Addition of PI3K inhibition could improve outcomes in patients with PIK3CA-mutated metastatic breast cancer

Recently published in The New England Journal of Medicine¹ results of a phase 3, double-blind, randomized trial show that the addition of inavolisib to the combination of palbociclib and fulvestrant led to significantly longer progression-free survival (PFS) over placebo plus palbociclib-fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive (ER
+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

Inavolisib is an oral, potent and highly selective kinase inhibitor that targets PIK3CA, a gene that is frequently mutated in breast cancer, and also promotes the degradation of mutated PI3Kα.  “This dual mechanism of action may achieve longer-lasting disease stabilization and improved tolerability, as well as potentially lead to better treatment outcomes in patients with PIK3CA-mutated HR+ HER2- advanced breast cancer when used in combination with palbociclib and fulvestrant,” said Cristina Saura, Head of the Vall d’Hebron University Hospital’s Breast Cancer Unit and VHIO’s Breast Cancer Group, and a co-author of this study.

PIK3CA: a commonly mutated gene in ER+ breast cancers

Female breast cancer is the second leading cause of global cancer incidence in 2022, with an estimated 2.3 million new cases, comprising 11.6% of all cancer cases². ER+/HER2- breast cancer is the most common breast cancer type, accounting for approximately 70% of all breast cancer cases. Alterations in the PIK3CA gene occur in between 35 and 40% of ER
+ tumors and associate with a poor prognosis in patients with metastatic disease.

“CDK4/6 inhibitors in combination with endocrine therapy is the standard first-line treatment for patients with advanced or metastatic ER+ HER2- breast cancer. However, the management of patients who present with disease recurrence while receiving adjuvant endocrine therapy or within 12 months after treatment remains an unmet clinical need,” observed Cristina Saura.

Led by corresponding author Nicholas C. Turner at the Royal Marsden Hospital and Institute of Cancer Research, London (UK), this present study was designed to assess if the addition of inavolisib to standard-of-care palbociclib-fulvestrant improves clinical outcomes over placebo plus palbociclib-fulvestrant.

This phase 3 trial included a total 325 patients with PIK3CA-mutated ER+ HER2- advanced or metastatic breast cancer who had progressed on adjuvant endocrine therapy. Median PFS was 15.0 months in the inavolisib group versus 7.3 months in the placebo group. An objective response occurred in 58.4% and 25.0 % of patients, respectively.

A tolerable and manageable safety profile was observed in both groups, with a similar incidence of grade 3 or 4 neutropenia. Additional adverse effects were reported in the inavolisib group including hyperglycemia, stomatitis and diarrhea—requiring specific management.

“The addition of PI3K inhibition doubled progression-free survival. While inavolisib has not yet been approved in Europe, results of this study highlight the importance of optimizing targeted treatment strategies to improve clinical outcomes in this patient population,” concluded Saura.

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References

1. Turner NC, Im SA, Saura C, Juric D, Loibl S, Kalinsky K, Schmid P, Loi S, Sunpaweravong P, Musolino A, Li H, Zhang Q, Nowecki Z, Leung R, Thanopoulou E, Shankar N, Lei G, Stout TJ, Hutchinson KE, Schutzman JL, Song C, Jhaveri KL. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med. 2024 Oct 31;391(17):1584-1596.
2. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263.