Dr Jhaveri on the Implications of Treatment With RLY-2608 in Advanced ER+ Breast Cancer

Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Patricia and James Cayne Chair for Junior Faculty, Memorial Sloan Kettering Cancer Center, discusses the implications of investigating treatment with the PI3Kα inhibitor RLY-2608 in a first-in-human phase 1 trial (NCT05216432) for patients with PIK3CA-mutant advanced estrogen receptor (ER)–positive breast cancer.

Investigators shared background on this open-label study at the 2024 ASCO Annual Meeting. Although single-agent PI3K inhibitors have shown activity in breast cancer, the durability of their benefit in ER-positive breast cancer is significantly enhanced when combined with endocrine therapy, Jhaveri begins. This is due to the crosstalk between the PI3K/AKT/mTOR pathway and the ER pathway. Inhibiting only the PI3K pathway can lead to upregulation of the ER pathway, she explains. However, inhibiting both pathways can potentially improve the efficacy of these agents and provide greater benefit, Jhaveri explains.

In ER-positive breast cancer, the treatment strategy for any new class of drugs typically involves using an endocrine therapy backbone in combination with a PI3K inhibitor, she continues. Therefore, in the phase 1 trial, RLY-2608 is being combined with endocrine therapy, Jhaveri states. Preliminary phase 1 clinical trial data, presented at the 2023 AACR Annual Meeting, showed early signals of clinical efficacy with this combination. One patient, who was heavily pretreated and had received antibody-drug conjugates such as fam-trastuzumab deruxtecan-nxki (Enhertu), achieved a partial response to RLY-2608 at a 400-mg twice-daily dose, she elucidates. However, because this analysis was conducted too early to assess efficacy, the phase 1 study primarily focuses on safety and tolerability, according to Jhaveri.

The safety and tolerability results that have been presented so far are encouraging, with no grade 3 hyperglycemia, diarrhea, or rashes reported, Jhaveri emphasizes. Instead, the observed adverse effects included manageable low-grade hypoglycemia and diarrhea, Jhaveri says. These early findings indicate that the combination is safe and well tolerated, Jhaveri notes. As investigators await additional results and more follow-up data with combination therapies involving an endocrine backbone and other drugs, a larger dataset will assist in building a better understanding of the efficacy of such treatments, Jhaveri concludes.