Abstract PS5-01-24: Evorpacept (ALX-148) combined with trastuzumab deruxtecan in patients with HER2 positive/HER2low metastatic breast cancer (mBC): results from the PRE-ISPY phase Ib trial

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Abstract Background Despite advances in therapies such as trastuzumab deruxtecan (T-DXd) for HER2-expressing metastatic breast cancer, the disease remains incurable, underscoring a critical unmet need. Evorpacept (evo) is a high-affinity CD47-blocker with an inactive IgG Fc region designed to enhance antibody-dependent cellular phagocytosis. Here, we report results from a phase Ib trial of evo + T-DXd in patients (pts) with advanced HER2-expressing (HER2+/HER2low) breast cancer [NCT05868226]. Methods PRE-ISPY Phase I/Ib trial is an open-label platform study evaluating therapies in the advanced disease setting to identify promising regimens for rapid transition into I-SPY2, K-SPY or other trials. This multicenter study arm included 30 pts with previously treated, T-DXd naïve, advanced/metastatic HER2+/HER2low breast cancer. Part 1 dose finding contained 2 cohorts (A and B) of 10 patients each evaluating 2 doses of evo 30 mg/kg and 45 mg/kg combined with standard doses of T-DXd 5.4 mg/kg IV Q3W. Part 2 expansion (cohort C) enrolled additional 10 patients at RP2D. The primary objectives were to establish safety, Recommended Phase 2 Dose (RP2D) and antitumor activity (Overall Response Rate, ORR) in HER2+/HER2low mBC pts. PFS, Disease Control Rate (DCR), evo PK and ADA, CD47 levels, were secondary endpoints. Results As of May 30th 2025, enrollment was complete with 30 pts (n=10 in each cohort A, B and C). Median follow-up was 6.6 months (4.6 in HER2+ vs 7.4 in HER2low), with 11 pts remaining on treatment at data cutoff. Median age (range) was 54 (30-76) yrs; 14 (47%), 8 (27%) and 2 pts (7%) had a history of liver, lung and brain metastasis, respectively; and 28 patients had measurable disease at enrollment. By local HER2 assessment, 7/10 (70%) pts in cohort A and 13/20 (65%) pts in cohorts B/C had HER2low mBC diagnosis, respectively. 13/30 (43%) of pts had 3 or more prior treatment lines in the advanced setting. There were no DLTs. The RP2D was evo 45 mg/kg and T-DXd 5.4 mg/kg IV Q3W. Among all 30 pts, treatment-emergent adverse events (TEAE) of any grade occurring in the most participants were nausea (73%), fatigue (67%), diarrhea (53%) and anemia (50%). Most of these events were Grade 1 or 2 in severity. Overall, 14 participants (47%) experienced Grade 3 events (anemia, hemolytic anemia, decreased counts of neutrophils, lymphocytes and platelets, dental caries, portal hypertension, fatigue, mastitis, back pain, hypokalemia, syncope, embolism, dyspnea, and pneumonia). Four pts experienced 8 total SAEs: grade 3 hemolytic anemia, grade 4 thrombocytopenia¸ grade 3 pneumonia, portal hypertension, embolism, mastitis, and grade 2 pyrexia, each event occurring once. All SAEs were resolved except for portal hypertension. There were no grade 5 TEAEs. One AE of special interest was described (grade 2 decreased left ventricular ejection fraction). There was one grade 1 ILD/pneumonitis. Dose reductions were made for 4 participants; one included a temporary dose hold. The confirmed ORR (cORR) was 33.3% (95% CI 17.9%-52.9%) and the DCR was 73.3% (95% CI 53.8%-87.0%). In HER2+ mBC pts, cORR was 40% (95% CI 13.7%-72.6%) and the DCR was 90% (95% CI 54.1%-99.4%). In the HER2low pts (n=20), cORR was 30% (95% CI 12.8%-54.3%) and DCR was 65% (95% CI: 40.9%-83.7%). Median progression free survival (mPFS) was 8.6 months, with a mPFS of 5.6 months in HER2low (13/20 events) and not yet reached in HER2+ (2/10 events). Updated data and correlatives will be provided at the Symposium. Conclusions In this phase I study, Evo + T-DXd demonstrated a manageable safety profile comparable with T-DXd alone and evidence of antitumor activity in pretreated HER2+/HER2low mBC. There were no new safety signals. Citation Format: P. R. POHLMANN, N. Chen, J. A. Mouabbi, N. Jahan, M. Rampurwala, A. Discacciati, M. Eklund, A. Chapple, G. L. Hirst, S. Venters, L. Brown-Swigart, E. Petricoin III, A. D. Borowsky, L. J. van 't Veer, A. L. Delson, S. M. Asare, S. Jaffari, P. Henderson, D. Tripathy, L. J. Esserman, H. S. Rugo, R. Nanda, E. Stringer-Reasor, D. Yee, F. Meric-Bernstam, D. A. Potter. Evorpacept (ALX-148) combined with trastuzumab deruxtecan in patients with HER2 positive/HER2low metastatic breast cancer (mBC): results from the PRE-ISPY phase Ib trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-24.

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