Addition of inavolisib to palbociclib and fulvestrant reduces risk of progression

Combining inavolisib, a selective PI3Kα inhibitor, with palbociclib and fulvestrant improves progression-free survival (PFS) over palbociclib/fulvestrant in patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer recurring on or within 12 months of endocrine therapy, according to results from the INAVO120 study.

There is an unmet need for more effective treatments that overcome resistance in patients with PIK3CA-mutated HR-positive/HER2-negative breast cancer [1]. Inavolisib is an oral, potent, and selective PI3Kα inhibitor that promotes the degradation of mutant p110α, which may improve the therapeutic window. In a phase 1 study (NCT03006172) the triplet inavolisib/palbociclib/fulvestrant had a manageable safety profile and demonstrated promising antitumour activity in PIK3CA-mutated HR-positive/HER2-negative breast cancer [2].

The phase 3 INAVO120 study (NCT04191499) aimed to assess the efficacy of the addition of inavolisib versus placebo to palbociclib /fulvestrant in patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer who recurred on or within 12 months of endocrine therapy and who had no prior therapy for advanced/metastatic breast cancer. INAVO120 enrolled 325 patients, who were 1:1 randomised to inavolisib/palbociclib/fulvestrant or placebo/palbociclib/fulvestrant until progression of disease or toxicity. The primary endpoint was PFS. Prof. Komal Jhaveri (Memorial Sloan Kettering Cancer Center, NY, USA) presented the primary analysis results [3].

At a median follow-up of 21 months, the addition of inavolisib to palbociclib/fulvestrant significantly improved PFS over placebo: 15.0 versus 7.3 months (HR 0.43; 95% CI 0.32–0.59; P<0.0001). At 18 months, 46.2% of the participants in the inavolisib arm were progression-free, versus 21.1% in the placebo arm. A PFS benefit of inavolisib was seen in all prespecified subgroups. In addition, a benefit of inavolisib was observed in objective response rate (58.4% vs 25.0%) as well as in median duration of response (18.4 vs 9.6 months). A clear trend in overall survival benefit of inavolisib was observed (HR 0.64; 95% CI 0.43–0.97; P=0.0338).

The addition of inavolisib to palbociclib/fulvestrant did increase adverse event rates, in particular for hyperglycaemia (58.6% vs 8.6.%) and diarrhoea (48.1% vs 16.0%).

Based on these results, Prof. Jhaveri concluded that “inavolisib in combination with palbociclib and fulvestrant may represent a new standard-of-care for patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer.”

1. Cardoso F, et al. Ann Oncol. 2020;31:1623-1649.
2. Herrera-Abreu MT, et al. Cancer Res. 2016;76:2301-2313.
3. Jhaveri KL, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis. Abstract GS03-13, SABCS 2023, 5–9 December, San Antonio, TX, USA.

 

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Posted on 11 January 202411 January 2024