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Outcomes of Fulvestrant, Palbociclib, and Avelumab Treatment After Progression on CDK4/6i and Aromatase Inhibitor Therapy for HR+/HER2− Metastatic Breast Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting.
METHODS
The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P.
RESULTS
Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations.
CONCLUSION
The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.
Additional Info
Disclosure statements are available on the authors' profiles:
PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer
J. Clin. Oncol 2024 Mar 21;[EPub Ahead of Print], EL Mayer, Y Ren, N Wagle, R Mahtani, C Ma, A DeMichele, M Cristofanilli, J Meisel, KD Miller, Y Abdou, EC Riley, R Qamar, P Sharma, S Reid, N Sinclair, M Faggen, CC Block, N Ko, AH Partridge, WY Chen, M DeMeo, V Attaya, A Okpoebo, J Alberti, Y Liu, E Gauthier, HJ Burstein, MM Regan, SM TolaneyFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The first-line therapy for patients with HR+/HER2− metastatic breast cancer (MBC) consists of a CDK4/6 inhibitor and endocrine therapy (ET) for the majority of patients. The median progression-free survival (PFS) duration associated with the use of three commercially available CDK4/6 inhibitors is approximately 2 years. However, all patients eventually experience disease progression, and the optimal second-line treatment is not well-established. One strategy has been to continue treatment with a CDK4/6 inhibitor and switch out the ET, based on the goal of overcoming endocrine resistance while keeping cell cycle inhibition intact.
The PACE trial tested this hypothesis in a randomized, three-arm, open-label study. After progression on palbociclib (P) and ET, consisting of either an aromatase inhibitor or a selective estrogen receptor modulator, patients were randomized to receive fulvestrant (F), a selective estrogen receptor downregulator, as monotherapy; F + P; or F + P in combination with avelumab (A), an immune checkpoint inhibitor (ICI). The rationale for the third arm was based on the preclinical synergy observed between ICIs and CDK4/6 inhibitors. Of note, approximately 90% of the patients had received P as their CDK4/6 inhibitor in the first-line setting, and most patients had >1 year of therapy and were ready to receive second-line ET, representing a largely endocrine-sensitive population. The trial results were negative. There was no difference in the median PFS duration, which was the primary endpoint of the trial, with a median PFS duration of 4.8 months for the F arm, 4.6 months for the F + P arm, and 8.1 months for the F + P + A arm. The overall survival duration was numerically longer for the F + P + A combination arm at 42.5 months; however, this did not achieve statistical significance.
This well-conducted study corroborates previous findings that switching ET at the time of progression after first-line CDK4/6 inhibitor therapy does not appear to benefit patients. The MAINTAIN trial, in contrast, showed a statistical improvement with a switch of both the ET and the CDK4/6 inhibitor (in this case, from P to ribociclib and from an aromatase inhibitor to F). The clinical benefit remained modest, in the order of 2 to 3 months. Now that there are targeted agents for the treatment of patients with HR+/HER2− MBC, it makes sense to perform comprehensive genomic profiling of patient tumors at progression and treat based on the presence of ESR1, PIK3CA, AKT, or PTEN alterations. Most patients will have an alteration in one of these genes, with a corresponding targeted therapy. Other patients might be candidates for everolimus and F therapy. The data for A in the PACE trial are interesting, and the pattern of better median overall survival outcomes after treatment is consistent with what is observed in patients with triple-negative breast cancer treated with ICIs. Further research is clearly indicated to determine the value of adding an ICI in the treatment of patients with HR+/HER2− MBC.