CLL with BTK inhibitors?

Professor Yang Liang: Since the 1950s, CLL has entered a treatable era, albeit with limited available drugs such as prednisone and alkylating agents. The CLL 4 study in the 2000s established the position of FC chemotherapy in CLL treatment, with the addition of rituximab making FCR the gold standard in CLL treatment. The emergence of the first BTK inhibitor, ibrutinib, in 2013, and its introduction to China in 2017, has been crucial for adopting a low-toxicity and high-efficiency treatment strategy. Given that CLL often occurs in elderly patients, who may not tolerate or complete the full course of treatment with FCR due to its intensity, leading to treatment abandonment or death, the introduction of BTK inhibitors has changed this scenario. Since the arrival of ibrutinib in China in 2017, followed by other covalent BTK inhibitors such as acalabrutinib, zanubrutinib, and orelabrutinib, based on international phase III studies, many of these studies aimed to obtain indications for approval, and several comparisons of drug efficacy were conducted. However, for patients with CLL, overall survival (OS) is paramount. Given the excellent efficacy of BTK inhibitors, the data from these large phase III studies currently show no significant differences in OS among different BTK inhibitors within the same category, with only slight differences observed in certain surrogate endpoints such as objective response rates and adverse reactions.

Oncology Frontier – Hematology Frontier：These international large phase III clinical trials will have a significant impact on drug registration and treatment patterns, and their study designs have also attracted widespread attention. Could you please provide a key introduction and commentary on the recently published ALPINE study design?

Professor Yang Liang: The ALPINE study is a global large phase III study led by Professor Jennifer R. Brown of the Dana-Farber Cancer Institute in the United States, mainly exploring the efficacy of zanubrutinib compared to ibrutinib in the treatment of relapsed/refractory CLL patients. Researchers believe that zanubrutinib is superior to ibrutinib in terms of patient survival and adverse reactions. However, upon careful analysis, we found several issues with this study: Firstly, it was an open-label study. For phase III studies aiming for indication approval, open-label is not the most suitable approach. Currently, the FDA, EMA, NMPA, and major journals all recommend blinded trials for phase III studies because open-label studies are likely to introduce unavoidable biases into the results.

Secondly, the study conducted an early interim analysis of progression-free survival (PFS), which may bias the final results. For chronic diseases, PFS is not the optimal surrogate endpoint, and open-label PFS may pose more problems, requiring pre-specified PFS analyses. The ALPINE study stipulated the release of PFS upon the occurrence of 205 events, but at the time of actual study disclosure, only 65 events had occurred, potentially influencing both subjects and researchers due to expectations for new drugs. Additionally, the interim assessment suggested analyzing safety and toxicity rather than efficacy.

Thirdly, the criteria for discontinuing treatment between groups in the event of non-hematologic toxicity were different, with the zanubrutinib group being more flexible and the ibrutinib group being more stringent.

Fourthly, despite being a randomized controlled study, there seemed to be a higher proportion of high-risk patients (beyond third-line and with complex karyotypes) allocated to the ibrutinib group. Fifthly, the survival benefit of ibrutinib in the ALPINE study differed from that in other classical studies, with patients’ survival being significantly shorter than in the RESONATE and ELEVATE-RR trials. Furthermore, an oral presentation at the 2023 EHA congress indicated significant differences in ibrutinib efficacy across different studies (2-year PFS for ibrutinib-treated patients in the RESONATE corrected sample and ALPINE were 81% and 66%, respectively; corresponding median PFS was 40.7 months and 34.2 months, P=0.0048), suggesting potential protocol design biases in the ALPINE study. In-depth analysis of this study can enhance the design and quality of our own clinical research, with universal significance.

Oncology Frontier – Hematology Frontier：In your opinion, what are the key considerations in the future research design of BTK inhibitors for CLL treatment? How will these affect research outcomes and clinical practice?

Professor Yang Liang: We should adhere to several principles mentioned above: Firstly, for different BTK inhibitors (especially within the same category), head-to-head studies are generally not recommended, as they may yield negative results, but if necessary, blinded analyses are recommended for head-to-head studies. Secondly, the analysis and disclosure of PFS need to be cautious. Not only should PFS be pre-specified, but mid-term PFS results should also be disclosed strictly according to the study protocol’s specified timing. If it’s an open-label study, toxicity and safety should be disclosed instead of drug efficacy. Thirdly, apart from the assessment by researchers themselves, results should be validated by a third-party independent review committee because the ALPINE trial’s researchers’ results were inconsistent with those of the independent review committee. Additionally, baseline characteristics of study groups should be balanced without any bias. Efforts should be made to use OS as the study endpoint, with PFS and ORR as secondary assessment endpoints, as PFS alone is insufficient to draw conclusions about drug benefits. Therefore, results interpretation for any study should be cautious and not overly interpreted.

Professor Yang Liang Director and Chief Physician of the Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Researcher, Doctoral Supervisor, Postdoctoral Supervisor