Inavolisib: a new treatment strategy for endocrine-resistant PIK3CA-associated luminal HER2-negative breast cancer

Current capabilities of endocrine-targeted therapy for HR+HER2-negative metastatic breast cancer (mBC) enable long-term disease control, while the use of CDK4/6 inhibitors in early lines of treatment significantly increases overall survival. Against this relatively favorable backdrop, a distinct subgroup emerges: patients with PIK3CA-associated tumors who progress during adjuvant endocrine therapy (AET) or within 12 months of its completion (primary or secondary endocrine resistance). Standard endocrine therapy and chemotherapy show limited efficacy in this cohort, leading to rapid progression and early mortality. The clinical introduction of a new class of agents targeting the PI3K/AKT/mTOR signaling pathway has expanded therapeutic options, improving progression-free survival (PFS) and objective response rates (ORR). However, significant improvement in overall survival has not been achieved for a long time. The development of a triple-therapy strategy for hormone-resistant PIK3CA-mut luminal HER2-negative mBC (metastatic breast cancer) represents a true breakthrough. It involves the use of fulvestrant in combination with the CDK4/6 inhibitor (iCDK4/6) palbociclib and the novel PI3K inhibitor (iPI3K) inavolisib as first-line treatment. This publication presents data from the phase III randomised clinical trial INAVO120, which demonstrated the efficacy and safety of the triple combination “inavolisib + palbociclib + fulvestrant” compared with the standard approach “palbociclib + fulvestrant” in patients with PIK3CA-associated HR+HER2-negative metastatic breast cancer who experienced disease progression during adjuvant endocrine therapy (AET) or within 1 year after its completion. The addition of inavolisib, compared with the control group, statistically significantly and clinically meaningfully improved all assessed efficacy endpoints, including: progression-free survival (PFS) (median PFS of 17.2 months vs. 7.3 months (hazard ratio [HR] 0.42; 95 % confidence interval [CI] 0.32–0.55); objective response rate (ORR): 62.7 % vs. 28.0 % (p<0.001); overall survival (median OS of 34 months vs. 27 months (HR 0.67; 95 % CI 0.48–0.94; p=0.02)). Inavolisib is the first PI3K inhibitor that has significantly increased the life expectancy of patients with an aggressive type of HR+HER2-negative metastatic breast cancer. The triplet regimen “inavolisib + palbociclib + fulvestrant” represents a new standard of first-line therapy for PIK3CA-mut HR+HER2-negative mBC with early progression after radical treatment.

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