By | 22 December 2023 | 0 Comments

A Paradigm Shift in Targeted Therapy for HR+/HER2- Advanced Breast Cancer

In recent years, inhibitors against PI3K targets have been successfully developed, with a total of five PI3K inhibitors currently approved worldwide. However, the development of PI3K inhibitors has suffered many setbacks due to toxicity issues that have not been effectively addressed, and several drugs have been withdrawn from the market or withdrawn from indications due to a variety of serious adverse effects. The results of the INAVO20 study presented at the 2023 SABCS Congress showed that Inavolisib, a novel PI3K inhibitor, successfully overcame the challenge of the PIK3CA mutation and resulted in a significant prolongation of progression-free survival (PFS) in patients with HR+/HER2- breast cancer, a pivotal result that is one of the transformative medical advances in breast cancer and will hopefully become the first-line standard of care. Let's take a closer look at the mechanism of action of Inavolisib and explore the reasons behind its development success.

A history of twists and turns in the development of inhibitors targeting the PAM pathway

PI3K/ AKT/mTOR (PAM) signaling pathway plays an important role in breast cancer development, and in recent years, a variety of inhibitors targeting the PAM signaling pathway are in full swing. Currently, PAM signaling pathway inhibitors are mainly classified into three categories, namely, PI3K inhibitors, AKT inhibitors and mTOR inhibitors.PI3K inhibitors can be broadly classified into three major categories, namely, pan-PI3K inhibitors (pan-PI3K), subtype-specific PI3K inhibitors, and dual inhibitors targeting PI3K/mTOR, according to their mechanism of action. Among them, pan-PI3K inhibitors are often discontinued due to strong toxic side effects, and subtype-specific PI3K inhibitors have become the mainstream direction nowadays. It is reported that the only PI3K inhibitor that has been marketed globally for breast cancer is Alpelisib, a PI3Kα inhibitor; in addition to PI3K inhibitors, PAM signaling pathway inhibitors that have been marketed include AKT inhibitors such as Capivasertib and mTOR inhibitors such as everolimus. Among them, Alpelisib is the first inhibitor targeting PI3Kα isoforms, which inhibits PI3Kα activity and induces an increase in estrogen receptor transcription in breast cancer cells, and has synergistic antitumor activity in combination with fulvestrant.In 2019, Alpelisib was approved for use in the United States for the combination treatment of men or postmenopausal women who have disease progression during endocrine therapy or after treatment, and who carry PAM. indication for HR+/HER2-advanced or metastatic breast cancer harboring a PI3KCA mutation whose disease has progressed after treatment.

A Paradigm Shift in Targeted Therapy for HR+/HER2- Advanced Breast Cancer

Unique Mechanism, Highly Selective PI3Kα Inhibitor Inavolisib Offers New Options for HR+ Breast Cancer

Role of PAM pathway in tumor growth and proliferation
Mutation, amplification or inactivation of many sites in the PAM pathway can participate in the regulation of tumor cell growth, proliferation and survival, which is closely related to the occurrence, progression and metastasis of a variety of malignant tumors such as breast cancer [2]. Moreover, over-activation of the PAM signaling pathway is one of the important mechanisms of breast cancer treatment resistance.PI3K is located in the upstream of the PAM signaling pathway, and plays an important role in the pathway by activating downstream effectors through the conversion of PIP2 to PIP3.PIK3CA gene encodes PI3K, and PI3K signaling pathway abnormality caused by mutations in the PIK3CA gene can cause uncontrolled cell proliferation and tumorigenesis, which is a key factor in the development of malignant tumors. proliferation and tumorigenesis, and PIK3CA mutation is a poor prognostic biomarker for HR+/HER2- breast cancer [3,4].

PI3K/AKT pathway activation promotes non-dependent and anti-estrogen resistance
Experimental and clinical evidence suggests that upregulation of the PI3K/AKT pathway promotes estrogen (ER)-dependent and non-dependent transcription, contributes to endocrine resistance, and leads to tumor cell survival and proliferation [5-7]. Whereas breast cancer cells are heavily dependent on PI3K signaling when adapting to hormone deficiency [8], activation of the PI3K pathway leads to estrogen-independent activation of ER, ER phosphorylation, and subsequent upregulation of ER-regulated genes [8,9]. And ER upregulation is closely related to primary or acquired resistance in HR+ breast cancer treated with CDK4/6 inhibitors.

Dual mechanism of action of Inavolisib
It is encouraging to see the emergence of Inavolisib, a new-generation PI3K inhibitor that combines highly selective inhibition of PI3Κα with specific degradation of PI3Κα mutant proteins. With this unique dual mechanism of action, Inavolisib will provide PIK3CA-mutated patients with HR+/HER2-advanced breast cancer with better tolerability, more durable disease control, and may better improve the prognosis of patients with advanced breast cancer. improve prognosis and become a more favorable option for patients with advanced breast cancer.
Specifically, Inavolisib selectively binds to the p110α catalytic subunit, thereby blocking kinase activity. In addition, its selective inhibition of PI3Kα is 300 times more potent than other class I PI3K isoforms, which can selectively degrade p110α mutants without significantly altering the wild-type p110α protein. p110α reduction prevents the accumulation of PIP3, which attenuates the downstream ATK signaling, thus inhibiting cell proliferation and improving the therapeutic potential of PIK3CA mutant tumors, and avoid systemic side effects due to inhibition of wild-type signaling.
Preclinical data suggest that CDK4/6 inhibitors and selective estrogen receptor downregulators can be used in combination with Inavolisib to inhibit pro-survival mechanisms. In view of this, Inavolisib is expected to provide a more precise, efficient and safe treatment option for patients with PI3Kα-mutant HR+/HER2-advanced breast cancer.

