Amy Tiersten, MD, Mount Sinai, New York, New York, discussed results from the phase 1/2 ASPIRE study, investigating combination anastrozole, palbociclib, trastuzumab, and pertuzumab for previously untreated patients with HR-positive, HER2-positive metastatic breast cancer.

Dr Tiersten stated, “the combination of anastrozole, palbociclib, trastuzumab, and pertuzumab in the front-line setting was well tolerated and effective with a clinical benefit rate of 97%.”

These results were first presented at the 2023 San Antonio Breast Cancer Symposium. 

Transcript:

My name is Amy Tiersten, I'm a professor of medicine and the Clinical Director of Breast Medical Oncology at Mount Sinai Hospital in New York City.

The ASPIRE protocol is a multicenter phase 1/2 trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in hormone receptor (HR)-positive, HER2-positive metastatic breast cancer. In terms of study rationale, standard of care front-line treatment for HR-positive HER2-positive metastatic breast cancer generally consists of cytotoxic chemotherapy and the HER2 targeting antibodies trastuzumab and pertuzumab however, cross talk between HER2 and endrogen receptor (ER) signaling pathways may contribute to endocrine resistance. Therefore, anti-HER2 agents in combination with anti-estrogen therapy may restore endocrine sensitivity. HER2/HER3 signaling promotes cell survival by way of PI3K-AKT activation where ER-CDK4/6-Rb signaling promotes cell cycle progression, therefore combination of dual antibodies with anti-estrogen therapy and a CDK 4/6 inhibitor would interrupt both pathways and provide a novel, all biologic chemotherapy free approach for the treatment of HR-positive HER2-positive metastatic breast cancer. In terms of the trial design, key eligibility criteria were women or men with metastatic breast cancer that had at least 1% ER or PR-positivity and were HER2-positive, who had no prior therapy for systemic disease; we did allow patients with measurable or valuable disease, including bone only metastasis.

In the phase 1 portion, 9 patients were enrolled, and we escalated palbociclib from 100 milligrams in the first 3 patients to 125 milligrams in an additional 6 patients in combination with standard dosing of anastrozole, trastuzumab, and pertuzumab using a 3-plus-3 design. A GNRH agonist was added for men and premenopausal women. There were no DLTs in the phase 1 portion, and in the phase 2 portion an additional 24 patients were treated at the MTD of 125 milligrams of palbociclib; so there were 30 patients in the intention-to-treat efficacy analysis. The primary endpoint for the study was clinical benefit rate with secondary endpoints of progression-free survival (PFS), overall survival (OS), and safety. In terms of patient characteristics, the median age was 58, 72% of the participants were white, 72 participants were postmenopausal, 43% had de novo metastatic disease, 63% had visceral disease, and there was 1 male on trial.

In terms of clinical response rate for our primary end point of clinical benefit rate, there was a 97% clinical benefit rate, 4 patients had a complete response, 18 patients had a partial response, 7 patients had stable disease, no patients had progressive disease as their best response, the median time to response was 2.8 months, median duration of response was 37.8 months, and median follow-up at this time is 30 months. Median progression-free survival was 21.2 months, median survival has not yet been reached as only 1 patient died after receiving 2 plus years of protocol treatment; 5 patients remain on active treatment. In terms of toxicity, the regimen was very well tolerated with safety data consistent with the known toxicity profiles of the individual agents with the most common adverse events of neutropenia, diarrhea, and leukopenia. One patient did have to discontinue trastuzumab and pertuzumab due to cardiac toxicity after about 3 months of protocol treatment but remains NED presently on anastrozole and palbociclib now for almost 4 years.

In conclusion, the monarcHER trial previously demonstrated increased efficacy of the combination of abemaciclib, fulvestrant, and trastuzumab compared to chemotherapy plus trastuzumab in patients with HR-positive HER2-positive metastatic breast cancer who had had at least 2 prior therapies, and the median in this trial of prior therapies was 4. Our trial found that the combination of anastrozole, palbociclib, trastuzumab, and pertuzumab in the front-line setting was well tolerated and effective with a clinical benefit rate of 97%, including patients with visceral disease and premenopausal women. This combination can provide a chemotherapy free front-line regimen for our patients.

Source:

Patel R, Cascetta K, Klein P, et al. A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (ASPIRE). Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9; San Antonio, Texas. Abstract RF02-01