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First, the choice of CDK4/6 inhibitors in the precision era
Background: HR+ (hormone receptor positive) breast cancer although the overall prognosis is better, but it is inevitable that patients will progress to advanced stages, advanced patients mainly rely on endocrine therapy and chemotherapy, in recent years, breakthroughs have been made in combination targeted therapy in endocrine therapy strategies, with CDK4/6 (cyclin-dependent kinase 4 and 6, CDK4/ 6) Targeted therapy drugs represented by the hormone receptor give patients with hormone receptor-positive breast cancer longer survival and better quality of life.
Professor Song Guohong will discuss how to choose CDK4/6 inhibitors in the era of precision, which is divided into the following three parts: CDK4/6 inhibitors combined with AI (aromataseinhibitor) is the first-line criterion for HR+ advanced breast cancer; the choice of CDK4/6 inhibitors is explored from the perspective of drug efficacy; and the choice of CDK4/6 inhibitors is explored from different safety outcomes
2. Professor Song Guohong's discussion on the choice of CDK4/6 inhibitors in the precision era
1. CDK4/6 inhibitors combined with AI are the first-line criteria for HR+ advanced breast cancer
Treatments for HR+ advanced breast cancer have undergone several years of change, as early as 1896, oophorectomy played a role in the treatment of advanced breast cancer, followed by a number of endocrine therapy drugs, including tamoxifen (Oncomox, Soltamox, Crisafeno, tamoxifen, Tamofen), aromatase inhibitors (AI), drug-induced ovarian suppression, fulvestrant (Faslodex, Fulvestrant), Everolimus (Afinitor), etc., followed by landmark CDK4/6 inhibitors such as palbociclib (Ibrance), Abemaciclib (Verzenio) and reseboxili (kryxana, Kisqali, ribociclib), currently listed in China are pastoxili, Abexil two CDK4/6 inhibitors. There are many clinical studies of CDK4/6 inhibitors, including the use of AI combined with CDK4/6 inhibitors for first-line HR+, HER2-advanced breast cancer, second-line fulvestrant combined with CDK4/6 inhibitors, including pabosili, abexil and various clinical studies have achieved very good results, including PFS (progression-free survival, progression-free survival) benefits, OS (Overall Survival, OS) benefits, so for this treatment of HR+ breast cancer, the era of endocrine combined CDK4/6 inhibitor targeted therapy has been fully opened.
Mechanism of action of CDK4/6 inhibitors:
CDK4/6 binds to Cyclin D (cyclin D) to form a complex that promotes the clinical differentiation of 2D proteins, releases ERF (Epidermal repair factor), and promotes the transformation of the cell cycle from G1 (first gap, pre-synthesis) to S (synthesis, DNA synthesis), thereby promoting the proliferation of tumor cells. The CDK4/6-Cyclin D complex plays a key role in the G1-S phase of the breast cancer cell cycle. The application of CDK4/6 inhibitors can inhibit the formation of CDK4/6- Cyclin D complex, thereby blocking a series of subsequent activations, inhibiting the transformation of the cell cycle from G1 stage to S phase, inhibiting the proliferation of cells, and thus achieving the effect of inhibiting tumor cell proliferation. So far, CDK4/6 inhibitors listed in different countries are as follows:
Pabsili: Approved in Europe, the United States and China
Abésili: Approved in Europe, the United States and China
Rebolcili: Approved only in Europe and the United States, not listed in China
For receptor-positive breast cancer and HER2- (human epidermal growth factor receptor 2-positive) breast cancer, domestic guidelines currently recommend endocrine plus CDK4/6 inhibitors as the first-line standard of care. At present, endocrine therapy has fully entered the era of endocrine targeted therapy.
CDK4/6 inhibitors + AI first-line therapy significantly improved the prognosis of patients with HR+HER2-breast cancer (hormone receptor, human epidermal growth factor receptor 2-positive breast cancer), and there have been many clinical studies of first-line endocrine therapy options, such as:
(1) Pabosili's classic PALMOMA-2 study:
The Pabosili classic PALMOMA-2 study, a randomized (2:1) multicenter international double-blind Phase III trial, enrolled 666 patients in more than 200 centers worldwide, received palbociclib (125 mg d1-21, q28d) and a combination of letrozole (2.5 mg qd), and the control group took letrozole + placebo as a first-line regimen for the treatment of women with postmenopausal ER+/HER2- advanced breast cancer , a study that assessed its progression-free survival (PFS).
