A phase III, double-blind, randomised INAVO120 study met the primary endpoint, showing that the addition of inavolisib to palbociclib–fulvestrant resulted in substantially longer progression-free survival (PFS) than placebo plus palbociclib–fulvestrant in patients with PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease had recurred during or within 12 months after the completion of adjuvant endocrine therapy.
A low percentage of patients discontinued treatment because of adverse events, although the incidence of some side-effects was higher in the inavolisib group. The findings are published by Dr. Nicholas C. Turner of the Royal Marsden Hospital and Institute of Cancer Research in London, UK and colleagues on 30 October 2024 in The New England Journal of Medicine.
Activating mutations in PIK3CA occur in approximately 35-40% of HR-positive breast cancers. The presence of such mutations is a poor prognostic factor in patients with advanced breast cancer and is a predictive biomarker of response to PI3K inhibitors. The three key oncogenic pathways (oestrogen receptor, CDK4/6, and PI3K) that drive HR-positive locally advanced or metastatic breast cancer are highly interconnected, with complex feedback mechanisms that may drive adaptation and resistance to treatment. Previous use of their simultaneous blockade has been unsuccessful, largely because of treatment-related side-effects.
The enhanced selective inhibition of p110α and degradation of mutated p110α with inavolisib may lead to a wider therapeutic window. A first-in-human phase showed that inavolisib can be combined with palbociclib plus fulvestrant at the maximum single-agent dose of each drug with no drug–drug interactions, an acceptable side-effect profile, and promising preliminary antitumour activity in PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer.
In INAVO120, the study team compared first-line inavolisib at an oral dose of 9 mg once daily plus palbociclib–fulvestrant (inavolisib group) with placebo plus palbociclib–fulvestrant (placebo group) in patients with PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy.
Beyond disease recurrence or progression during or within 12 months after the completion of adjuvant endocrine therapy in all included patients, the study was also enriched for patients with other clinicopathologic characteristics associated with a poor prognosis, like metastases in at least three organs in approximately 50% of the patients, and liver metastases in approximately 50%. PIK3CA mutation status in more than 90% of the patients was determined with the use of ctDNA-based testing. The primary endpoint was PFS as assessed by the investigator.
A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median PFS was 15.0 months (95% confidence interval [CI] 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death 0.43; 95% CI 0.32 to 0.59; p < 0.001).
The benefit of inavolisib was generally observed across all key prespecified clinical subgroups and sensitivity analyses and was supported by the analysis of secondary endpoints, with meaningful improvements in the percentage of patients with a response and the response duration. An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. Overall survival analysis showed a numerical trend in favour of the inavolisib regimen at the interim analysis; follow-up is ongoing.
Inavolisib plus palbociclib–fulvestrant had a safety profile consistent with the safety profiles of the individual drugs in the regimen. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group, grade 3 or 4 hyperglycaemia 5.6% and 0%, grade 3 or 4 stomatitis or mucosal inflammation 5.6% and 0%, and grade 3 or 4 diarrhoea 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any study agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.
Hyperglycemia is a class effect of PI3K inhibitors. The protocol allowed prophylactic use of metformin in patients with a high risk of hyperglycaemia and recommended early use of dexamethasone mouthwash as treatment or prophylaxis for stomatitis.
The authors concluded that their study showed that inavolisib can be combined with a CDK4/6 inhibitor and endocrine therapy at the full dose of each drug with an acceptable safety level and side-effect profile.
In an accompanied editorial, Dr. William J. Gradishar of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University in Chicago, IL, US wrote that the response to subsequent treatment with endocrine therapy, targeted therapy, or both will need to be evaluated to determine whether a phenotype with greater resistance to endocrine therapy emerges. Another indisputable concern is the front-loading of the cost of such a regimen in terms of both drug prices and the mitigation of side-effects. If a clear survival signal emerges, this strategy will be even more compelling in this population of patients.
This work was supported by F. Hoffmann–La Roche and a grant from the Memorial Sloan Kettering Cancer Center.
References
- Turner NC, Im S-A, Saura C, et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med 2024;391:1584-1596.
- Gradishar WJ. Improving the Outcome of Bad-Acting Hormone Receptor–Positive Breast Cancer. N Engl J Med 2024;391:1644-1647.