Several studies presented at the 2024 ESMO Breast Cancer (ESMO BC) conference demonstrated the potential efficacy of new CDK4 selective inhibitors and the lasting benefits of pan-AKT inhibitors.The latest results from the first human study of a new CDK4 selective inhibitor were presented at the 2024 ESMO BC conference (May 15-17, Berlin). This study showed promising efficacy and safety in heavily pretreated hormone receptor-positive (HR+)/HER2- metastatic breast cancer (mBC) patients. Among 25 patients who progressed on prior CDK4/6 inhibitor therapy combined with endocrine therapy (ET) and had measurable disease, the first-in-class next-generation CDK4 selective inhibitor PF-07220060 combined with ET (letrozole or fulvestrant) resulted in 1 complete response (CR) and 7 partial responses (PR) (Abstract 184MO). The clinical benefit response rate for the total population was 64.0%, with a median progression-free survival (PFS) of 8.1 months. Responses were independent of ESR1 or PI3K pathway mutations.

“Considering that all patients in the study had previously received CDK4/6 inhibitor therapy and about two-thirds had also received fulvestrant, the objective response rate and PFS shown by PF-07220060+ET are very promising for these patients,” said Dr. Philippe Aftimos from the Jules Bordet Institute, Université Libre de Bruxelles, Belgium.

Among 33 patients, the most common treatment-related adverse events (TEAEs) were neutropenia (grade 3, 18.2%), diarrhea (grade 3, 0%), and nausea (grade 3, 3.0%). TEAEs led to treatment discontinuation in 1 patient (3.0%) and dose reduction in 5 patients (15.2%). Hematological TEAEs were manageable with dose interruption or reduction. Dr. Aftimos commented, “Hypothetically, selective CDK4 inhibition may reduce hematologic toxicity compared to CDK4/6 inhibitors, and PF-07220060 appears to demonstrate this.” A phase 3 study of PF-07220060+ET is ongoing (NCT06105632).

In another presentation, updated results from the phase 3 CAPItello-291 study showed that the potent selective pan-AKT inhibitor capivasertib combined with fulvestrant provided benefits over placebo in HR+/HER2- breast cancer patients resistant to aromatase inhibitors (AIs), with benefits persisting through the second progression-free survival (PFS2) period. This was observed in both the overall population (hazard ratio [HR] 0.70) and the population with PIK3CA/AKT1/PTEN alterations (HR 0.52) (Abstract 183MO). The combination of capivasertib and fulvestrant delayed the time from randomization to the start of subsequent chemotherapy by 4.2 months and 5.0 months in the overall population and PIK3CA/AKT1/PTEN altered population, respectively, with associated hazard ratios of 0.63 and 0.56.

“Based on the CAPItello-291 study, capivasertib combined with fulvestrant was recently approved for the treatment of locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations,” Aftimos said. “These updated results suggest that delaying the start of subsequent chemotherapy with capivasertib is highly relevant for patients due to the associated adverse events of chemotherapy.”

While CDK4/6 inhibitors have become the standard adjuvant therapy for high-risk breast cancer patients, Aftimos cautioned that alternative treatments are needed for HR+/HER2- breast cancer patients who relapse during or after these therapies. New targeted drugs, such as CDK2 and KAT6 inhibitors, combined with ET are also under development. Additionally, using antibody-drug conjugates earlier in the treatment sequence (after failure of ET+CDK4/6 inhibitors or at least two lines of ET but before chemotherapy) may be promising. We look forward to the results of studies like DESTINY-Breast06 (NCT04494425), which explores the efficacy of T-DXd in this setting.