Abemaciclib Is Effective in Palbociclib-Resistant Hormone Receptor–Positive Metastatic Breast Cancers

Abstract

Cyclin-dependent-kinase-4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines, as well as in vivo patient-derived xenografts (PDX) and ex vivo PDX-derived organoids from patients who progressed on CDK4/6i. PR and AR breast cancer cells exhibited distinct transcriptomic and proteomic profiles that sensitized them to different classes of inhibitors; PR cells upregulated G2/M pathways and responded to abemaciclib, while AR cells upregulated mediators of the oxidative phosphorylation pathway (OXPHOS) and responded to OXPHOS inhibitors. PDX and organoid models derived from palbociclib-resistant breast cancer patients remained responsive to abemaciclib. Resistance to palbociclib while maintaining sensitivity to abemaciclib was associated with pathway-specific transcriptional activity but was not associated with any individual genetic alterations. Lastly, data from a cohort of 52 patients indicated that patients with HR-positive/HER2-negative MBC who progressed on palbociclib-containing regimens can exhibit a meaningful overall clinical benefit from abemaciclib-based therapy when administered after palbociclib. These findings provide the rationale for clinical trials evaluating the benefit of abemaciclib treatment following progression on a prior CDK4/6i.

Abemaciclib plus endocrine therapy versus chemotherapy after progression on prior palbociclib in HR+/HER2‐ metastatic breast cancer: A single center real‐world study in China

“…However, We did not observe sequential abemaciclib obtained longer PFS compared to nonsequential abemaciclib (6.0 vs. 6.0 months) though patients received fewer lines of prior systemic therapy and had longer PFS from prior palbociclib in the sequential arm compared to the nonsequential arm, in line with the study by Navarro‐Yepes et al (6.2 vs. 6.1 months), 45 contrary to the retrospective study by Wander et al, (8.4 vs. 3.0 months, p = 0.0013) 47 . Interestingly, Navarro‐Yepes et al found sequential abemaciclib obtained significantly longer median OS for patients treated sequentially (42.7 months vs.17.3 months) 45 . Real‐world data from the Flatiron Health Network showed that continuation of CDK4/6 inhibitor after progression on first‐line CDK4/6 inhibitor was significantly associated with improved PFS and OS 48 .…”

“…Importantly, this study found palbociclib‐resistant cells upregulated G2‐M pathways and abemaciclib could mediate G2 arrest of palbociclib‐resistant cells. Furthermore, these findings were confirmed by both patient‐derived xenografts (PDX) and PDX‐derived organoids models of palbociclib‐resistant BC 45 . Overall, these promising results indicate that the use of abemaciclib plus different ET after progression on prior palbociclib might be a feasible treatment strategy in addition to chemotherapy.…”

“…Furthermore, these findings were confirmed by both patient‐derived xenografts (PDX) and PDX‐derived organoids models of palbociclib‐resistant BC. 45 Overall, these promising results indicate that the use of abemaciclib plus different ET after progression on prior palbociclib might be a feasible treatment strategy in addition to chemotherapy. However, MAINTAIN trial offered the initial evidence that using ribociclib and switching ET had significantly improved the median PFS compared to placebo plus switching ET after progression on a prior CDK4/6 inhibitor (86.5% palbociclib) (5.29 months vs. 2.76 months).…”

“… 47 Interestingly, Navarro‐Yepes et al found sequential abemaciclib obtained significantly longer median OS for patients treated sequentially (42.7 months vs.17.3 months). 45 Real‐world data from the Flatiron Health Network showed that continuation of CDK4/6 inhibitor after progression on first‐line CDK4/6 inhibitor was significantly associated with improved PFS and OS. 48 Hence, sequential abemaciclib plus switching ET after progression on first‐line palbociclib warrants further investigation in randomized prospective trials.…”

Moving toward precision medicine to predict drug sensitivity in patients with metastatic breast cancer

“… 72 , 73 , 74 For instance, nonluminal subtypes within the HR+/HER2– disease have been associated with a poorer response to endocrine therapy, 75 , 76 while different transcriptomic profiles have been reported among cells resistant to different CdK4/6 inhibitors, which could have relevant clinical implications. 77 Therefore transcriptomics represents a powerful tool to understand the phenotypical characteristics of BC and to guide treatment choices. Intrinsic subtypes are now being used as inclusion criteria in several prospective trials (e.g.…”