Rilvegostomig Combo Helped Some Patients Avoid Chemotherapy in Early Breast Cancer

Neoadjuvant treatment with rilvegostomig plus trastuzumab deruxtecan (Enhertu; T-DXd) (RT-DXd) demonstrated promising antitumor activity in patients with high-risk, early-stage breast cancer whose tumors were classified as immune-positive, according to findings from the phase 2 I-SPY2.2 trial published in JAMA Oncology.¹ The response-adapted treatment strategy also allowed many patients who achieved a pathologic complete response (pCR) to avoid additional chemotherapy.

Rilvegostomig is an investigational bispecific antibody targeting PD-1 and TIGIT immune checkpoints and, in I-SPY2.2, is combined with T-DXd, an antibody-drug conjugate (ADC) targeting. The study evaluated the regimen as an initial treatment for patients with high-risk, stage II or III, HER2-negative breast cancer, including tumors with low or ultralow HER2 expression.² 

Among 105 patients who received RT-DXd as their initial treatment, the modeled pCR rate was 54% in immune-positive tumors.¹ Rates were similar in patients with hormone receptor (HR)–positive and HR-negative, immune-positive disease, at 57% and 52%, respectively. The regimen did not meet the study’s predefined efficacy threshold in immune-negative tumors. 

Biomarker Status May Help Guide Treatment De-Eescalation

I-SPY2.2 uses an adaptive treatment design in which patients receive up to 3 sequential treatment blocks, depending on their tumor response and biomarker classification. Following RT-DXd, subsequent treatment could include taxane-based therapy, with or without immunotherapy, followed by doxorubicin and cyclophosphamide, with or without immunotherapy.

Among immune-positive patients who achieved pCR, 21 (62%) required only the initial RT-DXd treatment block. Additionally, 33 (97%) avoided anthracycline-based chemotherapy.¹

The overall treatment strategy did not demonstrate superiority over concurrent control regimens in the study’s modeled pCR comparisons. These findings suggest that biomarker-guided treatment selection may help identify patients who can achieve a response with less treatment, although they do not establish that RT-DXd improves outcomes compared with standard treatment.

Safety Findings Highlight Interstitial Lung Disease Risk

The most common adverse events included fatigue and nausea. Interstitial lung disease (ILD) occurred in 13 patients (12.4%) receiving RT-DXd, including 1 grade 3 event. Enrollment was paused twice for safety reviews after cases of grade 2 or higher ILD were identified. With enhanced monitoring and protocol-guided management, the reported ILD cases resolved.¹

The investigators noted that close monitoring was important for detecting and managing ILD, a recognized safety concern associated with T-DXd. The study incorporated serial chest computed tomography and specialist review to support early identification of pulmonary toxicity.

Further Studies Needed to Confirm Benefit

The findings support further investigation of RT-DXd in biomarker-selected populations, particularly patients with immune-positive tumors who may be able to avoid some chemotherapy exposure. However, I-SPY2.2 was a phase 2, signal-finding study with relatively small patient subgroups, and larger trials are needed to confirm the regimen’s efficacy and determine its role in clinical practice.

The investigators also noted that the study could not clearly establish the individual contributions of rilvegostomig and T-DXd to the observed responses. Further research will be needed to determine whether the combination offers advantages over the ADC alone and whether response-guided treatment can safely reduce treatment burden without compromising outcomes.

REFERENCES

1. ’Sullivan CC, Kalinsky KM, Yau C, et al. Rilvegostomig plus trastuzumab-deruxtecan for early-stage breast cancer: the I-SPY2.2 randomized clinical trial. JAMA Oncol. Published online October 22, 2026. doi:10.1001/jamaoncol.2026.4258

2. I-SPY TRIAL: neoadjuvant and personalized adaptive novel agents to treat breast cancer (I-SPY). ClinicalTrials.gov. Updated May 6, 2026. Accessed October 23, 2026. https://clinicaltrials.gov/study/NCT01042379