Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study

Abstract

Cyclin dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the rst (1L) or second line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single institution analysis to identify treatments and outcomes after progression on a CDK4/6i. MethodsWe identi ed patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014-February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. ResultsPalbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6-34.9) vs 19.8 months (95% CI 15.7-29.6)].The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months -NE), single-agent ET was 6.0 months (95% CI 3.3-14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months-NE). ConclusionsFollowing progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Systematic literature review of real-world evidence for treatments in HR+/HER2- second-line LABC/mBC after first-line treatment with CDK4/6i

“…3 ). The weighted average median rwPFS for single-agent ET was 3.9 months ( n = 92 total patients) and was derived using data from two studies reporting median rwPFS values of 3.3 months ( n = 70) [ 38 ] and 6.0 months ( n = 22) [ 40 ]. For one study ( n = 7) that reported outcomes for single agent ET, median rwPFS was not reached during the follow-up period; as such, this study was excluded from the weighted average median rwPFS calculation [ 49 ].…”

“…Safety and tolerability data were reported in two studies [ 40 , 45 ]. One study investigating 2 L administration of the chemotherapy agent eribulin mesylate reported 27 patients (22.3%) with neutropenia, 3 patients (2.5%) with febrile neutropenia, 10 patients (8.3%) with peripheral neuropathy, and 14 patients (11.6%) with diarrhea [ 45 ].…”

“…A total of 55 patients (45.5%) discontinued eribulin mesylate treatment; 1 patient (0.83%) discontinued treatment due to adverse events [ 45 ]. Another study reported that 5 out of the 22 patients receiving the mTORi everolimus combined with ET in 2 L (22.7%) discontinued treatment due to toxicity [ 40 ]. PROs were not reported in any of the studies included in the SLR.…”

Giredestrant for Estrogen Receptor–Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study

“…The relevance of endocrine monotherapy as a comparator for second-/third-line treatment in ER1, HER2-aBC, while commonly used, might be argued in some regions where combination therapy is preferred, such as the United States (especially with fit patients). 6,32 Inherent to the open-label design, which was motivated by ethical concerns regarding intramuscular placebo administration, is the risk of investigator bias. For efficacy, there was a notable discordance between INV and BIRC assessments, and for safety, a trend toward underreporting of AEs in the PCET arm emerged in comparison with the expected rates from previous experience, likely related to the wellknown safety profile of comparator ETs.…”

“…The relevance of endocrine monotherapy as a comparator for second-/third-line treatment in ER+, HER2– aBC, while commonly used, might be argued in some regions where combination therapy is preferred, such as the United States (especially with fit patients). 6 , 32 …”