This article has been updated to correctly note that the zanidatamab data is from a Phase IIa trial and to clarify that this was the first release of progression-free survival data.
NEW YORK – At the San Antonio Breast Cancer Symposium, researchers shared data on two new potential combination treatment regimens for hormone receptor (HR)-positive, HER2-positive metastatic breast cancer that wouldn't require patients to get chemotherapy.
In this type of breast cancer, not only do estrogen and progesterone receptors attach to ER and PR hormones to fuel cancer cells but HER2 overexpression on cancer cells also promote their growth. As a result, these types of tumors tend to be large and are considered more aggressive than HR-positive, HER2-negative tumors. Patients with these cancers typically receive hormone drugs as well as HER2-targeted therapies.
In the ASPIRE trial, researchers led by Amy Tiersten, a professor of oncology and hematology at the Icahn School of Medicine at Mount Sinai, explored a chemotherapy-free approach as a first-line option for patients with HR-positive, HER2-positive metastatic breast cancer.
In HR- and HER2-driven breast cancer, the interaction of these different pathways can make tumors resistant to endocrine therapy. And as HER2/3 signaling is encouraging cancer cells to survive, the ER-CDK4/6-Rb signaling pathway is also helping cell cycle progression. Tiersten and colleagues aimed to shut down all these pathways and overcome endocrine resistance without the need for chemotherapy by combining a CDK4/6 inhibitor, Pfizer's Ibrance (palbociclib), with dual HER2 antibodies, Genentech's Herceptin (trastuzumab) and Perjeta (pertuzumab), plus the anti-estrogen therapy anastrozole.
The randomized MonarcHER trial provided support for this approach. In that Phase II study, researchers tested the activity of a different CDK4/6 inhibitor, Eli Lilly's Verzenio (abemaciclib), with just one HER2-targeted antibody, Herceptin, plus the anti-estrogen drug fulvestrant in HR-positive, HER2-positive advanced breast cancer patients. Researchers compared this regimen against Herceptin and chemotherapy in patients who had received at least two prior treatments.
In that study, the triple-drug combo significantly improved median progression-free survival over Herceptin-chemo, 8.3 months versus 5.7 months, respectively. Median overall survival with Verzenio-Herceptin-fulvestrant was 31.1 months, compared to 20.7 months with Herceptin-chemo, which was numerically longer but not a statistically significant improvement.
In the single-arm ASPIRE trial, Tiersten and colleagues wanted to test their chemo-free regimen in patients who hadn't had any prior systemic therapy for metastatic breast cancer. They also had to have ER or PR positivity in at least 1 percent of tumor cells as well as HER2 overexpression.
In 30 patients (including one male), there was a 97 percent clinical benefit rate on Ibrance-Herceptin-Perjeta-anastrozole, meaning most patients achieved a complete or partial response, or had stable disease for at least six months on this regimen. Four patients had a complete response, 18 had a partial response, seven had stable disease, and one patient was unevaluable. No patients progressed on the regimen.
At a median follow-up of around 30 months, the median duration of response on the regimen was 37.8 months. Median progression-free survival was 21.2 months and median overall survival has not yet been reached. "Only one patient has died after two-plus years on protocol," Tiersten said.
This multi-drug combination was well tolerated, and the toxicities were similar to what researchers have seen with each of these agents previously. The most common toxicities were neutropenia, diarrhea, and leukopenia.
Based on this data, Tiersten concluded that "this combination can provide a chemotherapy-free frontline regimen" for HR-positive, HER2-positive breast cancer patients, including for postmenopausal women and those with visceral disease.
In another late-breaking study presented on Friday, Santiago Escrivá-de-Romaní, a medical oncologist at the Vall d'Hebron Institute of Oncology in Spain, shared the first progression-free survival data from a Phase IIa trial of Jazz Pharmaceuticals' bispecific antibody zanidatamab, Ibrance, and fulvestrant in HR-positive, HER2-positive metastatic breast cancer. Zanidatamab binds to two non-overlapping extracellular domains of HER2 and is designed to prevent tumor cell signaling and proliferation by shutting down HER2 dimerization.
Escrivá-de-Romaní noted that the MonarcHER trial was also the inspiration for combining a CDK4/6 inhibitor, anti-estrogen treatment, and an anti-HER2 drug in this study. However, his group felt that a bispecific antibody like zanidatamab could more effectively block HER2.
In order to participate in the single-arm study the patients had to have received Herceptin, Perjeta, and Genentech's HER2 antibody-drug conjugate Kadcyla (ado-trastuzumab emtansine) previously. The patients that ended up enrolling in this study were heavily pretreated, having received a median of four prior treatments. Patients, however, had to be naïve to CDK4/6 inhibitors.
HR-positive breast cancer patients could enroll if they were also HER2-positive via local testing. Out of 51 patients enrolled in the trial, 32 were confirmed to have HER2-positive tumors via central testing and 18 were HER2-negative by central testing but positive by local testing; one patient had missing data. Researchers also performed the PAM50 subtyping test on 29 patients with adequate tissue samples.
At a median follow-up of 16 months, the primary endpoint of progression-free survival rate at six months was 67 percent in the overall population, 69 percent in those who were HER2-positive by central testing, and 63 percent among those who were HER2-positive by local testing only. Median progression-free survival was a year in all patients, 15 months in centrally determined HER2-positive patients, and eight months for the locally determined HER2-positive subset.
Across these same groups, the objective response rate was 35 percent, 48 percent, and 10 percent, respectively, on the zanidatamab-containing regimen. Three patients who were HER2-positive by central testing had a complete response.
In exploratory analysis using the PAM50 subtyping test, 41 percent of patients had luminal B disease and 55 percent had a HER2-enriched subtype. At six months, 67 percent of patients with luminal B disease were progression free as were 62 percent of HER2-enriched patients. Median progression-free survival was 12 months and 9 months, and the objective response rates were 30 percent and 27 percent, respectively. While the outcomes were numerically better in the luminal B subset compared to the HER2-enriched group, the difference wasn't statistically significant.
Neutropenia and diarrhea were the most common grade 3 or 4 adverse events occurring in 53 percent and 14 percent of patients, respectively. No patients died as a result of treatment-related toxicities.
Based on this data, Escrivá-de-Romaní concluded that zanidatamab in combination with Ibrance and fulvestrant demonstrated "promising" progression-free survival and durable responses at 15 months in a heavily pretreated population. The trial will continue until overall survival data are mature. "These results support further development of this novel chemotherapy-free treatment regimen for heavily pretreated patients with HER2-positive, HR-positive, metastatic breast cancer," Escrivá-de-Romaní concluded.