In conclusion, afuresertib plus fulvestrant was well-tolerated and had promising antitumor activities against pretreated, advanced HR-positive, HER2-negative breast cancer, supporting further studies with randomized controlled trials. This trial is registered with ClinicalTrials.gov (NCT04851613).

P1/2, N=180, Not yet recruiting, Shandong Suncadia Medicine Co., Ltd.

P1, N=136, Recruiting, Genentech, Inc. | Trial completion date: Jul 2029 --> Apr 2030 | Trial primary completion date: Jul 2029 --> Apr 2030

Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGFβ blocking antibody (NIS793), both individually and in combination with αPD-L1, within this rat model. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients.

SERENA-3 demonstrates that camizestrant 75 mg once daily (Phase III dose) is well-tolerated and achieves maximal reduction in ER through known mechanisms, that is, antagonism and degradation, by 5-7 days, and proliferation suppression determined by Ki67 expression, by 12-15 days. These data support camizestrant 75 mg once daily as the preferred dose for ongoing clinical development and highlight the importance of presurgical WOO studies in guiding dose selection.

P3, N=8000, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

Data were leveraged from preclinical and phase I/II studies in metastatic and early breast cancer, as a single agent and with palbociclib, to inform giredestrant dose selection. Our learnings challenge the MTD paradigm in drug development, particularly in targeted therapies, and demonstrate the importance of basing dose selection on the totality of evidence, including preclinical data, and may help inform the clinical development of future targeted therapies.

P1, N=396, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Jun 2027

Three HR+/HER2- mBC cohorts included 292 patients treated with palbociclib + fulvestrant, 274 patients treated with fulvestrant monotherapy, and 381 patients treated with paclitaxel-based therapy; the mTNBC cohort included 247 chemotherapy-treated patients. The alignment between several real-world and clinical trial endpoints is encouraging and supports the utility of real-world data in contextualizing outcomes, though interpretation may be influenced by data completeness and variability in clinical documentation. These insights are particularly relevant for populations with persistent unmet clinical needs.

Simulations using the combined pharmacokinetic-tumor size-time to event model demonstrated the adequacy of a 150 mg twice daily dose in combination with fulvestrant. There was a negligible impact of dose reductions on efficacy, likely due to the shallow exposure-response relationship. When analyzing survival data where the drug exposure changes significantly within an individual over time, it is important to maximize the use of available longitudinal data through simultaneous modeling of time-course tumor size and survival data.

P1, N=27, Not yet recruiting, Shanghai Best-Link Bioscience, LLC

Real-world safety, tolerability, and effectiveness of abemaciclib in Chinese patients with HR+/HER2- EBC and ABC were consistent with clinical trials, with no new safety signals, supporting its positive real-world benefit-risk profile.