K drug hits esophageal cancer across the board, leading a new standard of treatment

*For medical professionals to read and refer to the CSCO guidelines, PD-1 monoclonal antibody is recommended for the first-line treatment of advanced esophageal cancer.
In June 2020, two PD-1 immune checkpoint inhibitors were simultaneously approved for second-line treatment in China.
Unresectable Locally advanced or metastatic esophageal squamous cell carcinoma.

Since then, clinical research on immunotherapy for esophageal cancer has advanced at full speed.
A number of clinical studies carried out globally and in China have announced the results, which has rapidly advanced the immunotherapy of esophageal cancer from advanced second-line therapy to advanced first-line therapy, as well as locally advanced esophageal cancer The field of postoperative adjuvant and preoperative neoadjuvant therapy.

The European Society of Medical Oncology (ESMO) conference held in September 2020 announced that the PD-1 immune checkpoint inhibitor pembrolizumab (commonly known as K drug in China) combined with cisplatin and 5-fluorouracil (5-FU) is not available for first-line treatment Results of the Phase III clinical study (KEYNOTE-590) on the efficacy and safety of resection of locally advanced or metastatic esophageal cancer: whether it is in intention to treat (ITT), esophageal squamous cell carcinoma (ESCC), or PD-L1 CPS≥ In the ITT and ESCC population of 10, the overall survival (OS), disease progression-free survival (PFS), objective tumor response rate (ORR) and duration of response of K drug combined with platinum-containing chemotherapy (cisplatin and 5-fluorouracil) as first-line treatment (DOR) data show significant superiority compared to platinum-based chemotherapy as first-line treatment, and safety data are comparable to standard chemotherapy.

KEYNOTE-590: The OS of the overall population and the classified subgroups is based on the results of the KEYNOTE-590 study.
Following the first update of the 2020 V5 Guidelines for Esophageal Cancer and Gastroesophageal Intersection Cancer issued by the National Comprehensive Cancer Network (NCCN), to Currently, the latest version of 2021 V2 preferentially recommends K drug combined with platinum (oxaliplatin or cisplatin) chemotherapy regimens for the first-line treatment of unresectable locally advanced, local recurrence or metastatic HER2 negative expression of PD-L1 CPS ≥ 10 Esophageal cancer.The U.
S.
Food and Drug Administration (FDA) subsequently approved the treatment plan for the first-line treatment of unresectable locally advanced or metastatic esophageal cancer, regardless of the patient's PD-L1 expression.

Towards the end of 2020, a number of phase I/II clinical studies led by Chinese esophageal surgeons for neoadjuvant treatment of locally advanced esophageal cancer with immune-combined chemotherapy or radiotherapy and chemotherapy have announced exciting results on the international academic stage.

Among them, the postoperative pathological complete remission (pCR) rate brought by the K drug combined with concurrent radiotherapy and chemotherapy neoadjuvant treatment program reached 55.
6%.

The results of these studies have allowed the "fire of war" of esophageal cancer immunotherapy to rapidly spread to the neoadjuvant treatment stage of operable locally advanced esophageal cancer.

At the just-concluded Chinese Society of Clinical Oncology (CSCO) 2021 guidelines conference, multiple PD-1 immune checkpoint inhibitors, including K drugs, were recommended by level II experts in the "2021CSCO Guidelines for Diagnosis and Treatment of Esophageal Cancer" for metastasis First-line treatment of sexual esophageal cancer.

The "2021CSCO Guidelines for Diagnosis and Treatment of Esophageal Cancer" is recommended by experts for the treatment of metastatic esophageal cancer.
The "2021CSCO Guidelines for the Clinical Application of Immune Checkpoint Inhibitors" only give K drug and one PD-1 monoclonal antibody I grade expert recommendation for the first-line treatment of metastatic esophageal cancer.
Esophageal cancer (evidence level 1A).

