Breast Cancer Patients with Estrogen Receptor Mutations May Benefit from Early Switch to Fulvestrant/Palbociclib
Among patients with hormone receptor-positive breast cancer treated with an aromatase inhibitor plus palbociclib, those who displayed a rising ESR1 mutation detected in their blood before disease progression doubled their median progression-free survival following a switch to fulvestrant plus palbociclib, according to results from the phase III PADA-1 clinical trial presented during Thursday’s General Session at SABCS 2021.
“PADA-1 is the first trial to demonstrate that, in most patients, resistance-associated mutations in the estrogen receptor gene can be detected and targeted before tumor progression,” said presenter François-Clément Bidard, MD, PhD, Professor of Medical Oncology at Institut Curie and Paris-Saclay University in France. “The trial suggests a statistically and clinically significant benefit when fulvestrant is used during this very new window of opportunity.”
The PADA-1 trial recruited 1,017 patients with ERα-positive breast cancer that had no overexpression of the growth factor receptor HER2, who were being treated in a first-line setting with an aromatase inhibitor plus palbociclib. The patients provided blood samples for ESR1 mutation screening every two months.
Of the recruited patients, 407 experienced disease progression in the absence of an ESR1 mutation, and a mutation was detected in 279 patients prior to (219 patients) or concurrent with (60 patients) disease progression. Only those with an identified mutation who did not experience concurrent disease progression were randomly assigned either to continuing an aromatase inhibitor plus palbociclib (84 patients) or switched to fulvestrant plus palbociclib (88 patients).
After a median follow-up of 26 months, the median progression-free survival of patients who switched to fulvestrant was over twice as long as those who remained on an aromatase inhibitor—11.9 months, compared with 5.7 months.
Patients who progressed after continuing aromatase inhibitor treatment were given the option to crossover to the fulvestrant arm of the study. Among patients in the crossover cohort, the median progression-free survival was 3.5 months. This supported previous studies showing a relatively short benefit of fulvestrant when used as a second-line therapy, Dr. Bidard said, and emphasized the importance of early detection.
“This targeted approach, after the start of the first-line endocrine therapy but before the second line, yields a statistically and clinically significant gain in progression-free survival,” he said. “That benefit might not catch up when you wait, which might justify the adoption of the PADA-1 treatment strategy as a valid option in routine care.”
Abstract: GS3-05 Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2-metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial
Investigational Therapy Pyrotinib with Chemotherapy May Improve Outcomes in Patients with Pretreated HER2-positive Breast Cancer
Among patients with previously treated HER2-positive metastatic breast cancer, those who received pyrotinib plus capecitabine had longer overall survival than those who received lapatinib plus capecitabine, according to updated results from the phase III PHOEBE trial presented during Thursday’s General Session at SABCS.
“Patients with metastatic HER2-positive breast cancer are typically treated with the HER2-targeted therapies trastuzumab and pertuzumab in combination with a taxane, but resistance to this regimen inevitably develops,” said Binghe Xu, MD, PhD, Professor of Medical Oncology at the Chinese Academy of Medical Sciences.
Patients who progress on this standard therapy may then be treated with the HER2-targeted tyrosine kinase inhibitor (TKI) lapatinib in combination with the chemotherapeutic capecitabine or with alternative HER2-targeted therapies, such as trastuzumab emtansine. However, lapatinib and many other available HER2-targeted TKIs are reversible and do not sustain the inhibition of HER2 signaling. This may facilitate the development of treatment resistance, Dr. Xu noted. In addition, trastuzumab emtansine (T-DM1), which is the preferred regimen for second-line therapy after trastuzumab in many international guidelines, is not approved for metastatic disease in many countries.
“There is an urgent unmet need for additional HER2-targeted therapies for patients who progress on standard therapies in countries and regions where access to HER2-directed agents is scarce,” said Dr. Xu.
Pyrotinib, which was tested in the PHOEBE trial, is an irreversible tyrosine kinase receptor inhibitor that targets HER2, as well as the related proteins HER4 and epidermal growth factor receptor (EGFR), also known as HER1. A prior phase II clinical trial found that pyrotinib plus capecitabine led to clinical responses in previously treated patients with HER2-positive metastatic breast cancer. The phase III PHOEBE trial sought to understand the impact of pyrotinib compared with that of lapatinib in this patient population.
“Among the patients enrolled in the study, pyrotinib plus capecitabine had a manageable safety profile and led to a statistically and clinically significant improvement in progression-free and overall survival compared with that for lapatinib,” said Dr. Xu. He noted that the results of the PHOEBE clinical trial led to the approval of pyrotinib in combination with capecitabine as second-line standard-of-care treatment for HER2-positive metastatic breast cancer in China. “The updated analysis of overall survival we present here reaffirms pyrotinib plus capecitabine as a viable treatment option in this patient population.”
Abstract: GS3-02 Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer
The following abstracts were also presented during Thursday’s General Session. These presentations will be available to registered SABCS participants for on-demand viewing until March 10, 2022. Click here to find these and other abstracts presented this week at SABCS 2021.
GS3-01 Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03
GS3-03 Genomic analysis of 733 HER2+ breast cancers identifies recurrent pathways alterations associated with anti-HER2 resistance and new therapeutic vulnerabilities
GS3-06 Primary results of the cTRAK TN trial: A clinical trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer
GS3-07 Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial
GS3-09 Loss of ASXL1 tumor suppressor promotes resistance to CDK4/6 inhibitors in ER+ breast cancer
GS3-10 Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC)