Investigator-initiated trials (IITs) refer to clinical research initiated by investigators, conducted in healthcare institutions, and aimed at studying disease diagnosis, treatment, rehabilitation, prognosis, etiology, prevention, and health maintenance. Unlike industry-sponsored trials, IITs are not intended for drug or medical device registration. In recent years, IITs have become an essential part of clinical research, providing critical data and insights for drug development in China. However, the rapid increase in IITs has underscored the need for enhanced management and standardization.

At the 2024 2024 Chinese Congress on Holistic Integrative Oncology  (CCHIO) held on November 17, Dr. Chunxia Su from Shanghai Pulmonary Hospital delivered a keynote address titled Comprehensive Management and Research Design of IITs in Lung Cancer at the Clinical Research on Oncology Drugs Subforum. She shared insights into building a systematic management framework for lung cancer IITs and advancements in research design and implementation. Oncology Frontier has compiled the key points from her presentation for readers.

Comprehensive Management of IITs

With the intensification of global trends in drug development and the growing capacity for pharmaceutical innovation in China, the number of clinical studies conducted in the country has been steadily increasing. Analysis of the overall numbers reveals that, aside from clinical trials aimed at drug registration, investigator-initiated trials (IITs) have begun to play an increasingly prominent role. Between 2010 and 2019, the number of cancer-related IITs registered on ClinicalTrials.gov (CT.gov) and the Chinese Clinical Trial Registry (ChiCTR) rose steadily, with a particularly sharp increase from 2015 to 2019. Among the top ten types of tumors for which IITs are conducted, five are digestive system cancers, accounting for 33.9% (2,779/8,199), including colorectal cancer, liver cancer, gastric cancer, esophageal cancer, and pancreatic cancer. However, lung cancer ranks highest as an individual tumor type.

As a valuable supplement to registration-oriented clinical trials, the number of IITs related to innovative cancer drugs in China has grown significantly in recent years. Many cancer patients participating in IITs have benefited from extended survival and improved quality of life through access to new drugs or treatments. Analysis of trends in treatment-related IITs registered on CT.gov and ChiCTR over the past decade (2010–2019) indicates that IIT research institutions are primarily concentrated in first-tier cities such as Beijing, Shanghai, and Guangzhou. Over time, the number of studies has increased annually. According to 2023 statistics on IIT project types, translational medicine research remains the most dominant category, accounting for approximately 28%. Notably, as more clinical institutions engage in or lead high-level international multicenter studies and gain widespread recognition within the global academic community, domestic researchers are increasingly motivated to conduct clinical research. Consequently, the number of IITs focusing on new technologies and innovative drug development has steadily grown.

Regarding whether IITs can support drug approval, Dr. Chunxia Su pointed out that in May 2012, the Center for Drug Evaluation (CDE) of the National Medical Products Administration issued the Technical Guidelines for Adding New Indications for Marketed Anti-Cancer Drugs, which states: “Clinical study data submitted for new indication applications can originate from two sources: clinical studies initiated by pharmaceutical companies and investigator-initiated trials (IITs). High-quality IIT results can serve as critical references for the approval of new indications.” For instance, the EACH study facilitated the inclusion of oxaliplatin as an indication for advanced liver cancer.

For IITs to succeed, it is crucial to ensure that the overall study design has an exploratory purpose. Throughout the study process, new treatment strategies can be defined or optimized, such as comparing single-agent versus combination therapies, determining drug dosages, or adjusting dosing frequencies. The design must demonstrate innovation—not only in terms of technology or target populations but also in mechanistic exploration. Additionally, optimizing target populations for specific indications is a key objective of IIT study design.

For small-scale IITs, which may involve only 30–50 patients, it is ideal to complete enrollment within a year. This aspect of planning must be considered during the initial study design phase. Beyond choosing the study objectives, several critical factors must also be addressed in IITs, including the selection of control groups and the determination of study endpoints. When selecting control groups, it is essential to balance scientific rigor with feasibility, particularly in exploratory Phase II studies, where the necessity of a control group must be evaluated. Similarly, the choice of study endpoints is another critical consideration. Endpoints may include multiple indicators, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Researchers must select endpoints that reflect real-world technical capabilities and align with the study’s unique characteristics. These endpoints should produce strong results within the observation period and gain broad recognition, increasing the likelihood of study success.

