Research Rewind: Notable Phase 1/2 Breast Cancer Trial Readouts From Quarter 2 of 2026

The breast cancer research arena continues to make waves with early-phase studies that could influence future clinical trial directions. Read our recap of the most recent phase 1/2 data readouts to learn more.

What efficacy data have been seen so far with zovegalisib, atirmociclib, and fulvestrant in HR-positive, HER2-negative metastatic breast cancer?

First-line zovegalisib (RLY-2608) plus atirmociclib (PF-07220060) and fulvestrant (Faslodex) yielded responses in heavily pretreated, CDK4/6 inhibitor–exposed patients with PI3Kα-mutated hormone receptor (HR)–positive, HER2-negative metastatic breast cancer.¹ Data from the dose-finding portion of the phase 1 ReDiscover study (NCT05216432) showed that at a median follow-up of 7.4 months, treatment with the triplet regimen led to an overall response rate (ORR) of 44% and a tumor reduction rate of 85% among response-evaluable patients in this population (n = 34). Based on these trial findings, a phase 3 trial evaluating frontline zovegalisib plus atirmociclib and an aromatase inhibitor in patients with endocrine-sensitive disease is planned to start in 2027.

What biomarker data have been reported with zanidatamab plus evorpacept in HER2-positive metastatic breast cancer?

CD47 expression and circulating tumor DNA dynamics were shown to be potential biomarkers of response to zanidatamab-hrii (Ziihera) in combination with evorpacept (ALX148) in patients with heavily pretreated HER2-positive metastatic breast cancer.² Exploratory biomarker data from a phase 1b/2 trial (NCT05027139) presented at the 2026 ESMO Breast Cancer Congress showed that of 24 evaluable patients who had been previously treated with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and a median of 5 prior HER2-targeted therapies (range, 3-7), the confirmed ORR was 33.3%. Additionally, the median progression-free survival (PFS) was 3.6 months (95% CI, 1.7-11.0).

CD47 expression level was a key determinant of response, among evaluable patients with available CD47 immunohistochemistry data (n = 17), all 5 patients with HER2-positive disease whose tumors expressed CD47 on at least 20% of tumor cells achieved a complete response (CR) or a partial response (PR) with a median duration of response of 20.2 months (95% CI, 5.6-not evaluable [NE]). Furthermore, the median PFS was 22.1 months (95% CI, 7.4-NE) among patients with HER2-positive disease and CD47 expression levels of 20% or higher vs 3.4 months (95% CI, 1.5-NE) in patients with CD47 expression levels lower than 20%.

How did ADC therapy following prior treatment with a different ADC perform in patients with HER2-positive breast cancer in the SATEEN trial?

Post–fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) use of sacituzumab govitecan-hziy (Trodelvy) plus trastuzumab (Herceptin) generated an ORR of 3.7% (95% CI, 0.1%-19%) in patients with HER2-positive metastatic breast cancer, failing to meet the primary end point of the phase 2 SATEEN trial (NCT05113251).³ Findings presented at ESMO Breast 2026 showed 1 confirmed PR among evaluable patients (n = 27). Only 14.8% (95% CI, 4%-33%) of these patients experienced a clinical benefit lasting at least 18 weeks. Due to these data, the trial was stopped for futility after the first stage of the Simon’s 2-stage design.

“Sacituzumab govitecan and T-DXd have similar payloads,” Kelly E. McCann, MD, PhD, an associate professor at the University of California San Diego, said in an interview with OncLive^®. “That is the most important consideration. There were biomarkers that were drawn and more data on the biology of cross-resistance. There was only 1 objective response; [this was] not a huge trial, but the ORR was quite low. I think that speaks to the fact that [when] using antibody-drug conjugate [ADC] after ADC, if the payload is the same, there is significant cross resistance, which we’ve seen in manyretrospective analyses. But now this is a prospective trial that also bore that out.”

What is the early-phase efficacy of neoadjuvant rilvegostomig plus T-DXd in HER2-negative breast cancer?

Treatment with neoadjuvant rilvegostomig (AZD2936) combined with T-DXd led to high pathologic CR (pCR) rates in patients with immune-positive response predictive subtypes (RPS) of high-risk HER2-negative breast cancer.⁴ Findings from the phase 2 I-SPY 2.2 trial (NCT01042379) presented at the 2026 ASCO Annual Meeting showed that among patients with an immune-positive RPS, rilvegostomig plus T-DXd alone, administered prior to any additional treatments, elicited a pCR rate of 57% (95% CI, 35%-78%) in patients with HR-positive, HER2-negative, immune-positive disease (n = 12). This rate was 52% (95% CI, 32%-71%) among patients with HR-negative, HER2-negative, immune-positive disease (n = 35). Across all treatment blocks, 72% of immune-positive patients (n = 34/47) had a pCR; 62% of those pCRs were observed following rilvegostomig plus T-DXd alone, enabling surgery without chemotherapy, and 97% of those pCRs were achieved by end of response-adaptive escalation therapy without anthracycline/cyclophosphamide.

References

1. Relay Therapeutics announces clinical data for zovegalisib plus atirmociclib triplet combination supportive of further development in frontline metastatic breast cancer. News release. Relay Therapeutics. April 27, 2026. Accessed July 14, 2026. https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-clinical-data-zovegalisib-plus
2. Meric-Bernstam F, Wisinski KB, Fang B, et al. Exploratory biomarker analysis from a phase 1b/2 trial of zanidatamab + evorpacept in patients with HER2-positive metastatic breast cancer. Presented at: 2026 ESMO Breast Cancer Congress. May 6-8, 2026; Berlin, Germany. Abstract 72P.
3. Tarantino P, Yu L, Faggen M, et al. Efficacy and safety of sacituzumab govitecan (SG) plus trastuzumab in patients with HER2+ metastatic breast cancer after prior trastuzumab deruxtecan (T-DXd): results from the phase II SATEEN trial. Presented at: 2025 ESMO Breast Cancer Congress. May 6-8, 2026; Berlin, Germany. Abstract LBA4.
4. O’Sullivan CC, Kalinsky KM, 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):LBA514. doi:10.1200/JCO.2026.44.17_suppl.LBA514