1. The median progression-free survival was 15.0 months in the inavolisib and 7.3 months in the placebo group, with HR 0.43 (significant).

2. Grade 3-4 adverse events were reported in 88.3% of the inavolisib group vs 82.1% in the placebo group

Evidence Rating Level: 1 (Excellent)

Study Rundown: PIK3CA mutations are present in 35-40% of hormone receptor-positive breast cancers. Inavolisib, a selective PI3K inhibitor targeting mutated p110α, has shown potential in combination therapies for PIK3CA-mutated breast cancer. This phase 3 study investigated the effectiveness of inavolisib vs placebo when combined with palbociclib and fulvestrant in this patient group. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), and safety. Median PFS was 15.0 months in the inavolisib and 7.3 months in the placebo group, with HR 0.43 (significant). PFS at 6 months, 12 months, and 18 months was 82.9%, 55.9%, and 46.2% in the inavolisib group and 55.9%, 32.6%, and 21.1%, respectively, in the placebo group. Some data suggested little improvement in adults over the age of 65 who previously received both an aromatase inhibitor and tamoxifen. OS at 6 months, 12 months, and 18 months was 97.3%, 85.9%, and 73.7% in the inavolisib group and 89.9%, 74.9%, and 67.5%, respectively, in the placebo group, with HR 0.64 (non-significant). ORR occurred in 58.4% in the inavolisib group vs 25.0% in the placebo group and the median DoR was 18.4 months and 9.6 months, respectively with HR 0.57. With regards to safety, grade 3-4 adverse events were reported in 88.3% in the inavolisib group vs 82.1% in the placebo group with some differences noted in thrombocytopenia (14.2% vs 4.3%), stomatitis or mucosal inflammation (5.6% vs 0%), hyperglycemia (5.6% vs 0%), and diarrhea (3.7% vs 0%). There was a difference in grade 5 events (3.7% vs 1.2%) however none of the deaths were considered by the investigator to be related to the trial agents. The study’s strengths include the methodology, and the limitations include the small sample size and the limited follow-up period. Overall, this trial demonstrated that in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, the addition of inavolisib compared to placebo to palbociclib and fulvestrant led to some improved outcomes.

Click to read the study in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα

In-Depth [randomized controlled trial]: This international phase 3, double-blind, trial enrolled adults (both premenopausal/postmenopausal) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had disease recurrence/progression after completion of adjuvant endocrine therapy. These patients were randomized (1:1) to inavolisib (n=161) or placebo (n=164), each given with palbociclib and fulvestrant. Median PFS was 15.0 months in the inavolisib and 7.3 months in the placebo group, with HR 0.43 (95%CI, 0.32-0.59, p<0.001). PFS at 6 months, 12 months, and 18 months was 82.9%, 55.9%, and 46.2% in the inavolisib group and 55.9%, 32.6%, and 21.1%, respectively, in the placebo group. Some data suggested little improvement in adults over the age of 65 who had previously received both an aromatase inhibitor and tamoxifen. OS at 6 months, 12 months, and 18 months was 97.3%, 85.9%, and 73.7% in the inavolisib group and 89.9%, 74.9%, and 67.5%, respectively, in the placebo group, with HR 0.64 (95%CI, 0.43-0.97, p=0.03, which did not cross the predefined boundary for the significance of <0.0098). ORR occurred in 58.4% in the inavolisib group vs 25.0% in the placebo group and the median DoR was 18.4 months and 9.6 months, respectively with HR 0.57 (95%CI, 0.33-0.99). With regards to safety, grade 3-4 adverse events were reported in 88.3% in the inavolisib group vs 82.1% in the placebo group with some differences noted in thrombocytopenia (14.2% vs 4.3%), stomatitis or mucosal inflammation (5.6% vs 0%), hyperglycemia (5.6% vs 0%), and diarrhea (3.7% vs 0%). There was a difference in grade 5 events (3.7% vs 1.2%) however none of the deaths were considered by the investigator to be related to the trial agents. Overall, this trial demonstrated that in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, the addition of inavolisib compared to placebo to palbociclib and fulvestrant led to some improved outcomes.

Image: PD

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