New exploration of treatment mode after CDK4/6i failure in HR+HER2- advanced breast cancer

Targeted CDK4/6 inhibitors have become the standard treatment for HR+/HER2- advanced breast cancer, but there are often patients with CDK4/6i failure in clinical practice, so how should these patients be further treated?

At the "Tianjin International Breast Cancer Conference" meeting in 2022, Professor Liu Jian from the Department of Breast Medicine, Fujian Cancer Hospital, with the title of "New Exploration of Treatment Models after Failure of HR+HER2- Advanced Breast Cancer CDK4/6i", made a presentation on the relevant content.

The 2022 NCCN guidelines recommend the treatment of patients with HR+/HER2- breast cancer

The CSCO-BC guidelines have formulated detailed rules for the stratification of HR+/HER2- advanced breast cancer, which added the stratification of CDK4/6i failure to guide the treatment of such patients

So what is the normative treatment model for HR+HER2- advanced breast cancer after CDK4/6i failure?

1.

A real-world study from the United States included 525 postmenopausal HR+/HER2-mBC patients (208 in 1-line patients and 317 in 2-4 lines) who progressed on CDK4/6 inhibitors between 2012 and 2017 in the MarketScan database.

One study included 200 HR+/HER2- breast cancer patients from 5 hospitals in China (Fudan University Cancer Hospital, Jiangsu Provincial People's Hospital, Zhejiang Cancer Hospital, Hunan Cancer Hospital, Ruijin Hospital Affiliated to Shanghai Jiaotong University).

Goxatuzumab (SG) is the world's first and only approved Trop-2 ADC.

TROPiCS-02 is a Phase 3 study of SG in HR+/HER2- breast cancer with the primary endpoint of blinded independent central review (BICR) assessment of PFS in the intent-to-treat analysis population (RECIST v1.

DESTINY-Breast04 is a phase Ill study for HER2-low mBC, comparing the therapeutic effect of T-DXd and TPC (capecitabine, eribulin, gemcitabine, paclitaxel, nab-paclitaxel) single-agent chemotherapy, The proportion of patients who failed previous CDK4/6i therapy was 64%-71%

2.

The overall patient mPFS reached 5.

Repositide: The MAINTAIN trial of fulvestrant or acetaminophen in patients with unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer that has progressed after antiestrogen therapy in combination with a cyclin-dependent kinase 4/6 inhibitor.

In the 5th edition of the 2020 ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC5), 74 cross-line use is not recommended.

The NCCN Breast Cancer Guidelines (2022.

The Chinese Anti-Cancer Association Guidelines and Standards for the Diagnosis and Treatment of Breast Cancer (2021 edition) of the treatment principles for hormone receptor-positive HER2-negative MBC point out that there is limited evidence for the cross-line use of CDK4/6 inhibitors and should be chosen carefully

CDK4/6 inhibitors with different safety profiles can be substituted under special circumstances

Strategies for switching between different CDK4/6 inhibitors when severe neutropenia occurs are as follows:

In non-hematological adverse reactions, switching between different CDK4/6 inhibitors:

Dulciligui introduces a piperidine structure to avoid potential hepatotoxicity: Glutathione, which is bound by glutamic acid, cysteine ​​and glycine, is a tripeptide containing a sulfhydryl group

3.
The third treatment mode after CDK4/6i failure: changing targeted drugs with different mechanisms of action

BOLERO-5 is a double-blind, randomized, phase II study evaluating the efficacy of EVE+AI therapy in Chinese postmenopausal women with ER+HER2- locally advanced, recurrent disease who progressed after treatment with trozole or anastrozole
.
Patients were randomized 1:1 to receive EVE (10mgqd)+AI (25mgqd) or placebo (PBO)+AI (25mgqd) Primary endpoint: progression-free survival (PFS)
.
The results showed that the median PFS of patients treated with everolimus combined with AI was prolonged compared with AI monotherapy, whether assessed by investigator or BIRC
.

The TRINIT-1 study is a multicenter, open-label, single-arm, phase I/II study that enrolled 104 patients with HR+HER2- advanced breast cancer, 96 of whom had previously received CDK4/6 inhibitor therapy.
Received the CDK4/6 inhibitor + mTOR inhibitor + A1 three-drug combination therapy to explore the efficacy of the three-drug regimen after the progression of CDK4/6 inhibitor therapy
.
The results showed that the clinical benefit rate of patients at 24 weeks could reach 41%, exceeding the pre-specified primary endpoint (>10%), the median PFS was 5.
7 months, and the median OS was not reached at the data cutoff (95%CI: NE,NE)
.

Sapanisertib is an oral potent and selective adenosine triphosphate competitive inhibitor of mTOR kinase with dual specificity for mTORC1 and nTORC2
.
A phased, open-label, randomized, three-arm study exploring the combination of sapanisertib with once-daily (QD) or once-weekly (QW) fulvestrant compared with fulvestrant monotherapy to evaluate whether combination therapy improves Outcomes, postmenopausal women with ER+/HER2- advanced or metastatic breast cancer who progressed during or after aromatase inhibitor therapy
.
PFS was 3.
5 months in the single-agent fulvestrant group, compared with 7.
2 months in the fulvestrant + sapanisertib QD group, and 5.
6 months in the fulvestrant + sapanisertib QW group.
Treatment due to adverse events in both combination arms Discontinuation rates were higher in the fulvestrant monotherapy group (32% and 36% vs 4%, respectively)
.

The ACE study is a randomized, double-blind, placebo-controlled Phase 3 study of Chidamide plus exemestane in the treatment of HR+HER2-ABC, including 365 patients with HR+HER2-ABC who were randomly assigned to Chidamide+ In the EXE group (n=244) and the placebo+EXE group (n=121), 57.
5% (47.
7% for ET and 30.
1% for chemotherapy) and 32.
8% for metastatic disease had received prior treatment for metastatic disease The patient was insensitive to prior ET therapy
.
Significant differences were found in the primary study endpoint PFS (7.
4m vs 3.
8m (investigator assessment), 9.
2m vs 3.
8m (IRC assessment))
.

A real-world study of 2,000 patients with advanced breast cancer with Chidamide showed a PFS of 6.
4 months
.

E0C103A3101 is a phase 3 study of entinostat combined with exemestane in the treatment of HR+/HER2-ABC, which re-validates the efficacy of HDACi+Ai in the Chinese population
.

The data from Liu Jian's team's study of Chidamide in the treatment of advanced breast cancer showed that the median PFS (non-visceral metastasis vs visceral metastasis) was September vs June.
The median PFS of Chidamide as the treatment for each line was compared: 1 Line (9m) vs 2 line (6m) vs ≥ 3 line (6m)
.

The PI3K inhibitor Alpelisib + fulvestrant significantly prolonged PFS in patients with PIK3CA mutations
.

2020ASCO BYLieve is a Phase 2, open-label, 3-cohort, uncontrolled study evaluating alpelisib + endocrine therapy (fulvestrant or letrozole) in HR+, HER2 patients with PK3CA mutations in a previously CDK inhibitor-treated population - Efficacy and safety in patients with advanced breast cancer
.
The results showed that the CDKi+A cohort met the primary endpoint (95% C1 lower limit > 30%), with 50.
4% of patients surviving without disease progression at 6 months
.

4.
Summary

Regarding the treatment pattern after HR+HER2-CDK4/6i failure:

Chemotherapy is the most commonly used, of which ACD drugs may become upstarts

Inhibitors of PI3K/AKT/mTOR pathway are new options

CDK4/6i cross-line use awaits new evidence