Prof. Leiping Wang: CDK4/6 inhibitors come out surprisingly, HR+/HER2-advanced breast cancer enters a new era of targeted combined endocrine therapy

*Only for medical professionals to read and reference CDK4/6 inhibitors have come out surprisingly, providing more treatment opportunities for HR+/HER2- advanced breast cancer.

The emergence of CDK4/6 inhibitors has prompted HR+/HER2-advanced breast cancer to enter a new era of targeted combined endocrine therapy.
Currently, a total of three CDK4/6 inhibitors worldwide have been approved for marketing, and their mechanism of action, efficacy, and safety exist.
Some differences also have a certain impact on the choice of clinical applications.

The "medical community" specially invited Professor Wang Leiping from Fudan University Affiliated Tumor Hospital to share opinions on related topics.

 CDK4/6 inhibitors came out surprisingly, HR+/HER2-advanced breast cancer has entered the era of targeted therapy.
Wonderful video of Professor Wang Leiping.
According to statistics, breast cancer has become the cancer with the highest incidence in the world[1].

Hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative are the most common subtypes of breast cancer, accounting for about 60%.

In short, the HR+/HER2- discussed in this article is the most common type of breast cancer in clinical practice.

 “Compared with HR-, patients can receive endocrine therapy, and the prognosis is generally considered to be better.

Before targeted drugs enter the field of endocrine therapy, the drugs focus on the gonadal axis.

In the first-line treatment of advanced stage, the effects of endocrine drugs The progression-free survival (PFS) is about six months to one and a half years, which brings great help to patients.

" Professor Wang Leiping said.

 The advent of CDK4/6 inhibitors can be called "amazing" and has changed the current status of breast cancer treatment.

At present, a total of three CDK4/6 inhibitors have been approved for marketing, and seven key clinical trials of the three drugs have confirmed each other, prompting the creation of a new era of targeted endocrine therapy for HR+/HER2-advanced breast cancer.

 Professor Wang further explained: “Meta analysis shows that the risk ratio (HR) of CDK4/6 inhibitors in the first-line and second-line treatment of HR+/HER2- advanced breast cancer is concentrated at about 0.
55.

PFS has almost doubled.
For example, in the MONARCH-3 study, in the first-line treatment of abecilil combined with non-steroidal aromatase inhibitors, PFS was extended from 14.
7 months to 28.
1 months [2].

 "In addition to PFS, clinicians are also concerned about tumors.
Reduce the scale and speed.

Taking abexiride as an example, the objective response rate (ORR) increased from 21.
3% to 48.
1% in the second-line treatment of HR+/HER2- advanced breast cancer in combination with fulvestrant [3].

In addition, to achieve 30% tumor regression, abexiride can be about half a year earlier than fulvestrant as a single agent.

"Of course, clinicians are most concerned about whether patients can get a longer overall survival (OS).

According to published data, CDK4/6 inhibitors can successfully convert the prolongation of PFS into prolongation of OS.

Taking abesiride as an example, in the second-line treatment of HR+/HER2- advanced breast cancer with fulvestrant, PFS increased from 9.
3 months to 16.
4 months, while OS increased from 37.
3 months to 46.
7 months.
This prolonged the overall survival time of 9.
4 months, which is the goal that clinicians really pursue.

Therefore, CDK4/6 inhibitors have made a very significant change in the field of breast cancer endocrine therapy.

"Professor Wang emphasized.
There are
 differences in efficacy and safety between different CDK4/6 inhibitors.
Professor Leiping Wang’s wonderful video In the seven key clinical trials of three CDK4/6 inhibitors that have been approved for marketing, the main efficacy parameters are They are very close, so the first difference that clinicians pay attention to is their different adverse reaction spectrum.

 Professor Wang explained in detail: "The most common adverse reaction of piperacillil is neutrophil decline, which accounts for about 80%; and The proportion of Abexili is only about 40%.

In addition, the most common adverse reaction of abexiride is diarrhea, which accounts for about 80%; but the proportion of diarrhea that occurs with piperacillide is only more than 20%.

The difference in the adverse reactions of the two CDK4/6 inhibitors stems from the subtle differences in the mechanism of action.

 Professor Wang pointed out: "CDK4 and CDK6 are two different cyclin-dependent kinases.
CDK4 is more involved in the proliferation of tumor cells; CDK6 is expressed on bone marrow hematopoietic stem cells, which helps hematopoietic stem cells to quickly enter the proliferation cycle in a short period of time.

Compared with CDK6, Abbezilide has a higher selectivity for CDK4, while the inhibition constants of pipebecillil for CDK4 and CDK6 are similar, which explains why pipebezilil has more obvious bone marrow suppression.

" Why is there such a high proportion of diarrhea? It is worth noting that in addition to CDK4 and CDK6, Abexicil also has varying degrees of inhibition on CDK9, CDK2, CDK1 and other molecules.

CDK9 is involved in the transcription of intestinal cells.
Therefore, the patient will have obvious diarrhea in the first month of treatment.

" "There are more targets, which may partly explain why abexilide has a higher single-drug efficiency.

According to published data, abexilid is a single agent.
After HR+/HER2-advanced breast cancer multi-line treatment, the ORR is still as high as 19.
7%.

