N. Engl. J. Med.
Alpelisib for -Mutated, Hormone Receptor-Positive Advanced Breast Cancer.
Abstract
Background
PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies.
Methods
In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety.
Results
A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively.
Conclusions
Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).
Related Questions
At what time points during a patient's treatment for metastatic ER+ breast cancer are you checking liquid NGS for endocrine pathway alterations?
Traditionally, liquid NGS testing for PIK3CA, PTEN/AKT/PIK3CA, and ESR1 alterations has been performed at discrete clinical decision points, primarily at progression on endocrine therapy or when considering targeted agents.Currently, I order NGS at disease onset, even for those who do not fit INAVO ...
Is there any data to use PIK3CA-directed agents in mutated metastatic triple-negative breast cancer?
PIK3CA inhibitors are not currently approved for use in patients with triple-negative (ER, PR, and HER2-negative) breast cancer. There is preclinical and early clinical work that indicates promise in patients with ER/PR negative, HER2 negative, PIK3CA mutated breast. A quick search finds that there ...
What disease characteristics will guide your choice of alpelisib plus fulvestrant (per SOLAR-1) versus capivasertib plus fulvestrant (per CAPItello-291) in PIK3CA mutated advanced ER+/HER2- breast cancer after progression on 1L ET regimen, given both are now approved in this population?
In the absence of head-to-head comparison, I would use cross-trial comparison to compare the efficacy and safety of alpelisib vs capivasertib. mPFS are similar for both: HR 0.65 (11 vs 5.7 months) for alpelisib (SOLAR-1); and mPFS HR 0.6 (7.2 vs 3.6 months) for capivasertib (CAPItello-291). Therefor...
How do you select systemic therapy for recurrent HR+ HER2 negative breast cancer in the bones in a premenopausal woman within a year of starting adjuvant AI with OFS plus abemaciclib and zoledronic acid?
This is, unfortunately, a case of primary endocrine resistance, and recurrence on adjuvant Abemaciclib makes the case more challenging for this pre-menopausal patient.It would be reasonable to repeat tissue biopsy to rule out a change in hormone receptor status and consider blood based ctDNA analysi...
What is the preferred sequence of systemic therapy in a patient with endocrine resistant HR+ metastatic breast cancer?
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Is there any role for alpelisib in a patient who has triple positive breast cancer and an activating PIK3CA mutation?
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When would you consider fulvestrant + alpelisib in a postmenopausal patient who has HR+, PIK3CA mutant, metastatic breast cancer instead of initial CDK4/6 inhibitor therapy?
Given that SOLAR-1 study enrolled patients who previously progressed after at least 1 line of endocrine therapy for metastatic disease, I would not offer alpelisib as front line therapy. My preference for front line therapy for metastatic, HR+, PIK3CA mutation-positive breast cancer is a combination...
Would you risk offering alpelisib or everolimus to a patient with metastatic ER+ HER2- breast CA with Type 1 DM?
In the randomized phase 3 study with alpelisib (Andre, 2019 NEJM) patient with type 1 diabetes or uncontrolled type 2 diabetes were excluded. Nonetheless, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib–fulvestrant group). Given lack of data and high incid...
How do you decide between a PARP inhibitor or alpelisib for patients with metastatic ER+, gBRCA+, PI3K mutated breast CA with progression on CDK 4/6 inhibitor/fulvestrant?
There is preclinical data that blockade of pik3ca/mtor pathway can sensitize cancer cells to PARP inhibitors by inhibiting homologous repair (Ibrahim et al Cancer Discovery 2012). We published case series data for our patients treated on the BROCADE trial showing a tripling of PFS for BRCA2+ ER posi...
What would be your next treatment in a postmenopausal woman with metastatic ER+ lobular cancer with progression on palbociclib/letrozole with multiple liver metastasis?
I will assume this patient achieved median PFS and DOR as seen in first line studies with AI/CDKi prior to her progression. Some options for next line treatment include:1) Fulvestrant single agent2) Fulvestrant + everolimus / Exemestane + Everolimus3) Fulvestrant + alternate CDKi (preferably on tria...