Rilvegostomig Combo Demonstrates Activity in HER2-Negative Breast Cancer

Findings from the phase 2 I-SPY 2.2 trial (NCT01042379) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting showed substantial activity with neoadjuvant rilvegostomig plus fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) among patients with mmune-positive, high-risk, HER2-negative breast cancer.¹

The findings showed that pathologic complete response (pCR) rates in immune-positive subgroups reached an estimated 53%, exceeding predefined efficacy thresholds following treatment with the dual PD-1/TIGIT bispecific antibody rilvegostomig and the HER2-directed antibody-drug conjugate (ADC) T-DXd.

“I-SPY 2.2 enrolls patients with early-stage, high-risk breast cancer, personalizing systemic therapy to maximize pCR rates. The goal is to identify optimal neoadjuvant regimens and reduce unnecessary toxicity in immune-positive response predictive subtypes,” presenting investigator Ciara C. O’Sullivan, MB, BCh, BAO, of Mayo Clinic Rochester, explained.

Trial Background and Rationale

I-SPY 2.2 is a phase 2 adaptive neoadjuvant platform trial designed to evaluate novel treatment strategies across sequential treatment blocks while identifying patients who may achieve pCR without escalation to standard chemotherapy. Eligible patients with stage II or III HER2-negative disease received rilvegostomig plus T-DXd for up to 4 cycles in Block A. Patients predicted to achieve pCR could proceed directly to surgery, whereas others advanced to Block B to receive taxane-based chemotherapy and to Block C to receive anthracycline-based therapy, with immune-positive patients also receiving pembrolizumab (Keytruda) in these blocks. Some patients were randomly assigned to proceed immediately to Block B as a control arm. There was a safety run-in due to the risk of interstitial lung disease (ILD) with the investigational combination.

Forty-five percent of patients had immune-positive response predictor subtypes, and the most common subtype of patients overall was those with hormone receptor (HR)–positive, HER2-negative, immune-negative disease (45%, n = 46).

Efficacy of the Combination Strategy

Among 105 patients treated with rilvegostomig plus T-DXd in Block A, the estimated pCR rate reached 57% in HR-positive, immune-positive disease and 52% in HR-negative, immune-positive disease. However, the pCR rates were 3% and 8% in these respective groups with immune-negative disease. According to O’Sullivan, the findings suggest that the combination’s activity was concentrated within immune-positive response-predictive subtypes. “[Rilvegostomig] plus T-DXd alone had low efficacy in immune-negative breast cancer, but high efficacy in immune-positive breast cancer,” she said during her presentation.

The investigators also evaluated outcomes across the entire treatment strategy, including subsequent treatment blocks. Among immune-positive patients, 62% achieved pCR without needing chemotherapy; overall, 72% of immune-positive patients achieved pCR, and 97% of those who ultimately achieved pCR did so before requiring anthracycline-containing therapy.

Additional Efficacy and Safety Analyses

The study investigators concluded that although overall estimated pCR rates were similar between experimental strategies and concurrent controls in immune-positive disease (66% vs 65% in HR positive and 72% vs 70% in HR negative), treatment beginning with rilvegostomig plus T-DXd enabled many patients to avoid additional chemotherapy exposure.
A sensitivity analysis examined outcomes according to HER2 immunohistochemistry (IHC) status among immune-positive patients. Although patient numbers were limited, estimated pCR rates were 74% with rilvegostomig plus T-DXd compared with 62% among controls in patients with HER2 IHC 1+ or 2+ disease, corresponding to a posterior probability of superiority of 0.82. O’Sullivan noted that these findings suggest the combination “may improve pCR rates” in HER2-low immune-positive tumors relative to control therapy.

Safety analyses focused heavily on ILD, a recognized toxicity associated with T-DXd. Because of concerns regarding overlapping pulmonary toxicity from combining an ADC with immunotherapy, investigators implemented an intensive monitoring strategy that included pulmonary function testing and high-resolution chest CT scans every 6 weeks, with real-time review of abnormalities by a multidisciplinary task force that included pulmonologists. During Block A, ILD occurred in 12 patients (13.3%) with an additional 2 cases in Block B, primarily low grade with 1 brief grade 3 event. Eight patients discontinued both T-DXd and rilvegostomig; the others had already completed their treatment. All recovered without recurrence.

According to O’Sullivan, having input from a pulmonologist was highly beneficial and the chest CT scans aided in detecting ILD early, whereas pulmonary function tests and 6-minute walk tests provided little additional benefit.

The most common adverse events in Block A were fatigue (84.8%), nausea (81.0%), and alopecia (58.1%). When comparing to the control arm that went directly to chemotherapy and immunotherapy, O’Sullivan noted that “there were similar rates of fatigue, nausea, and constipation; there were decreased rates of anemia, neutropenia, musculoskeletal pain, and rash.”

The investigators concluded that neoadjuvant rilvegostomig plus trastuzumab deruxtecan was tolerable and highly active in immune-positive HER2-negative breast cancer. Although overall efficacy across the full treatment strategy was comparable with standard approaches, the ability to achieve pCR early and omit subsequent chemotherapy may represent an important step toward treatment deescalation for selected patients. Additional analyses, including quality-of-life outcomes, are planned.

Reference

O’Sullivan CC, Kalinsky K, Yau C, et al. Neoadjuvant rilvegostomig (R) + trastuzumab deruxtecan (T-DXd) in high-risk HER2-negative breast cancer: Results from the I-SPY 2.2 trial. J Clin Oncol. 2026;44(suppl 17). doi: 10.1200/JCO.2026.44.17_suppl.LBA514