With a promising future ahead, Inavolisib combination strategy will usher in a new era of first-line treatment for HR+ advanced breast cancer

Previous preclinical studies have shown [10] that Inavolisib is more effective in maintaining prolonged pathway inhibition compared to other PI3K inhibitors. For example, the GO39374 study, a phase I/Ib study of Inavolisib alone or in combination with endocrine therapy ± the CDK4/6 inhibitor perphentermine in PIK3CA-mutant HR+/HER2-advanced breast cancer, was divided into Groups A-F, with Inavolisib alone in Group A, Inavolisib + perphentermine in Group B + letrozole, Group C is Inavolisib + letrozole, Group D is Inavolisib + fulvestrant, and Groups E&F are Inavolisib + piperacilli + fulvestrant (Group F: coadministered with metformin).
The San Antonio Breast Cancer Symposium (SABCS) Congress 2021 presented data on Inavolisib in combination with fulvestrant for the treatment of female patients with PIK3CA-mutated, HR+/HER2- metastatic breast cancer (Group D), and the results showed [11] that Inavolisib + fulvestrant had preliminary antitumor activity, including in the case of disease progression after prior treatment with CDK4 /6 inhibitor therapy followed by disease progression. Approximately 26% (14/54 patients) of patients with measurable lesions achieved partial remission (PR; 4 patients in remission had received prior treatment with fulvestrant; 13 had received prior treatment with a CDK4/6 inhibitor). 10 patients (19%) achieved proven PR, with a clinical benefit rate (CBR) of 48% (29/60 patients) and a median PFS of 7.1 months. In addition, the safety profile was manageable, with no treatment-related AEs leading to withdrawal.
The 2022 American Society of Clinical Oncology (ASCO) Congress updated the long-term safety data from the GO39374 study, with 193 of all patients evaluated for safety as of January 1, 2022, and showed[12] that the most common treatment-related AEs of grade ≥3 in all populations were hyperglycemia (22%), neutropenia (23%), and leukocyte and platelet reduction (both 4%). All neutropenia occurred in the perphenazine-containing group.
Notably, the frequency of hyperglycemia, diarrhea, and stomatitis decreased over time, rashes also decreased or had a stable frequency over time, and rashes in patients in the long-term treatment group generally did not require medication. In addition, approximately 52% of patients in all populations experienced ≥1 episode that resulted in an adjustment to the study treatment regimen (drug interruption/dose reduction/discontinuation), 18% had a dose reduction due to an AE, and only 2% discontinued treatment due to an AE (Figure 4). These data demonstrate the encouraging safety and tolerability of Inavolisib, which continues to contribute to patients' quality of life.

2023 SABCS Congress, the randomized, double-blind, placebo-controlled, phase III clinical trial INAVO120 study evaluated the efficacy and safety of Inavolisib + perphentermine + fulvestrant versus placebo + perphentermine + fulvestrant in PIK3CA-mutant HR+/HER2-advanced breast cancer in patients who experienced disease progression during or within 12 months after completing adjuvant endocrine therapy and had not received prior systemic therapy for metastatic disease. disease progression within 12 months afterward and had not received prior systemic therapy for metastatic disease. The results showed[13] that the median PFS in the Inavolisib+pipecil+fluvastatin group versus the control group was 15.0 months versus 7.3 months (HR= 0.43, 95% CI 0.32-0.59; p<0.0001) with a statistically and clinically significant improvement and a 57% reduction in the risk of disease progression or death. Moreover, benefits consistent with the overall population were observed in all subgroups treated with Inavolisib + perphenazine + fulvestrant.

In terms of safety, PI3K inhibitors are mainly characterized by stomatitis and mucositis and hyperglycemia, and previously marketed PI3K inhibitors have a high incidence of adverse events that may be difficult for patients to tolerate. Among them, the main AEs of Alpelisib, a specific inhibitor of the PI3Kɑ isoform, were hyperglycemia and rash, with an incidence of grade ≥3 hyperglycemia of 36.6% and grade ≥3 rash of 9.9%, which led to the discontinuation of Alpelisib due to AEs in approximately 25% of the patients, with a median duration of treatment of 5.5 months [14,15].
In the INAVO120 study, Inavolisib demonstrated a relatively tolerable safety profile and, consistent with previous studies, no new safety signals, significantly addressing clinicians' concerns that the use of PI3K inhibitors would result in more serious adverse effects. Given the landmark breakthrough of the INAVO120 study in the first-line treatment of PIK3CA-mutant HR+/HER2-advanced breast cancer, in the future, the Inavolisib combination regimen is expected to become the first-line standard treatment modality for such patients.
With the widespread use of CDK4/6 inhibitors, there is no standard recommendation for treatment selection after CDK4/6 inhibitor resistance, and almost all HR+/HER2-advanced breast cancer patients' resistance to endocrine combination CDK4/6 inhibitors will be enhanced over time, and the emergence of resistance is associated with mutations in genes such as ESR1 and PIK3CA. In the future, it is expected that the phase III study of Inavolisib + Fulvestrant in CDK4/6 inhibitor-treated population will be completed as soon as possible, which will bring more therapeutic hope and options for HR+ advanced breast cancer. We also look forward to more extensive exploration in breast cancer to benefit more patients.

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