Of course, compared with single-drug use, CDK4/6 inhibitors combined with endocrine drugs, even in combination with endocrine drugs that have been proven to be resistant, have It helps to obtain better curative effects.

" Professor Wang added.

 Abexiride shines, effectively alleviating endocrine resistance Professor Leiping Wang's wonderful video CDK4/6 inhibitors can effectively alleviate endocrine therapy resistance.

Endocrine resistance is divided into primary resistance and secondary resistance.
Compared with secondary resistance, primary resistance is more difficult for clinicians.

Primary drug resistance means that previous endocrine therapy has not shown efficacy.
Before targeted drugs enter this field, primary drug resistance often means that patients need to enter the chemotherapy stage.

 Taking the emergence of primary drug-resistant HR+/HER2- advanced breast cancer during postoperative adjuvant treatment as an example, Professor Wang made relevant explanations: "The patient has just finished strong adjuvant chemotherapy, and the tumor has metastasized.
Resistant, and traditional endocrine therapy is difficult to achieve the treatment goals, abesiride provides clinicians and patients with new treatment opportunities.

According to the MONARCH-2 study [3], even for patients with primary drug resistance, basic endocrine therapy The addition of Abexicil can effectively improve PFS and OS.

In the MONARCH plus study cohort B, which is dominated by the Chinese population [4], the proportion of patients with primary drug resistance is higher, and the risk ratio is even better than that of MONARCH- 2 Research, which provides a new basis for clinical diagnosis and treatment.

"In addition to endocrine drug resistance, is there any cross-resistance among CDK4/6 inhibitors? In this regard, Professor Wang said: “In the small retrospective study, there are two impressive reports, including 58 and 87 patients.

These patients progressed after receiving piperacillil or Ribociclib treatment, and then adopted a The median PFS was 5.
4 and 5.
3 months for Besiciride treatment, respectively.

This seems to suggest that Abesiciride can alleviate some of the resistance of other CDK4/6 inhibitors.

Of course, conclusions are still needed for higher-level evidence.

"Professor Wang Leiping, Deputy Chief Physician, Department of Oncology, Fudan University Cancer Hospital, Doctor of Medicine, Member of the Youth Group of Breast Cancer, Chinese Medical Association, Member of the Breast Cancer Professional Committee of China Research Hospital, Member of the Breast Cancer Professional Committee of China Anti-Cancer Association, Youth Member of China Anti-Cancer Association Drug Clinical Research Committee Youth Member, Chinese Anti-Cancer Association "Breast Cancer Diagnosis and Treatment Guidelines" National Tour Group Reference Materials: [1]Latest global cancerdata: Cancer burden rises to 19.
3 million new cases and 10.
0 million cancerdeaths in 2020.
https:/ / -in-2020/[2] Goetz MP, Toi M, Campone M, Sohn J,Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC,Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, DiLeo A.
MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.
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MONARCH 2: Abemaciclibin Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast CancerWho Had Progressed While Receiving Endocrine Therapy.
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7585[4] Zhang QY, Sun T, Yin YM, Li HP, Yan M, Tong ZS, OppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ, Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD, Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925.
*This article is for medical professionals only Scientific information does not represent the views of this platformMONARCH 2: Abemaciclibin Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast CancerWho Had Progressed While Receiving Endocrine Therapy.
J Clin Oncol.
2017 Sep1;35(25):2875-2884.
doi: 10.
1200/JCO.
2017.
73.
7585[ 4] Zhang QY, Sun T, Yin YM, Li HP, Yan M, Tong ZS, OppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ,Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD,Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platformMONARCH 2: Abemaciclibin Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast CancerWho Had Progressed While Receiving Endocrine Therapy.
J Clin Oncol.
2017 Sep1;35(25):2875-2884.
doi: 10.
1200/JCO.
2017.
73.
7585[ 4] Zhang QY, Sun T, Yin YM, Li HP, Yan M, Tong ZS, OppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ,Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD,Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platformAbemaciclibin Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast CancerWho Had Progressed While Receiving Endocrine Therapy.
J Clin Oncol.
2017 Sep1;35(25):2875-2884.
doi: 10.
1200/JCO.
2017.
73.
7585[4] Zhang QY, Sun T, Yin YM, Li HP, Yan M, Tong ZS, OppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ,Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD,Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platformAbemaciclibin Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast CancerWho Had Progressed While Receiving Endocrine Therapy.
J Clin Oncol.
2017 Sep1;35(25):2875-2884.
doi: 10.
1200/JCO.
2017.
73.
7585[4] Zhang QY, Sun T, Yin YM, Li HP, Yan M, Tong ZS, OppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ,Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD,Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platformOppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ,Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD,Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925 .
*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platformOppermannCP, Liu YP, Costa R, Li M, Cheng Y, Ouyang QC, Chen X, Liao N, Wu XH, Wang XJ,Feng JF, Hegg R, Kanakasetty GB, Coccia-Portugal MA, Han RB, Lu Y, Chi HD,Jiang ZF, Hu XC.
MONARCH plus: abemaciclib plus endocrine therapy in women withHR+/HER2- advanced breast cancer: the multinational randomized phase III study.
Ther Adv Med Oncol.
2020 Oct 22;12:1758835920963925.
doi:10.
1177/1758835920963925 .
*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform