Editor's Note: From June 14-16, 2024, the 5th Comprehensive Cancer Treatment Academic Conference of the Xinghai Medical Forum was grandly held, bringing together cutting-edge developments from home and abroad. At the previous ASCO conference, the results of the I-SPY 2.2 study were released, providing new insights into optimizing neoadjuvant treatment plans for breast cancer, exploring the application of immune checkpoint inhibitors combined with antibody-drug conjugates (ADCs), and investigating step-up and step-down treatment strategies. At the Xinghai Forum, Oncology Frontier invited Professor Shu Wang from Peking University People's Hospital, Professor Zhigang Yu from Qilu Hospital of Shandong University, Professor Haibo Wang from The Affiliated Hospital of Qingdao University, and Professor Guangyu Liu from Fudan University Shanghai Cancer Center to discuss the highlights of the I-SPY 2.2 study and its reference value for clinical practice.Oncology Frontier: The I-SPY platform has been around for 14 years, yielding fruitful results. What are the innovative highlights of the I-SPY 2.2 study reported at this ASCO conference in terms of design?
Professor Shu Wang: The field of oncology is rapidly advancing, with the development of targeted drugs based on abundant targets being one of the mainstream directions, bringing significant benefits to patients. In this context, the design and optimization of clinical research become even more crucial. Traditional large-scale randomized controlled trials may face issues such as insufficient patient enrollment and slow progress, making it difficult to quickly bring drugs to clinical use. The overall improvements in clinical research design brought by the 14-year journey of the I-SPY series are indeed remarkable, with many targeted drugs undergoing exploratory analyses with small samples on this platform.
The initial design of I-SPY aimed to explore whether small-sample studies of standard chemotherapy combined with novel drugs had potential phase III clinical benefits. Its statistical design is like a mid-term exam, potentially using high levels of pathological complete response (pCR) as evaluation targets. Successful “graduation” would then lead to large-scale studies. With the deepening understanding of molecular subtyping and the development of immunotherapy, the design of I-SPY has also evolved, including chemotherapy-free related fields.
This ASCO conference reported two cohorts from the I-SPY 2.2 study: one using the TROP-2 ADC Dato-DXd and the other using Dato-DXd combined with the immune checkpoint inhibitor durvalumab (Durva). The study optimized both the treatment process and predictive indicators, such as predicting the likelihood of pCR through imaging (MRI) and biopsy. It also incorporated the adaptive design concept from the ADPAT series, adjusting treatment plans based on patient responses. For example, in Block A, targeted or targeted-immune combination therapies were used without chemotherapy. If the predicted pCR likelihood was high after treatment, surgery was performed early; otherwise, treatment was intensified in the next stages (Blocks B and C). In Phase A, Dato-DXd+Durva achieved a pCR of 43% (20/47) in the Immune+ population, showing very promising data and the potential for phase III clinical research. Additionally, the targeted design of the I-SPY series, with the advantage of conducting molecular biology-related translational research, is notable. The I-SPY 2.2 study further optimized the three molecular subtypes of breast cancer proposed by Professor Charles M. Perou, introducing immune-related indicators (Immune) and DNA repair defects (DRD) to select populations more responsive to immunotherapy.
Overall, we hope more patients can achieve pCR in the short term, leading to long-term survival benefits. The I-SPY 2.2 study not only infers the efficacy of new drugs from biomarkers and tumor mechanisms but also clearly defines the advantage populations based on treatment responsiveness. The combination of molecular targets and treatment response is crucial. The introduction of new biomarkers and predictive indicators in I-SPY 2.2 provides us with more exploration opportunities in this field. I believe the overall research design of the I-SPY series will continue to bring more surprises in the future.
Oncology Frontier: The I-SPY 2.2 study evaluates preRCB based on MRI and biopsy to determine whether patients achieve pCR and proceed to surgery. In clinical practice, do you adhere to fixed neoadjuvant regimens, or do you adjust based on imaging and pathological biopsy results?
Professor Zhigang Yu: The I-SPY 2.2 study reflects the endless pursuit of excellence in the field. Neoadjuvant therapy has become one of the standard treatment modalities for breast cancer, making previously inoperable tumors operable and enabling breast-conserving surgery. It also provides more biological information and treatment decision data for postoperative adjuvant therapy.
