Inavolisib regimen extends PFS in PIK3CA-mutated advanced breast cancer
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Key takeaways:
- Adding inavolisib to palbociclib and fulvestrant improved outcomes for patients with PIK3CA-mutated advanced breast cancer.
- Patients who received inavolisib had more grade 3 or higher adverse events.
The addition of inavolisib to palbociclib and fulvestrant more than doubled PFS for certain patients with advanced breast cancer, according to results of a randomized phase 3 trial.
The regimen also improved OS and response for adults with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative disease. However, it also was associated with more grade 3 or higher adverse events.
“Inavolisib plus palbociclib-fulvestrant may represent a new treatment option for these patients,” Nicholas Turner, MD, PhD, FRCP, professor and director of clinical research and development at The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, and colleagues wrote.
Background and methods
Approximately 35% to 40% of individuals with breast cancer have PIK3CA mutations, according to study background.
Prior studies showed PIK3CA mutations are associated with poor prognosis among patients with advanced breast cancer, but the mutations can be targeted with phosphatidylinositol 3-kinase (PI3K) inhibitors.
“Previous PI3K inhibitors have had toxic effects and an unacceptable side-effect profile when combined with standard-of-care agents,” researchers wrote.
Inavolisib (Itovebi, Genentech) inhibits part of the PI3K complex.
In the international INAVO120 trial, Turner and colleagues compared the addition of inavolisib or placebo to palbociclib (Ibrance, Pfizer) and fulvestrant.
Researchers enrolled 325 patients (median age, 54 years; range, 27-79; 98.2% women; 58.8% white; 38.2% Asian) with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of adjuvant endocrine therapy.
Trial participants had not received prior systemic therapy for locally advanced or metastatic disease.
Researchers randomly assigned patients 1:1 to 9 mg oral inavolisib or placebo once daily, plus 125 mg oral palbociclib for 21 straight days followed by 7 days off. Patients also received 500 mg fulvestrant administered intramuscularly on days 1 and 15 of the first 28-day cycle, followed by day 1 of every subsequent cycle.
Treatment continued until disease progression or unacceptable toxicity.
PFS served as the primary endpoint. OS, objective response rate, response duration, clinical benefit and safety served as secondary endpoints.
Results and next steps
Results showed significantly longer PFS (median, 15 months vs. 7.3 months; stratified HR = 0.43; 95% CI, 0.32-0.59). and OS (stratified HR = 0.64; 95% CI, 0.43-0.97) with inavolisib vs. placebo.
ORR (58.4% vs. 25%) and median duration of response (18.4 months vs. 9.6 months; HR = 0.57; 95% CI, 0.33-0.99) also favored inavolisib.
A higher percentage of patients assigned inavolisib experienced grade 3 or grade 4 adverse events (88.3% vs. 82.1%), including neutropenia (80.2% vs. 78.4%), stomatitis or mucosal inflammation (5.6% vs. 0%), hyperglycemia (5.6% vs. 0%) and diarrhea (3.7% vs. 0%).
More grade 5 adverse events occurred in the inavolisib group (3.7% vs. 1.2%).
A higher percentage of patients assigned inavolisib discontinued any drug in their regimen (6.8% vs. 0.6%), and 6.2% of patients assigned the experimental regimen discontinued inavolisib.
Researchers acknowledged study limitations, including use of only palbociclib as opposed to other approved CDK4/CDK6 inhibitors, and lack of patients who received adjuvant therapy with CDK4/6 inhibitors.
The FDA approved the inavolisib regimen based on results of the INAVO120 trial.
“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,” William J. Gradishar, MD, professor at Feinberg School of Medicine at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, wrote in an accompanying editorial. “Another indisputable concern is the front-loading of the cost of such a regimen in terms of both drug prices and the mitigation of toxic effects. If a clear survival signal emerges, this strategy will be even more compelling in this population of patients.”
References:
- Gradishar WJ. N Engl J Med. 2024;doi:10.1056/NEJMe2411229.
- Turner NC, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404625.
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