In IITs, funding security, partnership selection, sponsor support, and the maximum utilization of clinical cohort study resources for translational research are also essential evaluation criteria during the study design process. Therefore, a well-executed IIT relies on multi-dimensional design, broad support, and collaboration across various departments.

Design and Implementation of IITs

Dr. Chunxia Su emphasized the importance of understanding the full process of IIT study design while effectively applying the PICOS principle during implementation.

• P (Population/Patient): Specifies the characteristics of patients or study participants, including age, gender, and disease status, to define the target population. In IITs, this step is crucial as researchers must ensure that the selected patient group aligns with the study’s purpose and requirements.
• I (Intervention): Describes the intervention measures or treatments used to address the patient’s condition. In IITs, interventions may include new drugs, treatment methods, or devices. Researchers need to clearly outline these interventions.
• C (Comparison): Defines the characteristics of the control group, such as alternative treatments or non-intervention cases. The setup of control groups is critical for evaluating the efficacy of the intervention.
• O (Outcome): Clarifies the primary or secondary outcomes of interest, such as survival rates, symptom improvement, or side effects. These outcomes represent the study’s goals.
• S (Study Design): Specifies the type of study design, such as randomized controlled trials, cohort studies, or case-control studies. The choice of study design determines the methods and data collection processes, ensuring the study’s reliability and validity.

The PICOS framework plays a key role in refining research questions, guiding study design, and conducting literature reviews. By employing PICOS, researchers can enhance the precision and consistency of their studies, improve reproducibility and comparability, and standardize interventions to ensure uniformity throughout the research, enabling accurate comparisons and analyses.

Advances in NSCLC Research

In non-small cell lung cancer (NSCLC), research progression has moved from late-stage to early-stage settings, with immunotherapy leading to significant changes in treatment paradigms. For instance, studies on the PD-L1 biomarker, such as real-world research on pembrolizumab, evaluated clinical outcomes in late-stage NSCLC patients undergoing maintenance therapy. Data from 1,944 patients showed that those with PD-L1 ≥50% benefited more from first-line pembrolizumab maintenance therapy. Furthermore, studies like Keynote-189 and Keynote-407 demonstrated the efficacy of PD-1 inhibitors combined with chemotherapy in PD-L1-negative populations, establishing immunotherapy as the standard treatment for advanced NSCLC in domestic and international guidelines.

Currently approved treatment strategies for advanced NSCLC include PD-1 plus chemotherapy, PD-L1 plus chemotherapy, dual immunotherapy (dual ICI), and dual immunotherapy combined with chemotherapy. Among these, research has reported that nivolumab plus ipilimumab (with or without chemotherapy) achieved the best overall survival (OS) and progression-free survival (PFS) rates in PD-L1-negative populations. However, dual immunotherapy also led to higher adverse event rates, underscoring the need for further exploration of new treatment strategies.

Emerging Therapeutic Advances

Compared to the clinical use of PD-L1 combined with CTLA-4-based dual immunotherapy, PD-1/CTLA-4 bispecific antibody drugs demonstrate unique advantages. These drugs preferentially bind to CTLA-4 on activated T cells expressing PD-1, thereby promoting greater T-cell proliferation while maintaining safety. In PD-L1-negative NSCLC, PD-1/CTLA-4 bispecific antibodies have shown significant anti-tumor activity, with objective response rates (ORRs) ranging from 55.6% to 86.7% and median PFS between 8.54 and 13.4 months. While these results are promising, the relatively small sample sizes require further validation through prospective clinical studies.

Case Example of Study Design

Professor Su highlighted the critical importance of study design before initiating a project. She cited a prospective, multicenter clinical study aimed at evaluating the 1-year PFS rate of first-line PD-1/CTLA-4 bispecific antibody combined with chemotherapy. Secondary objectives included evaluating DCR, ORR, PFS, and OS, with exploratory endpoints focusing on PD-1/CTLA-4 bispecific antibodies. According to previous data, the 1-year PFS rate for PD-L1-negative NSCLC patients undergoing immunotherapy combined with chemotherapy does not exceed 26%. It was estimated that first-line PD-1/CTLA-4 bispecific antibody combined with chemotherapy could improve the 1-year PFS rate to 40%. Using a single-rate testing method, the sample size was set at 54 patients, showcasing the thoughtful design. Professor Su also emphasized the importance of attention to detail post-project initiation, requiring close collaboration among clinicians, clinical research coordinators (CRCs), and principal investigators (PIs). During the study, clinical specimens were leveraged for translational research to lay a foundation for biomarker exploration.

Advances in SCLC Treatment

In small cell lung cancer (SCLC), treatment strategies for extensive-stage SCLC (ES-SCLC) have continued to evolve. Studies such as IMpower133 and CASPIAN introduced immunotherapy, marking a new era for ES-SCLC treatment. However, these studies primarily focused on PD-L1 efficacy in ES-SCLC, with limited biomarker exploration. Both studies reported median PFS and OS of approximately 6 and 12 months, respectively, while identifying a subset of long-term survivors. Analyzing the characteristics of these long-term survivors can facilitate precision treatment for ES-SCLC.

To address this, Professor Su’s team initiated an IIT aimed at exploring the efficacy of PD-1 in ES-SCLC and identifying potential biomarkers of immunotherapy efficacy. This study has three key highlights:

1. Innovative analysis of PD-1 efficacy in ES-SCLC, challenging the prevailing focus on PD-L1. Subsequent large-scale Phase III trials confirmed PD-1’s efficacy in ES-SCLC.
2. Adoption of the 1-year PFS rate as the primary endpoint.
3. Dynamic collection of study specimens, including tissue, blood, and stool, to create a comprehensive biobank that captures the ES-SCLC microenvironment.

The study ensured real-time updates through project progress meetings, rigorous adverse event reporting systems, online physician-patient communication platforms, and standardized data management, enabling the project’s smooth execution.

Role of AI in Clinical Research

Professor Su discussed the increasing role of artificial intelligence (AI) in clinical research. Technologies like machine learning have become essential for data analysis, predictive modeling, and optimizing patient recruitment. AI accelerates drug discovery, enhances trial accuracy, and reduces costs. Biomarker-based immunotherapy research can further refine treatment benefits and reduce toxicity. Moving forward, IITs can leverage AI to explore more biomarkers for efficacy and toxicity, shifting the clinical research focus to a patient-centered approach that delivers meaningful survival benefits.

Conclusion

IITs are becoming increasingly critical in clinical research, addressing real-world clinical questions and promoting advancements in medical science. However, as the number of IITs grows, challenges such as complex project types, inconsistent study designs, and inadequate regulatory systems have become apparent.

In this report, Professor Su delved into comprehensive management and study design for lung cancer IITs. She outlined the basic concepts, current status, and significance of IITs while emphasizing solutions to key challenges, including regulatory and institutional improvements and capacity-building for researchers. Through real-world examples, she demonstrated thoughtful study design, project implementation, and data management, offering valuable insights for standardizing IIT management. As regulatory frameworks improve, IITs are expected to expand into broader and more impactful clinical applications.

Dr. Chunxia Su

• Professor at Tongji University, Chief Physician at Shanghai Pulmonary Hospital
• PhD advisor and postdoctoral supervisor
• Director, Clinical Research Center, Shanghai Pulmonary Hospital
• Deputy Director, Department of Oncology, Shanghai Pulmonary Hospital
• Chief Scientist, National Key Research Program
• Outstanding Academic Leader, Shanghai
• Member, Youth Committee of the Chinese Medical Association’s Oncology Branch
• Executive Member, US-China Anti-Cancer Association (USCACA)
• Committee Member, Multidisciplinary Collaborative Committee of the International Association for the Study of Lung Cancer (IASLC)
• Chair, Clinical Translational Research Foundation for Oncology, China Primary Health Care Foundation
• Secretary-General, Clinical Research Committee of Anticancer Drugs, China Anti-Cancer Association
• Vice Chair, Patient Education Committee, Chinese Society of Clinical Oncology (CSCO)
• Deputy Secretary-General, CSCO Translational Research Committee
• Member, CSCO Immunotherapy Committee
• Member, Tumor Immunotherapy Branch, Chinese Medical Promotion Association
• Vice President, Shanghai Anti-Cancer Youth Association
• Secretary-General, Molecular Targeting and Immunotherapy Committee for Lung Cancer, Shanghai Anti-Cancer Association