The 2021 CSCO Immune Checkpoint Inhibitors Clinical Application Guidelines for the recommendation and evidence level of esophageal cancer immunotherapy The indications of K drugs combined with platinum-containing chemotherapy for the first-line treatment of unresectable locally advanced or metastatic esophageal cancer were submitted to my country in November 2020 The National Medical Products Administration (NMPA) has been accepted and is expected to be approved this year, which means that the domestic first-line esophageal cancer treatment pattern will undergo a "great change.
"
During the CSCO Guidelines Conference in 2021, this platform invited the Deputy Chairman and Secretary-General of the CSCO Esophageal Cancer Expert Committee and Professor Huang Jing of the Department of Oncology, Cancer Hospital of the Chinese Academy of Medical Sciences, to discuss the significance of immunotherapy in the first-line treatment of advanced esophageal cancer, and the esophagus The future of cancer immunotherapy shared personal views.

Compared with the 2020 CSCO Guidelines, what updates are there in the new version of the "CSCO Guidelines for the Diagnosis and Treatment of Esophageal Cancer" regarding expert recommendations for metastatic esophageal cancer? Professor Huang Jing: The CSCO guidelines recommend immunotherapy for the first-line treatment of advanced esophageal cancer for the first time.

Based on the results of the KEYNOTE-590 study, the new version of the guidelines gives K drugs combined with platinum-containing chemotherapy as the first-line treatment for people with PD-L1 CPS ≥ 10 (including esophageal squamous cell carcinoma and adenocarcinoma) level II expert recommendation, level of evidence 1A.

Based on the results of the Phase III clinical study CheckMate-649 announced at the ESMO Conference in 2020, nivolumab combined with chemotherapy for the first-line treatment of esophageal adenocarcinoma is also recommended by level II experts, and the level of evidence is 1A.

Why is the updated guideline only recommended by level II experts in the first-line treatment of immunization? Professor Huang Jing: The CSCO guidelines recommend a treatment plan not only to consider whether the efficacy and safety of the plan are supported by evidence-based medicine, but also to take into account the accessibility of the treatment plan.

Although my country's NMPA has officially accepted the application of K-drug combined with chemotherapy for the first-line treatment of esophageal cancer in 2020, it has not yet officially approved the treatment plan for clinical application.

In view of this, this guide is only recommended by level II experts of the program; it is believed that the guide will be updated after the program is officially approved.

The results of the KEYNOTE-590 study showed that the K-drug plus chemotherapy first-line treatment plan not only brings significant OS benefits to people with PD-L1 CPS ≥ 10, but also brings significant OS benefits to the overall population and the esophageal squamous cell carcinoma population.

 Why this guideline only recommends this first-line treatment plan for people with PD-L1 CPS ≥ 10? Professor Huang Jing: The results of the KEYNOTE-590 study have brought high-level evidence-based medical evidence for the first-line treatment of K-drug combined with chemotherapy for unresectable locally advanced and metastatic esophageal cancer, but the study results also show that PD-L1 CPS≥ Compared with the population with PD-L1 CPS<10, the survival benefit from this treatment program is more significant for the 10 population.

Therefore, before the NMPA has approved the program for the treatment of the entire population, the CSCO guidelines chose to recommend this program for the most likely and benefited population.

After the NPMA approves the program for the entire population, regardless of PD-L1 expression, the CSCO guidelines next year will also be updated accordingly.

Just like this year’s latest edition of the NCCN Guidelines for the Diagnosis and Treatment of Esophageal Cancer (2021 V2) was released before the US FDA approved K-drug combined with chemotherapy for the first-line treatment of the whole population, so this program is only recommended for esophageal cancer with PD-L1 CPS ≥ 10 The population; but the next edition of the NCCN guidelines may be adjusted according to the indications approved by the FDA.

