Dr Tolaney on the Development of Mutation-Selective PI3K Inhibitors in Breast Cancer

Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, associate director, Susan F. Smith Center for Women’s Cancers, senior physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses the ongoing development of mutation-selective PI3K inhibitors for patients with PI3K-mutant metastatic breast cancer.

These agents have the potential to target PI3K mutations with high specificity and spare wild-type PI3K, thus minimizing toxicities associated with PI3K inhibitors, Tolaney begins. Traditional PI3K inhibitors, such as alpelisib (Piqray), have demonstrated efficacy in breast cancer but are often accompanied by significant adverse effects, such as hyperglycemia and rash, which poses a challenge for patients, Tolaney explains.

Agents such as RLY-2608 and STX-478 show promise due to their mutation-selective nature, Tolaney states. Early phase 1 data indicate that these inhibitors may offer robust efficacy with a markedly reduced toxicity profile, she reports. Although the data are still immature and based on small patient cohorts, the initial findings are encouraging, according to Tolaney. RLY-2608, in particular, has demonstrated significant efficacy with minimal toxicity in patients with advanced solid tumors, which is an indication that it might become a well-tolerated standard treatment option in the future, Tolaney notes.

The introduction of these mutation-selective inhibitors also paves the way for novel combination strategies, Tolaney continues. Historically, combining PI3K inhibitors with other therapeutic agents has been challenging due to overlapping toxicities, she says. However, the improved safety profiles of these new inhibitors could allow for more innovative and effective treatment regimens, Tolaney emphasizes. For example, inavolisib (GDC-0077) has been successfully combined with palbociclib (Ibrance) and fulvestrant (Faslodex) in patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer with well-controlled blood sugar levels, indicating the potential for broader applications, Tolaney says.

RLY-2608 is currently under investigation in combination with fulvestrant and in triplet combinations that include CDK4/6 inhibitors in patients with advanced breast cancer, Tolaney details, adding that these studies are assessing the efficacy and safety of these combinations in larger, more diverse patient populations. If the toxicity profiles of these combinations remain favorable, these novel agents could significantly enhance the treatment paradigm for patients with PI3K-mutant cancers, Tolaney says. Ongoing research and forthcoming data will be crucial in determining the role of these PI3K inhibitors in clinical practice and in devising optimal combination strategies for various patient populations, Tolaney concludes.