Professor Yan Min commented on the PHILA study: Pyrrolidinib writes a new chapter on small molecule anti-HER2-positive advanced breast cancer

Since the advent of trastuzumab, the treatment model of HER2-positive breast cancer has been continuously innovated with the development and clinical popularization of many anti-HER2-targeted drugs, and the emergence of small molecule tyrosine kinase inhibitors (TKI) drugs has further enriched the treatment options for HER2-positive breast cancer, and its combination potential with macromolecular targeted drugs has also become a hot topic

Recently, the PHILA study on pirrolidinib combined with trastuzumab and docetaxel (THPy) as a first-line protocol for advanced HER2-positive breast cancer was published at the 2022 Annual Meeting of the European Society of Oncology (ESMO), once again revealing the important value

Expert Profiles

Professor Yan Min

• Department of Breast Medicine, Henan Provincial Cancer Hospital, Deputy Director of Henan Breast Disease Diagnosis and Treatment Center, Chief Physician, Doctor of Medicine

• Standing Member of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO).

  
  

• Standing Committee Member of breast disease research center of Chinese Association of Women Physicians

• Standing Committee Member of Breast Cancer Group of oncologist Branch of Chinese Medical Doctor Association

• Standing Committee Member of Tumor Metastasis Professional Committee of China Medical Education Association

• Member of the Expert Committee on Multiple Primary and Unknown Primary Tumors of the Chinese Anti-Cancer Association

• Member of the Expert Committee on Capacity Building and Continuing Education of the National Health Commission

• Vice Chairman of the Breast Science Group of the Precision Medicine and Tumor MDT Professional Committee of the Chinese Society of Research Hospitals

• Vice Chairman of Breast Cancer Expert Committee of Henan Cancer Diagnosis and Treatment Quality Control Center

• Vice Chairman of the Breast Professional Committee of Henan Life Care Association

• Vice Chairman of Breast Disease Management and Innovation Branch of Henan Hospital Association

A number of large-scale studies have established a dominant position in the clinical application of pirroltinib

Pyrrolidinib is a small molecule TKI drug independently researched by China, and with the release of "stunning" data in recent years, it has become a "dark horse" that stands out in the HER2-positive breast cancer TKIs, and continues to make a strong voice

Professor Yan Min said that so far, pyrrolatinib has published a number of large-scale research results and shown very good clinical application prospects

• The results of the Phase III clinical trial ^{[PHENIX study[2]} showed that pirroltinib combined with capecitabine was effective in improving the objective response rate (ORR) (68.

  
  

• Phase III clinical trialSOEBE studies^[3] also included tax carpacia drugs and trastuzumab treated patients, and the group design was similar to that of the phase II trial, comparing the efficacy and safety

  
  

Based on the above two Phase III studies, pirroltinib was included in the national medical insurance in 2019 and officially obtained full approval from

The PHILA study is a national multicenter, randomized, double-blind, placebo-controlled Phase III clinical study to explore the efficacy and safety of the THPy regimen in first-line treatment in patients with HER2-positive advanced breast cancer, with a control group of placebo combined with trastuzumab and docetaxel

The results of the study were fully recognized by
Professor Yan Min.

She mentioned that the classic CLEOPATRA study also set trastuzumab plus docetaxel as a control group.
At that time, the median PFS result was 18.
7 months versus 12.
4 months, that is, the status of first-line standard therapy for the tripa dual-target combined docetaxel (THP) protocol had been established; and the PHILA study used a combination of large molecules and small molecules, and the superiority of mechanism complementarity was also confirmed in more eye-catching data: macromolecular trastuzumab binds to the extracellular domain of HER2; small molecule TKI diffuses through the cell membrane and binds to the intramembrane domain of herr family ^{proteins[ 4]}
。
The two should be "combined inside and outside" to achieve the anti-tumor effect
of extracellular synergistic targeting HER2.

Professor Yan Min believes that due to the current treatment pattern of tripa dual-target therapy becoming more and more popular in adjuvant and neoadjuvant therapy, the "size combination" scheme may provide a better solution for the treatment of current HER2-positive advanced breast cancer patients; On the other hand, compared with the current situation that the indications for advanced breast cancer of paltozumab have not been included in the scope of medical insurance reimbursement, the program including trastuzumab and pyrrolidinib also has advantages
in reducing the economic burden of patients and improving patients' long-term treatment compliance.

"Penetrating" the blood-brain barrier, piroctinib builds a defense line for brain transfer

Brain metastases occur in approximately 30 to 50 percent of patients with HER2-positive advanced breast cancer ^[5], and brain metastases are also the main cause of treatment failure in these patients, ultimately leading to a shortened
survival in these patients.