However, we still face the issue of tumor heterogeneity, including spatial and temporal heterogeneity. Spatial heterogeneity may prevent pathological tests from fully reflecting the tumor’s status, making fixed neoadjuvant treatment regimens less likely to achieve pCR. Temporal heterogeneity refers to changes in the patient’s internal environment and tumor microenvironment over time with treatment. Relying solely on preoperative biopsy feedback to address these changes is insufficient. We may need to comprehensively evaluate these changes through a combination of patient diet, lifestyle, ethnicity, imaging, and other data using digital twin technology. The I-SPY study provides a good framework and brings new hope.
In clinical practice, we presented a poster at this year’s ASCO conference: For HER2-positive breast cancer patients, after two cycles of neoadjuvant therapy, we used biopsy pathology results and hematological indicators to predict pCR likelihood, providing a reference for adjusting neoadjuvant treatment plans. It is important to standardize neoadjuvant therapy in clinical practice, ensuring adequate treatment cycles and using MRI and other methods to assist in evaluating efficacy. We also need to focus on collecting patient information in clinical work to lay the groundwork for future big data processing.
Oncology Frontier: Currently, only Dato-DXd + durvalumab in the Immune+ subtype has reached the “graduation threshold” in the I-SPY 2.2 study. How do you view the efficacy results of this study, and what is your perspective on using RPS classification to guide neoadjuvant treatment plans?
Professor Wang Haibo: The design of the I-SPY 2.2 study provides more ideas for clinical practice, especially in the step-up and step-down strategies for neoadjuvant therapy. With the emergence of more immunotherapeutic and ADC drugs, the immunotherapy of triple-negative breast cancer (TNBC) is gradually becoming possible. The I-SPY 2.2 study showed that for the Immune+ population, the novel TROP-2 ADC Dato-DXd combined with Durva achieved very good treatment results, with a pCR rate of 43% and a model-predicted pCR of 65%. For the hormone receptor-negative (HR-) population, Dato-DXd combined with Durva had a pCR rate of 33% and a model-predicted pCR rate of 44%. The ideal results stem from the reliable drug combination mechanism. Dato-DXd further optimizes the drug-antibody ratio, with stronger drug-loading and bystander effects. Dxd, as a topoisomerase I inhibitor, has shown synergistic effects with PD-L1 and other immunotherapeutic drugs in previous studies, laying the foundation for the good efficacy of the Dato-DXd combined with Durva regimen.
The results of the I-SPY 2.2 study suggest that for TNBC, in the context of the rapid development of new drugs, we can explore the direction of ADC combined with immunotherapy, enabling patients to avoid chemotherapy while achieving synergistic effects and reducing toxicity. Additionally, the study’s evaluation of efficacy through a combination of imaging and pathology and guiding subsequent treatments based on this is of great clinical significance.
Oncology Frontier: In recent years, you and your team have won the Shanghai Science and Technology Progress Award for establishing individualized neoadjuvant treatment strategies based on molecular subtyping for breast cancer. Could you share your main research findings and your experience with individualized neoadjuvant treatment?
Professor Guangyu Liu: The I-SPY 2.2 study at this year’s ASCO conference has garnered widespread attention. Our center’s research is similar in many ways, such as conducting in-depth analyses based on traditional breast cancer subtypes to find new treatment targets and make treatments more precise. Under the leadership of Professor Shao Zhimin, our team is exploring entirely new subtypes of breast cancer, such as the “Fudan Four Subtypes” for triple-negative breast cancer. For example, with the new Fudan subtypes of luminal breast cancer, if we aim to achieve clinical research results in the short term among the combinations of immunotherapy, ADCs, and targeted drugs, neoadjuvant therapy is an excellent platform. Over ten years ago, we began focusing on using neoadjuvant therapy’s pCR and non-pCR to screen new drugs, requiring only a small number of cases and a short course of treatment to obtain exploratory results. In this regard, the new treatment regimens brought by the I-SPY 2.2 study are highly forward-looking.
Now, our team hopes to establish a neoadjuvant research platform at Fudan University Shanghai Cancer Center, incorporating our neoadjuvant therapy patients to aid in new drug screening. For example, we can start with step-down treatments by first using relatively less toxic drugs and then predicting efficacy through evaluation methods like breast PET and core needle biopsy as in the I-SPY 2.2 study. If we obtain relatively good results, patients can avoid high-intensity neoadjuvant treatments. On the other hand, these methods can also predict whether patients can undergo step-down surgeries for areas such as the breast and axilla. These are some of the ongoing efforts of our team in the neoadjuvant field.
