Palbociclib Rechallenge for Hormone Receptor–Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial

Abstract

Purpose: 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/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Patients and Methods: The multicenter, open-label, phase II BioPER trial included women who had experienced progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125mg, 100mg, or 75mg 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. Co-primary 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%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 co-primary 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 (hazard ratio, 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.

Predicting clinical benefit from continuation of cyclin dependent kinase (CDK) 4/6 inhibitors beyond progression

“…While the BioPER study was a single arm trial not designed to show superiority, and cross-trial comparisons should be taken with a grain of salt, the mPFS seen here (3.2 months) is comparable to control arms (fulvestrant alone) of other 2L ET trials (5,7,8). Similarly, the PACE study (16) was not able to show superiority of the continuation of palbociclib beyond first progression (versus fulvestrant alone), raising the possibility that patients progressing on 1L palbociclib may have developed resistance to the drug, although in PACE, there was a suggestion that patients with tumors harboring ESR1 mutations may continue to derive some benefit from palbociclib, again limited by the small numbers, and in direct conflict with the resistance signature presented in the current article (14). The larger, randomized phase 2 PALMIRA trial (NCT03809988) will try to answer the question of clinical benefit of continuing palbociclib in 198 patients who have progressed on palbociclib plus an AI after deriving clinical benefit from it.…”

“…Recent observational data (13) suggests potential benefit of continuing CDK4/6 blockade beyond progression on CDK4/6i therapy. In the January 1 st , 2023 issue of Clinical Cancer Research, Albanell et al (14) reported data from the phase 2 BioPER trial, which had the co-primary objectives of estimating clinical benefit from continuation of palbociclib beyond progression as well as exploring potential biomarkers of clinical benefit. This small single arm study included 33 patients with ER + /HER2 − mBC who progressed on immediately prior palbociclib plus ET after having achieved clinical benefit on it (response or stable disease ≥24 weeks).…”

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial

“…The high level of HER2-enriched lesions might be due to the more aggressive features of metastatic disease and endocrine treatment-refractory disease potentially losing its luminal features after disease progression 40 . Furthermore, in the recent BioPER trial, after treatment with a CDK4/CDK6 inhibitor, 37.5% of the samples showed a HER2-enriched subtype 53 , suggesting that HER2-enriched tumors are prominent in patients that are heavily pretreated and/or that have been exposed to CDK4/CDK6 inhibition, as was the case for 94% of ER + GELATO patients. Interestingly, in GELATO, 90% of primary tumors were classified as either luminal A or luminal B (Supplementary Table 4), suggestive of an acquired HER2-enriched phenotype later in the disease course.…”

CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective

“…The phase II BioPER single-arm study enrolled 33 patients with advanced ER+/HER2-breast cancer who had prior clinical benefit to but subsequently progressed on palbociclib plus ET ( Albanell et al, 2023 ). Patients continued palbociclib but had switch of their ET.…”

“…Clinical benefit rate was 34% and median PFS was 2.6 months ( Albanell et al, 2023 ). A composite biomarker signature incorporating low Rb score (defined as <1% tumor cells with positive nuclear staining on immunohistochemistry), high cyclin E1 (defined as ≥10% tumor cells with positive nuclear staining on immunohistochemistry), and ESR1 mutation was associated with poorer PFS ( Albanell et al, 2023 ). Other trials evaluating continued CDK4/6 inhibition are in progress and included in Supplementary Table S2 .…”