Newswise — Breast cancer that has spread to other parts of the body (metastatic) is particularly hard to treat. New research from Yale Cancer Center reveals first-of-its-kind data from a phase I study in patients with hormone receptor positive HER2-negative metastatic breast cancer. The results, which assess the safety and efficacy of a treatment known as PF-07248144, offer new hope for treating this aggressive type of breast cancer.

Yale researchers found that PF-07248144, both as a standalone therapy and in combination with the hormone therapyfulvestrant (an estrogen receptor antagonist agent), was well-tolerated and effective at treating patients with hormone receptor-positive, HER2-negative metastatic breast cancer. PF-07248144 targets and blocks the proteins KAT6A and KAT6B, which can help cancer grow and spread when they are not working properly, or are dysregulated.

Senior author of the study, Patricia LoRusso, DO, Associate Director for Experimental Therapeutics at Yale Cancer Center, presented the findings at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 1. The results of the study were published on the same day in Nature Medicine.

“We're now realizing how important epigenetics (field of study focused on modification of gene expression rather than the alteration of the underlying DNA) is in terms of understanding the biology of cancer and targeting the disease for treatment interventions,” said LoRusso.

For nearly three years, 107 patients were enrolled in the phase I trial and received at least one dose of PF-07248144. 29 patients received PF-07248144 at 5 dose levels, 35 patients received PF-07248144 at 5 mg daily, and 43 patients received PF-07248144 at 5 mg daily in combination with 500 mg fulvestrant. According to LoRusso, “the goal of the study was to overcome the patient’s ESR1 mutation and enhance, or resume response in combination with hormonal therapy (fulvestrant).”

In a review of the data, the combination of PF-07248144 with fulvestrant showed an objective response rate (ORR) of 30.2% and a median duration of response (DOR) of nine months. For patients who were treated with only PF-07248144, the ORR was lower at 11%, however the median DOR was slightly better at 12 months. Most side effects related to the treatment were manageable. The most common were taste alteration, a decrease in white blood cell count, and anemia.

The phase I trial is still ongoing, however the preliminary findings are encouraging and support further research of PF-07248144 in larger trials.

“Although this was not a randomized trial, the degree and duration of response of the combination of PF-07248144 with fulvestrant appear at least preliminarily in this trial to be better than historical data with fulvestrant alone,” said LoRusso.

Toru Mokuhara from National Cancer Hospital East in Kashiwa, Japan, was the study’s first author. Other authors include Yeon Hee Park, David Sommerhalder, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Jee Hyun Kim, Hiroji Iwata, Toshinari Yamashita, Rachel M. Layman, Timothy Clay, Yee Soo Chae, Catherine Oakman, Fengting Yan,Gun Min Kim,Seock-Ah Im, Geoffrey J. Lindeman, Hope S. Rugo, Marlon Liyanage, Michelle Saul, Christophe Le Corre, Athanasia Skoura, Li Liu, and Meng Li.

Journal Link: Nature Medicine, Jun-2024

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Nature Medicine, Jun-2024