The use of small molecule TKI drugs such as pirroltinib is more likely to cross the blood-brain barrier than macromolecular monoclonal antibodies, effectively controlling brain metastases and prolonging patient survival ^[4
].

Previously, the PERMEATE study^[5] published in The Lancet Oncology and led by Professor Yan Min showed that pyrrolotinib plus capecistatin had better intracranial ORR (74.
6%, 95% CI: 61.
6 to 85.
0) and mPFS (11.
3 months, 95% CI: 7.
7 to 14.
6) benefits for patients with brain metastases in HER2-positive advanced breast cancer without local radiotherapy
。
The study was also able to name "PERMEATE" because of the good blood-brain barrier permeability shown by pyrrolotinib to take its permeable, diffuse meaning
.

Professor Yan Min further pointed out that pyrrolotinib can not only bring benefits to patients who have developed brain metastases, but also the PHENIX, PHOEBE and PHILA studies have also suggested that pirroltinib has a good response rate of extracranial lesions, which has practical clinical significance
for reducing the risk of brain metastasis and delaying the occurrence of brain metastases.

Do a good job of safety management, and the benefits of pirroltinib are more lasting

The PHILA study reported that the overall safety of pyrrolidinib combined with trastuzumab and docetaxel was controllable, no new safety signals were seen, and common adverse reactions were diarrhea, hematological toxicity, vomiting, etc
.

Among them, grade 3 diarrhea occurs mainly in the first cycle of medication and is significantly reduced
thereafter.

Professor Yan Min mentioned that small molecule TKI drugs such as pirroltinib and chemotherapy drugs can cause diarrhea, and the superposition of the two effects may lead to poor tolerance in some patients and forced to interrupt treatment
.

Therefore, diarrhea management is often a focus topic in researchers' meetings
.

However, it is worth mentioning that the Henan Provincial Cancer Hospital, where Professor Yan Min is located, is the sub-center with the largest number of patients enrolled in the PHILA study, but there are very few patients who interrupt treatment due to diarrhea, and until now, a considerable proportion of patients have maintained medication
.

In this regard, Professor Yan Min did not hesitate to share the excellent patient management experience explored by his center in many previous large-scale studies, including:

• Do a good job of education before the patient enrollment study, build psychological expectations of adverse reactions, and guide patients to know the benefits of long-term treatment, so as to improve patient treatment compliance and prolong the treatment cycle
  .
  
  

• Preventive drug use, once diarrhea appears, give loperamide treatment as soon as possible to avoid negative states such as anorexia and fatigue caused by long-term diarrhea, and reduce the psychological burden
  of fear and other patients.
  
  

• Low leukocytes are also a common adverse effect in the PHILA study, but are more associated with docetaxel and can be prevented
  with long-acting whitening needles.
  
  

Professor Yan Min pointed out that in the clinic, it is necessary to clearly explain the severity of diarrhea at the beginning, as well as the consequences of diarrhea that may cause drug reduction or even withdrawal from the group, and at the same time let patients carry drugs preventively, so that patients can get timely treatment when they first have diarrhea, so as to avoid further damage
caused by diarrhea.

epilogue

"The significant clinical benefits of macromolecular trastuzumab in combination with small molecule pirrolinib combined with chemotherapy have been strongly demonstrated by the PHILA study
.

Professor Yan Min said, "Pyrrolidinib itself has been included in medical insurance, and it is expected that more research data can help it obtain first-line treatment indications, and the THPy program is expected to become the preferred program for clinical decision-making, bringing good news
to the majority of patients.
"
”

References:

[1] Ma F, Ouyang Q, Li W, et al.
Pyrotinib or lapatinib combined with capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a ran-domized, phase II study [J].
J Clin Oncol, 2019, 37 (29): 2610-2619.

[2] Yan M, Bian L, Hu X, et al.
Pyrotinib plus capecitabine for human epidermal factor receptor 2-positive metastatic breast cancer after trastuzumab and taxanes (PHENIX) : a randomized, double-blind, placebo controlled phase 3 study [J].
Transl Breast Cancer Res, 2020,1-13.

[3] Xu B, Yan M, Ma F, et al.
Pyrotinib plus capecitabine versus lapa-tinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, operrlabel, randomised, controlled, phase 3 trial[J].
Lancet Oncol, 2021, 22(3):351-360.

[4] Xuhong J C , Qi X W , Zhang Y , et al.
Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer[J].
American Journal of Cancer Research, 2019, 9(10):2103-2119.

[5] Yan M, Ouyang Q, Sun T, et al.
Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial[J].
Lancet Oncol, 2022,23(3):353-361.