(2) Abecilli's MONARCH-3 study:
MONARCH3 was a randomized, double-blind Phase III clinical study of 493 patients with postmenopausal and advanced breast cancer who were advanced HR-positive, HER2-negative, and unsystematically treated, and who were randomly grouped to receive Abemaciclibi/placebo (150 mg, bid) plus nonsteroidal aromatase inhibitors (anastrozole 1 mg qd, or letrozole 2.5 mg qd), respectively. The primary study endpoint was investigator-assessed PFS, and the secondary endpoint was efficacy assessment and safety. An interim analysis is planned after 189 incidents.
In the clinical study of PALMO-2, the first-line paboxil combined with AI, its PFS extended from 14.5 months to 27.6 months, there is a significant extension, but there is no median survival data, the clinical benefit rate increased from 70% to 84.9%, and the clinical benefit rate was significantly improved. For abexil, its PFS also extended significantly, from 14.8 months to 28.2 months, and the clinical benefit increased from 71% to 78%. Phase III study of first-line treatment of CDK4/6 inhibitors: compared with MONK-3, PALOMA-2 included more endocrine-insensitive people, and the results were more convincing. In summary, endocrine combined with CDK4/6 inhibitors is a first-line standard treatment unanimously recommended by domestic and foreign guidelines.
2. To explore the choice of CDK4/6 inhibitors from the perspective of drug efficacy
Subgroups with different characteristics (e.g., presence of bone metastases, visceral metastases, concomitant diseases, etc.) affect the relative benefit of CDK4/6 inhibitor combination therapy. In the clinical study of PALMO-2, pabotinib combined with AI (aromatase inhibitor) was not affected by the site of metastasis and previous endocrine therapy, age, etc., and had a significant benefit from PFS in various subgroups. Abecilli and AI benefited differently from PFS in different subgroups.
(1) Bone metastase patients:
The incidence of bone metastases is extremely high in breast cancer patients, and many patients have more bone metastases when they first metastasize. In the clinical study of PALMO-2, PFS was extended from 11 months to 36 months in patients with only bone metastases, and the absolute benefit reached 25 months. In the clinical study of MONARCH-3, its PFS ranged from 26 months to 38 months, and the benefit was relatively low. In patients with only bone metastases, the benefits of paboxil are significant. In meta-analysis (meta-analysis is a statistical method used to compare and synthesize the results of studies on the same scientific problem, and whether its conclusions are meaningful depends on the quality of the included studies, often used in quantitative pooled analysis in systematic reviews), six clinical studies were included to explore and found that the PFS of patients with peboxil combined with AI in patients with bone metastases alone was significantly superior to the AI regimen. In another meta-analysis, PFS in combination with AI in combination with AI for bone metastases alone was significantly superior to the underlying protocol.
(2) Visceral metastasis: lung metastases and liver metastases:
Paboxil combined with AI therapy significantly improves PFS in patients with lung metastases and liver metastases HR + HER2-advanced breast cancer. In real-world data, it can be seen that in patients with visceral metastases, pacbacili combined with AI therapy significantly prolongs PFS and OS; in patients with lung metastases, pacbacili combined with AI therapy significantly prolongs PFS and OS.
For patients with first-line therapy, PFS benefited significantly in clinical studies of PALMO-2, including both endocrine-sensitive and 22% of secondaryly resistant patients. In the CLINICAL STUDY OF MONKEY-3, the enrolled patients were all endocrine-sensitive, and Abecily's PFS did not benefit significantly. Overall, from the above analysis, it can be concluded that the combination of paboxil and AI in the treatment of patients with endocrine sensitivity, secondary endocrine resistance, and new metastases has a significant benefit from PFS, reducing the risk of disease progression to 40%-50%.
For whether concomitant diseases affect the prolongation of mPFS, a series of analyses of palboxil were carried out, and according to the clinical study of PALOMA-2, even with gastrointestinal diseases, musculoskeletal diseases, metabolic diseases, cardiovascular diseases, and paboxil combined with AI therapy significantly prolonged PFS.
The above studies have shown that cdk4/6 inhibitors combined with AI first-line treatment of PFS have been significantly improved, and the continued benefit has been maintained under subsequent treatment regimens to achieve the overall survival benefit.
