At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, Professor Ciara Catherine O'Sullivan from Mayo Clinic, representing the I-SPY 2.2 collaborator group, announced the neoadjuvant treatment results of Rilvegostomig (an anti-PD-1/TIGIT bispecific antibody) combined with Trastuzumab Deruxtecan (T-DXd) for early-stage high-risk HER2-negative breast cancer. Based on innovative Response Predictive Subtypes (RPS), the study aims to improve the pathological complete response (pCR) rate through precise drug combinations and explore the possibility of reducing traditional cytotoxic chemotherapy.01 Research Background and Innovative Design of the I-SPY 2.2 Platform
The treatment goal for high-risk early-stage breast cancer has shifted from mere survival extension to minimizing treatment-related toxicity while ensuring efficacy. Traditional “one-size-fits-all” chemotherapy regimens are often accompanied by significant side effects, whereas innovative drug combinations may achieve superior remission for patients with specific biological characteristics. The I-SPY 2.2 trial is a Phase II, neoadjuvant, sequential, multi-task randomized clinical trial. Its core innovation lies in the use of the RPS system, which combines gene expression profiles, hormone receptor (HR) status, and HER2 expression levels to perform more precise classification of patients. The study divides treatment into Block A (experimental biological targeting/immunotherapy), Block B (response-based subsequent treatment), and Block C (standard AC chemotherapy). If a patient is predicted to achieve pCR in the early stages (Block A or B), they can proceed directly to surgery, thereby achieving chemotherapy de-escalation.
02 Drug Mechanism: Synergistic Effect of Immune Bispecific Antibody and ADC
The regimen reported this time focuses on the combined application of Rilvegostomig (R) and Trastuzumab Deruxtecan (T-DXd). • Rilvegostomig (R): This is a PD-1/TIGIT bispecific antibody. TIGIT, as an emerging immune checkpoint, has a synergistic effect with the PD-1 pathway. Dual blockade can further relieve the inhibition of T cells by the tumor microenvironment and enhance the anti-tumor immune response. • Trastuzumab Deruxtecan (T-DXd): As a next-generation antibody-drug conjugate (ADC), T-DXd demonstrates excellent killing power in HER2-low and even some HER2-negative tumors through its highly efficient payload (topoisomerase I inhibitor) and significant “bystander effect.” Preclinical studies have confirmed that the combination of anti-PD-1/TIGIT inhibitors and T-DXd has stronger anti-tumor activity than the combination of T-DXd and PD-L1 inhibitors, which laid a solid foundation for the implementation of clinical trials.
03 Efficacy Performance under RPS Subtyping: Significant Benefit in the Immune-Positive Subtype
In the R+T-DXd arm of I-SPY 2.2, the patient population covered high-risk patients who were HR-positive and HR-negative, and HER2-negative (including HER2-low). The study focused on analyzing the “Immune-positive” response predictive subtype. Key Data: • Total Population and Immune-Positive Subtype: In all subtypes, the predicted pCR rate of R+T-DXd was similar to the concurrent control group. However, in the Immune-positive RPS subtype, after 4 cycles of R+T-DXd treatment, the predicted pCR rate reached 53%, which exceeded the pre-specified efficacy threshold of the study. • Chemotherapy-Sparing Potential: Notably, in the Immune-positive subtype, more than 60% of patients were expected to skip subsequent Block B and Block C chemotherapy after completing the R+T-DXd regimen and proceed directly to surgery. • Block A Monotherapy Phase Efficacy: o HR-positive subtype: The predicted pCR rate after Block A was 16% (mean distribution), exceeding the pre-specified threshold of 15% (probability of 0.58). o HR-negative subtype: The predicted pCR rate after Block A was 33%, performing better in the immune-positive group. • Comparative Analysis: In the immune-positive subtype, the pCR rate after R+T-DXd was 57% in HR-positive patients and 52% in HR-negative patients, showing consistent benefits across receptor statuses.
04 Sensitivity Analysis for HER2-low
Given the mechanism of action of T-DXd, the research team conducted a sensitivity analysis for patients with HER2 IHC 1+ or 2+/FISH negative (i.e., HER2-low). Among all immune-positive patients, the predicted pCR rate for HER2-low patients receiving R+T-DXd treatment was 74%, significantly higher than the 62% of the control group (probability of superiority 0.82). This data strongly proves that T-DXd has extremely high application value in HER2-low patients with an active immune microenvironment.
05 Safety Management: Real-time Monitoring Strategy for Interstitial Lung Disease (ILD)
Safety is the focus of this combination regimen, especially the known ILD risk of T-DXd. • ILD Incidence: During the study, a total of 14 interstitial lung disease (ILD) events were observed, of which 12 occurred in the Block A phase and 2 occurred in the Block B phase. In terms of grading, there were 9 cases of Grade 1 events, 4 cases of Grade 2 events, and 1 case of transient Grade 3 event. • Management and Recovery: Among the 12 patients who developed ILD in Block A, 8 discontinued R+T-DXd as required by the protocol, and the other 4 had completed 4 cycles of treatment. All patients who developed ILD recovered after treatment, and no recurrence occurred. • Monitoring Recommendations: I-SPY 2.2 implemented strict real-time safety run-in monitoring, including chest CT scans every 6 weeks, pulmonary function tests (PFTs), and 6-minute walk tests. • Concluding Recommendation: Professor O’Sullivan pointed out that chest CT scans every 6 weeks are the most effective means for early detection of ILD, while PFTs and 6-minute walk tests have limited additional benefit in terms of early warning. This strategy can serve as a benchmark for assessing lung safety in future clinical trials.
06 Expert Conclusions and Future Clinical Outlook
Professor Ciara Catherine O’Sullivan concluded that the Rilvegostomig combined with T-DXd regimen showed good tolerance in high-risk HER2-negative breast cancer patients in neoadjuvant treatment and showed strong clinical activity in specific subtypes. Core Conclusions:
- Precision Subtyping is Crucial: The immune-positive subtype is the dominant group for this combination regimen, and the improvement in pCR rate provides the possibility for “chemo-sparing” for this part of patients.
- Treatment Front-loading: R+T-DXd as Block A treatment can allow a significant proportion of immune-positive patients to have surgery earlier, avoiding the toxicity of traditional chemotherapy.
- Safety is Controllable: Through multi-disciplinary collaboration (such as the involvement of pulmonary specialists) and high-frequency imaging monitoring, T-DXd-related ILD risks can be effectively identified and managed. In the future, I-SPY 2.2 will continue to verify the application of this regimen in a wider range of subtypes and further optimize the monitoring process. This treatment model based on molecular subtyping rather than traditional anatomical staging is leading the neoadjuvant treatment of breast cancer into a high-quality development track of individualization, precision, and low toxicity.
