Neoadjuvant treatment for operable HER2-negative breast cancer remains a major clinical challenge. The emergence of antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), is reshaping traditional treatment paradigms while raising new questions about patient selection and optimal therapeutic strategies.At ASCO 2026, investigators presented results from the I-SPY 2.2 trial (Abstract #LBA515), which evaluated the PD-1/TIGIT bispecific antibody rilvegostomig combined with T-DXd as neoadjuvant therapy for high-risk HER2-negative breast cancer. Beyond demonstrating encouraging efficacy and manageable safety, the study also highlighted the predictive value of a novel response-predictive subtype (RPS), suggesting that immune-based classification may guide neoadjuvant immunotherapy beyond conventional molecular subtypes.
To discuss the implications for Chinese clinical practice, Oncology Frontier invited Juliang Zhang from Xijing Hospital, Air Force Medical University, to share his perspective in the “ASCO China Perspective” series.
Oncology Frontier: How do you interpret the key findings of the I-SPY 2.2 study evaluating rilvegostomig plus T-DXd in high-risk HER2-negative breast cancer?
Juliang Zhang:
I-SPY 2.2 is an adaptive platform trial using a Sequential Multiple Assignment Randomized Trial (SMART) design, which provides valuable insights for future clinical research. This year’s ASCO presentation was the first to evaluate the combination of T-DXd with a bispecific immune checkpoint inhibitor in the neoadjuvant setting for HER2-negative breast cancer.
The study demonstrated encouraging activity in selected patient populations. More importantly, it moved beyond conventional molecular classifications by introducing the response-predictive subtype (RPS). Among patients classified as Immune+, the combination of ADC therapy with dual checkpoint inhibition achieved promising pathological complete response (pCR) rates.
This concept may ultimately prove more impactful than the efficacy data alone, as it opens new possibilities for selecting patients based on immune biology rather than traditional receptor status.
Oncology Frontier: How do you view the future role of T-DXd and bispecific immunotherapy in HER2-negative breast cancer?
Juliang Zhang:
HER2-negative breast cancer encompasses two major groups: HR-positive/HER2-negative disease and triple-negative breast cancer (TNBC).
For TNBC, neoadjuvant treatment strategies are already well established, with immunotherapy-based regimens becoming standard practice. However, neoadjuvant treatment for HR-positive/HER2-negative disease remains much more controversial. Chemotherapy, endocrine therapy, and ADCs are all under active investigation.
Earlier studies have produced mixed results. In the Phase II TALENT trial, T-DXd monotherapy did not demonstrate a clear advantage over chemotherapy in HR-positive/HER2-low disease. Likewise, the DESTINY-Breast11 study suggested that T-DXd alone may not be sufficient in the neoadjuvant setting for HER2-positive disease, with combination strategies appearing more promising. The findings from I-SPY 2.2 are therefore consistent with the broader direction of current research.
For HR-positive/HER2-low breast cancer, where neoadjuvant options have traditionally been limited, this study provides valuable insights into both patient selection and rational combination strategies.
The bispecific checkpoint inhibitor itself is also innovative. By simultaneously targeting PD-1 and TIGIT, it may produce synergistic immune activation beyond conventional PD-1 blockade. The encouraging activity observed alongside T-DXd suggests broader opportunities for future combination approaches, including studies in TNBC with chemotherapy or other novel agents.
Oncology Frontier: Immune+ patients achieved the highest pCR rates and many avoided conventional chemotherapy. Could immune-based subtyping become part of routine practice in China?
Juliang Zhang:
The excellent outcomes observed in the Immune+ population are consistent with previous studies evaluating conventional PD-1/PD-L1 inhibitors plus chemotherapy.
What is particularly noteworthy is that HR-positive/HER2-negative patients—historically considered less responsive to immunotherapy—also demonstrated encouraging activity. In this study, pCR exceeded 60% in this subgroup, and many patients achieved pCR after Block A with rilvegostomig plus T-DXd alone, allowing them to avoid subsequent anthracycline-containing chemotherapy.
Among patients who ultimately achieved pCR, 64% avoided Block B chemotherapy, while 97% avoided anthracycline-based Block C treatment, representing a meaningful reduction in chemotherapy exposure.
At present, however, widespread adoption of this immune classification remains limited in China. Our clinical community is more familiar with the Fudan molecular classification developed by Professor Zhimin Shao and colleagues for TNBC, particularly the immune-modulatory subtype. That system has primarily been applied in advanced disease, and its role in early-stage breast cancer continues to be explored.
The RPS concept introduced by I-SPY 2.2 is certainly promising, but several important questions remain. We still need reliable methods to identify Immune+ patients, determine whether responses are consistent across different populations, and establish how to accurately detect Immune+ biology within each conventional molecular subtype.
Although evidence now supports immune checkpoint inhibitors in both early TNBC and selected HR-positive/HER2-negative breast cancer, clinicians continue to struggle with identifying patients most likely to benefit. PD-L1 testing remains the primary biomarker, yet its predictive value in early breast cancer is still imperfect.
If the Immune+ concept can be successfully validated, it may provide a more precise framework for selecting patients for immunotherapy across both early- and advanced-stage breast cancer, representing an important step beyond traditional molecular classification.
Professor
Juliang Zhang
Xijing Hospital, Air Force Medical University
