Roche's Inavolisib Granted Priority Review in China for PIK3CA-Mutated, HR-Positive/HER2-Negative Breast Cancer

On April 16, the National Medical Products Administration (NMPA) officially granted Roche's PI3K inhibitor GDC-0077 (generic name: Inavolisib) priority review status for use in combination with palbociclib and endocrine therapy to treat adult patients with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer. Inavolisib is expected to become the first approved PI3K inhibitor in China’s breast cancer field, filling the treatment gap for PIK3CA-mutated HR+/HER2- advanced breast cancer and ushering in a new era of precision treatment for HR+ breast cancer.

Inavolisib is expected to benefit breast cancer patients in China
Providing clinical benefits, and being safe and controllable

The National Medical Products Administration (NMPA) has granted Inavolisib priority review status for the treatment of PIK3CA-mutated HR+/HER2- locally advanced or metastatic breast cancer, primarily based on the positive results from the pivotal Phase III INAVO120 study [1].

INAVO120 Study [1] (NCT04191499) is a global, multicenter, double-blind, randomized controlled Phase III clinical trial designed to evaluate the efficacy and safety of Inavolisib + Palbociclib + Fulvestrant compared with Palbociclib + Fulvestrant in patients with PIK3CA-mutated HR+/HER2- locally advanced or metastatic breast cancer. The results showed that, compared with the control group receiving Palbociclib + Fulvestrant, the triple combination regimen of Inavolisib + Palbociclib + Fulvestrant achieved a clinically significant improvement in PFS (15.0 months vs 7.3 months), reducing the risk of disease progression or death by 57% (HR=0.43, 95% CI 0.32-0.59; P<0.0001). Furthermore, consistent benefits were observed across key subgroups, including patients from different regions, pre/post-menopausal status, presence or absence of liver metastases, primary endocrine resistance, or secondary endocrine resistance.

Data for other secondary endpoints also showed significant improvements in the objective response rate (ORR), duration of response (DOR), and disease control rate (DCR) in the combination therapy group. Although overall survival (OS) data are not yet mature, a trend toward benefit has been observed. Additionally, the safety of the Inavolisib combination therapy was manageable, with a low discontinuation rate and no new safety signals observed.

The results of the INAVO120 study [1] provide solid evidence-based medical support for Inavolisib in combination with Palbociclib and Fulvestrant as a first-line treatment option for patients with PIK3CA-mutated HR+/HER2- locally advanced or metastatic breast cancer.

Inavolisib Granted Priority Review,
Leading a New Era of Precision Diagnosis and Treatment for HR+ Breast Cancer in China

Approximately 40% of patients with HR+/HER2- advanced breast cancer in clinical settings have PIK3CA mutations [2]. Compared to patients with PIK3CA wild-type, those with PIK3CA mutations have a poorer prognosis, limited efficacy with traditional treatments, and are resistant to endocrine therapy and chemotherapy [2,3].

Inavolisib is a new generation of PI3Kα inhibitor. As one of the most promising PI3Kα inhibitors in its class, Inavolisib combines a dual mechanism of action with highly selective inhibition of PI3Kα and specific degradation of mutated PI3Kα proteins, enabling sustained pathway suppression [4-6]. The recent granting of priority review status in China is expected to accelerate the evaluation and approval process for Inavolisib, driving the translation of research outcomes into clinical practice. This breakthrough could transform the treatment landscape for PIK3CA-mutated HR+/HER2- advanced breast cancer, offering these patients a precise, efficient, and safe therapeutic option.

HR+/HER2- Advanced Breast Cancer Accounts for Approximately 70% of Total Breast Cancer Cases [7]. Endocrine therapy is a key treatment modality, but there are still populations with poor prognosis. The PI3K/AKT/mTOR (PAM) signaling pathway is widely activated in breast cancer and is closely related to the occurrence, progression, and poor prognosis of breast cancer [8,9]. PI3K is located upstream of the PAM signaling pathway and plays an important role by converting PIP2 into PIP3 to activate downstream effectors. There are many key molecules in the PI3K pathway, among which PIK3CA is the most frequently mutated gene. Clinically, approximately 40% of patients with HR+/HER2- advanced breast cancer have PIK3CA mutations [2], and these patients tend to have a poor prognosis and exhibit some degree of resistance to both endocrine therapy and chemotherapy, representing a significant unmet clinical need [2,3].

Inavolisib is a highly selective PI3Kα inhibitor, with a 300-fold greater selectivity for PI3Kα compared to other Class I PI3K subtypes. It can specifically degrade p110α mutants, prevent PIP3 accumulation, and reduce downstream AKT signaling, thereby inhibiting cell proliferation while minimizing systemic side effects caused by the inhibition of wild-type signaling [4-6]. Previous GO39374I/Ib phase studies [10-14] have demonstrated that Inavolisib, as monotherapy or in combination, exhibits anti-tumor activity and manageable safety profiles, with good long-term treatment safety. Currently, two Phase III clinical trials of Inavolisib are ongoing:

INAVO121 Study: Evaluating the efficacy and safety of Inavolisib/Alpelisib + Fulvestrant combination therapy in PIK3CA-mutated HR+/HER2- locally advanced/metastatic breast cancer patients.

INAVO122 Study: Evaluating the efficacy and safety of Inavolisib + Pertuzumab Trastuzumab Subcutaneous Formulation (Phesgo) combination therapy versus placebo + Phesgo as first-line maintenance treatment for patients with PIK3CA-mutated HER2+ advanced breast cancer.

References:
[1]Jhaverikletal.SABCS2023.AbstractGS03-13.
[2]NVasan,etal.AnnOncol.2019Dec1;30(Suppl_10):x3-x11.
[3]FMosele,etal.AnnOncol.2020Mar;31(3):377-386.
[4]EdgarKetal.SABCS2019.PosterP3-11-23.
[5]CancerDiscov.2021Sep20;candisc.0072.2021.
[6]SongKW,etal.CancerDiscov.2022Jan;12(1):204-219.
[7]DeSantisCE,etal.CACancerJClin,2016,66(1):31-42.
[8]LiuP,etal.Nat.Med.17,1116–1120(2011).

Editor: Baiji

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