Journal of the National Cancer Institute · 2026
A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (ASPIRE).
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Patel Rima, Kwa Maryann, Klein Paula, Fasano Julie, Moshier Erin, Kocyigit Hulya, Goel Anupama, Accordino Melissa, Shapiro Charles, Vaccaro Rita, Fiedler Laura, Addesso Sharolette, Bucwinska Weronika, Xing Xiao Y, Wilck Eric, Tiersten Amy
Аннотация
PURPOSE: The ASPIRE trial evaluated frontline anastrozole, palbociclib, trastuzumab, and pertuzumab in patients with HR-positive, HER2-positive metastatic breast cancer (MBC).
METHODS: This phase I/II trial enrolled patients with previously untreated, HR-positive, HER2-positive MBC. In Phase I, patients received escalating doses of palbociclib with trastuzumab, pertuzumab and anastrozole, using a 3 + 3 dose escalation design, and primary endpoint was maximum tolerated dose (MTD). Phase II followed an optimal Simon two-stage design where all patients received palbociclib at the MTD, plus anastrozole, trastuzumab, and pertuzumab and the primary endpoint was clinical benefit rate (CBR) in the first six months. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety.
RESULTS: In Phase I, no dose limiting toxicities were observed at the 100mg (N = 3) or 125mg (N = 6) dose levels, and thus, 125mg was the MTD. An additional 23 patients were enrolled to Phase II, with a total of 29 patients in the response-evaluable population. The primary endpoint of CBR was 97% (N = 28; 95% CI: 82-99%). At a median follow-up of 45.3 months, median PFS was 24.9 months (95% CI: 17.2-44.8). Median OS was not reached at a follow-up of 39.4 months. Most common treatment-related adverse events (TRAEs) were neutropenia, leukopenia, diarrhea, and anemia. Grade 3-4 TRAEs occurred in 62% (N = 18) of patients and most were hematologic.
CONCLUSIONS: The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab demonstrated promising activity in this single-arm trial of patients with HR-positive, HER2-positive MBC and warrants further study in randomized trials. The regimen could provide a chemotherapy-free alternative.
METHODS: This phase I/II trial enrolled patients with previously untreated, HR-positive, HER2-positive MBC. In Phase I, patients received escalating doses of palbociclib with trastuzumab, pertuzumab and anastrozole, using a 3 + 3 dose escalation design, and primary endpoint was maximum tolerated dose (MTD). Phase II followed an optimal Simon two-stage design where all patients received palbociclib at the MTD, plus anastrozole, trastuzumab, and pertuzumab and the primary endpoint was clinical benefit rate (CBR) in the first six months. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety.
RESULTS: In Phase I, no dose limiting toxicities were observed at the 100mg (N = 3) or 125mg (N = 6) dose levels, and thus, 125mg was the MTD. An additional 23 patients were enrolled to Phase II, with a total of 29 patients in the response-evaluable population. The primary endpoint of CBR was 97% (N = 28; 95% CI: 82-99%). At a median follow-up of 45.3 months, median PFS was 24.9 months (95% CI: 17.2-44.8). Median OS was not reached at a follow-up of 39.4 months. Most common treatment-related adverse events (TRAEs) were neutropenia, leukopenia, diarrhea, and anemia. Grade 3-4 TRAEs occurred in 62% (N = 18) of patients and most were hematologic.
CONCLUSIONS: The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab demonstrated promising activity in this single-arm trial of patients with HR-positive, HER2-positive MBC and warrants further study in randomized trials. The regimen could provide a chemotherapy-free alternative.