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Outcomes of Palbociclib Rechallenge in Patients With HR+/HER2− Advanced Breast Cancer
TAKE-HOME MESSAGE
- This nonrandomized phase II trial evaluated the outcomes in patients with HR+/HER2− advanced breast cancer who had previously received and derived benefits from palbociclib plus endocrine therapy. Upon the eventual progression of the disease, the patients were continued on palbociclib, and their endocrine therapy was switched to the physician's choice of alternative aromatase inhibitor or fulvestrant. Simultaneously, a biomarker signature that included ESR1, retinoblastoma (Rb), and cyclin E1 was evaluated. The clinical benefit rate (best response of stable disease or better) was 34.4%, and the median duration of progression-free survival (PFS) was 2.6 months. Patients with either ESR1 mutation, a low Rb score, or high cyclin E1 score demonstrated poorer outcomes (median PFS, 1.9 months vs 6.7 months in those with low-risk signatures).
- The BioPER trial is the first study to evaluate the outcomes of palbociclib rechallenge following disease progression, with an isolated change in endocrine therapy. The benefit observed was modest at best.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC).
PATIENTS AND METHODS
The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis.
RESULTS
Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018).
CONCLUSIONS
Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.
Additional Info
Disclosure statements are available on the authors' profiles:
Palbociclib Rechallenge for Hormone Receptor-Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial
Clin. Cancer Res 2023 Jan 04;29(1)67-80, J Albanell, JM Pérez-García, M Gil-Gil, G Curigliano, M Ruíz-Borrego, L Comerma, J Gibert, M Bellet, B Bermejo, L Calvo, J de la Haba, E Espinosa, AM Minisini, V Quiroga, A Santaballa Bertran, L Mina, B Bellosillo, F Rojo, S Menéndez, M Sampayo-Cordero, C Popa, A Malfettone, J Cortés, A Llombart-CussacFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors (ribociclib, palbociclib, and abemaciclib) in combination with endocrine therapy (ET) is the current standard first-line treatment for patients with hormone receptor (HR)–positive and human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer.1,2 There is a current interest in assessing the outcomes of the continuation of CDK4/6 inhibition after progression on these drugs.
The BioPER trial was a single-arm, multicenter, phase II study that aimed to assess the efficacy of the CDK4/6 inhibitor palbociclib in combination with ET after progression on prior palbociclib-based regimens for the treatment of metastatic HR-positive and HER2-negative breast cancer.3 A total of 32 postmenopausal patients were enrolled in the BioPER trial. The median duration of progression-free survival (PFS) on the prior palbociclib regimen was 13.8 months, and 75.0% of the patients had two prior lines of therapy (12.5% had prior chemotherapy). The clinical benefit rate was 34.4% (95% CI, 18.6–53.2; P < .001), and the median duration of PFS was 2.6 months. Notably, this study included robust biomarker analyses and found that, at baseline, 13.0% of the tumors had a loss of expression of the Rb protein. Patients with loss of Rb and those with high cyclin E1 expression did not demonstrate a clinical benefit with the continuation of palbociclib and had a shorter median duration of PFS.
Other studies have assessed the role of the continuation of CDK4/6 inhibition beyond progression. The MAINTAIN (NCT02632045) study was a phase II trial in which 120 patients were randomized to receive fulvestrant (83.0%) or exemestane (17.0%) with or without ribociclib after progression on CDK4/6 inhibitors (84.0% had received prior palbociclib) and ET.4 This study showed an improvement in PFS outcomes in patients who received ribociclib compared with placebo (5.3 months vs 2.76 months; HR, 0.56, 95% CI, 0.37–0.83; P = .004). At a median follow-up of 12 months, 25% of the patients on the ribociclib arm remained progression-free versus 7% on the placebo arm. The PACE (NCT03147287) study was another phase II trial in which 120 patients were randomized 1:2:1 to fulvestrant, fulvestrant with palbociclib, or fulvestrant, palbociclib, and avelumab after progression on CDK4/6 inhibition.5 The primary objective of the study was to compare the PFS outcomes for fulvestrant versus fulvestrant with palbociclib; of note, 91% of the patients received prior palbociclib. At a median follow-up of 18 months, there was no difference between the fulvestrant and fulvestrant and palbociclib arms in PFS outcomes (4.8 months vs 4.6 months) or overall survival outcomes (27.5 months vs 24.46 months). The avelumab arm appeared to have better outcomes.
MAINTAIN and PACE were small-scale studies, and the contrasting findings could be explained by the difference in samples sizes, patient populations, and possible differences between CDK4/6 inhibitors, as most patients in the MAINTAIN study received ribociclib after progression on palbociclib; however, in the PACE study, patients received palbociclib after previous palbociclib, as in the BioPER trial. CDK4/6 inhibition after progression on CDK4/6 inhibition is not the current standard of care, and there are larger ongoing studies that may provide more information about the efficacy of these treatments (EMBER-3 [NCT04975308] and PostMONARCH [NCT05169567]). Additionally, several novel ETs have been developed, and, in the future, we will need biomarkers to determine the optimal treatment sequencing for patients with advanced HR-positive and HER2-negative breast cancer. The biomarker analysis in the BioPER trial may help us identify patients who may benefit from CDK4/6 inhibition after progression.
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