Yet another combination to consider after CDK4/6i + ET in HR+ MBC!
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein, we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.
This double-blind, randomized phase III study enrolled patients with disease progression on previous CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i + ET. Patients were randomly assigned (1:1) to abemaciclib + fulvestrant or placebo + fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review, objective response rate (ORR), and safety.
This study randomly assigned 368 patients (abemaciclib + fulvestrant, n = 182; placebo + fulvestrant, n = 186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57 to 0.95; nominal P = .017), with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib + fulvestrant and placebo + fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55 [95% CI, 0.39 to 0.77]; nominal P < .001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib + fulvestrant versus placebo + fulvestrant (17% v 7%; nominal P = .015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib.
Abemaciclib + fulvestrant significantly improved PFS after disease progression on previous CDK4/6i + ET in patients with HR+, HER2– ABC, offering an additional targeted therapy option for these patients.
Our site participated in this study, where patients were tested for ESR1 mutations via circulating tumor DNA (ctDNA). Those who tested positive were switched to camizestrant (Cami), which demonstrated improved progression-free survival.
Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly utilizes the ubiquitin–proteasome system. It was compared to fulvestrant in patients who had received one prior line of hormonal therapy with a CDK4/6 inhibitor. Among patients with ESR1 mutations, Vepdegestrant demonstrated a median progression-free survival (PFS) of 5.0 months versus 2.1 months with fulvestrant. In the overall population, the median PFS was 3.8 months for Vepdegestrant and 3.6 months for fulvestrant, indicating that the drug showed particular efficacy in tumors harboring ESR1 mutations.
Elinzanitant, a neurokinin-targeted therapy, has been shown to reduce vasomotor symptoms compared to placebo. These symptoms are one of the reasons some of my patients discontinue aromatase inhibitor (AI) therapy, so Elinzanitant presents a promising alternative to help manage these side effects. Additionally, Fezolinetant is already approved and available on the market.
The INAVO120 trial evaluated inavolisib + palbociclib–fulvestrant vs placebo + palbociclib–fulvestrant in patients with PIK3CA-mutated, HR+/HER2– advanced breast cancer progressing on or shortly after adjuvant endocrine therapy (ET). Inavolisib significantly improved overall survival (OS) (34.0 vs 27.0 mo) and progression-free survival (PFS) (17.2 vs 7.3 mo), with a higher objective response rate (ORR) (62.7% vs 28.0%) and longer DoR (19.2 vs 11.1 mo). Toxicities were manageable but included more hyperglycemia (63.4%), stomatitis (55.3%), GI, and ocular AEs. Bottom line: this triplet sets a new bar for first-line PIK3CA-mutant HR+ MBC, but we’ll need to stay vigilant about metabolic and mucosal side effects as we bring it into practice.
Adding Palbociclib did not help, revealing that there is no need to continue with different hormonal therapy than the one used in first line. It also added more toxicity.