3. CdK4/6 inhibitor selection from different safety outcomes was explored
(1) Adverse reactions of CDK4/6 inhibitors:
For patients, we prefer to achieve a clinical benefit while ensuring the quality of life of patients. Adverse reactions of paboxili include a decrease in white blood cells, a decrease in neutrophils, a proportion of more than 80%, and dizziness and nausea. In addition to the reduction of neutrophils by more than 80%, there are 80% of diarrhea in the adverse reactions of abexili. These adverse reactions can affect the patient's compliance, in the case of discontinuation of the drug due to adverse reactions or halving of the dose, the permanent discontinuation of the pacbacili is 10% effective, and the dose is halved by about 36%. Therefore, in the process of clinical application, if you encounter serious adverse reactions, you will consider discontinuing the drug or reducing the dose. First-line treatment of pabuxili combined with AI has few adverse reactions, good tolerance, and high patient compliance. Adverse reactions of drugs are divided into perceptible adverse reactions and imperceptible adverse reactions, such as neutropenia caused by paboxilide is an imperceptible adverse reaction, so it has no effect on the patient's quality of life. In addition, according to the effect of abexil on rat intestinal epithelial cells, it can be seen that abexil is more toxic to the intestine, possibly because the transcriptional regulatory protein COK9 mediates Abexilide-related intestinal toxicity, while paboxil has less effect on intestinal epithelial cells.
The diarrhea caused by the treatment of Abexili and some thrombotic diseases may affect the prognosis and life safety of patients, so in the application process, we should pay close attention to these adverse reactions, give positive treatment in time, and hope to achieve better clinical treatment results while also reducing the negative impact on the quality of life of patients.
In the meta-analysis, the adverse reactions of pacbacili are neutropenia, and the adverse reactions of abexili in addition to neutropenia also include diarrhea, anemia, etc., so the overall safety and tolerability of pacbacili are better than those of abexil. Regarding the discontinuation rate, a network meta-analysis showed that the discontinuation rate of paboxil combined AI was significantly lower than that of abexil combined AI.
(2) Measures to deal with adverse reactions:
Therefore, adverse effects need to be closely monitored during CDK4/6 inhibitor therapy. For more attention to the blood routine of paboxil, in the first two months of medication, it is recommended to check the blood routine every two weeks, and if the subsequent blood routine is relatively stable, the interval between blood routine examinations can be appropriately extended. For abexili, the blood routine test is the same as that of paboxili, and it is also necessary to pay attention to the monitoring of electrolytes, such as the patient's electrolyte imbalance caused by diarrhea, to correct it in time, in addition to paying attention to the monitoring of liver function, the monitoring of thrombosis.
(3) The precautions for the use of CDK4/6 inhibitors in special populations are as follows:
There is no age difference in the use of CDK4/6 inhibitors, and there is no difference in the use of young and old people; it can also be used in patients with cardiovascular disease; but there are some differences in gastrointestinal disease, hepatobiliary disease, and hypercoagulant risk disease, paboxili is recommended, abexil should be used with caution and adverse reactions should be paid close attention; for pregnant women, both drugs are contraindicated.
(4) Summary:
In summary, for the selection of CDK4/6 inhibitors, the principle of tailoring should be followed, and a suitable CDK4/6 inhibitor should be selected according to the characteristics of the patient population and the characteristics of comorbidities. For elderly patients with more co-diseases, the recommended level of pastoxil is relatively high, and in other conditions, the recommended level of abexil is higher, so in the clinical use process should be selected according to the characteristics of different populations.
3. Summary of the meeting
(1) Endocrine combined with CDK4/6 inhibitors is the standard choice for first-line therapy in patients with receptor-positive and HER2-negative advanced breast cancer. Clinical studies of PALOMA-2 clearly show that the significant benefits of PFS include both endocrine-sensitive and inflammatory resistance, particularly in patients with only bone metastases, where PFS reaches 36 months, and for visceral metastases, as well as benefits in visceral metastases. There are also benefits for OS in real-world clinical studies.
(2) The adverse reactions of drugs such as neutropenia and diarrhea should be paid close attention to, and clinical drugs should be tailored according to the characteristics of the patient population and the characteristics of the diseases to achieve the greatest benefit of patients.