So, can the first-line treatment plan of pembrolizumab combined with chemotherapy be used for the treatment of people with PD-L1 CPS<10? Professor Huang Jing: According to the results of the KEYNOTE-590 study, this program brings significant OS benefits to the overall population and the esophageal squamous cell carcinoma population.
This means that the applicable population should be the entire population, regardless of CPS ≥ 10 or not; only PD- People with L1 CPS≥10 may have a higher chance of benefit and a greater degree of benefit.

In the clinical practice of first-line immunotherapy for metastatic esophageal cancer, how do you view the necessity of CPS testing? Professor Huang Jing: The CPS value of PD-L1 is related to the efficacy of drug K in the treatment of esophageal cancer, but PD-L1 is not perfect as a predictor of the efficacy of esophageal cancer immunotherapy.

Therefore, in clinical practice, I think that if conditions permit, you can choose to test PD-L1 CPS.

But the lack of test results does not mean that the treatment plan cannot be used.

KEYNOTE-590 is the only first-line immune treatment of esophageal cancer (including squamous cell carcinoma and adenocarcinoma) that has published the results of a Phase III clinical study.

 What are the implications of the findings for the treatment of esophageal cancer? Professor Huang Jing: KEYNOTE-590 is a research that has brought a major breakthrough in the treatment of esophageal cancer.
It is also the first successful research in the first-line treatment of esophageal cancer with immunotherapy, so it is a milestone in the field of esophageal cancer treatment.

Moreover, I think the results of the study will not only bring about a fundamental change in the treatment model for advanced esophageal cancer, but also for locally advanced esophageal cancer.

In the KEYNOTE-590 study, drug K combined with chemotherapy brought a 45% objective tumor response rate (ORR); if patients with stable disease (SD) are considered, the disease control rate (DCR) is higher.

High ORR and DCR suggest that this treatment plan helps to increase the R0 resection rate and pCR rate of locally advanced patients that can be surgically resected, and improve long-term survival benefits.

For some locally advanced patients who are not surgically resectable, this treatment plan brings strong tumor shrinkage and reduces tumor burden, thereby increasing the possibility of these transformational resections, and improving the possibility of long-term survival or even cure for these patients.

Therefore, this program brings unlimited possibilities for the future of effective systemic therapy combined with local therapy, and may have a significant impact on clinical practice.

Immunization + neoadjuvant therapy program brings considerable pCR rate.

Will immunotherapy in the future prevent some patients with locally advanced esophageal cancer from surgery? Professor Huang Jing: I think this is entirely possible.

Our hospital has carried out an exploratory study of 30 cases of immunization combined with multiple drugs in the first-line treatment of unresectable locally advanced and distant metastatic esophageal squamous cell carcinoma patients, and found that the effective rate was as high as 80%, and 16% obtained CR (imaging complete remission) ), and the patients with CR are basically locally advanced patients.

I think that in the future, some patients with locally advanced esophageal cancer will be cured through systemic treatment, or systemic combined with local treatment, without surgery.

Expert Profile Professor Huang Jing Doctor of Medicine, Chief Physician, Professor, PhD Supervisor, Deputy Director of Internal Medicine, National Cancer Center/Tumor Hospital of Chinese Academy of Medical Sciences, Director of Internal Medicine, Cancer Hospital of Chinese Academy of Medical Sciences, Shenzhen Hospital, Deputy Director of Colorectal Tumor Professional Committee, Beijing Medical Association Vice Chairman of the Cancer Rehabilitation Branch of the Society of Geriatrics, Chinese Society of Clinical Oncology (CSCO) Vice Chairman and Secretary-General of the CSCO Esophageal Cancer Expert Committee Member of the Standing Committee of the Esophageal Cancer Professional Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the Colorectal Tumor Professional Committee of the Chinese Physician Association Chinese Physician Vice Chairman of the Medical Treatment Committee of the Colorectal Tumor Professional Committee of the Association, Vice Chairman of the Gastric Cancer Group of the Cross-Strait Medical and Health Exchange Association of Cancer Prevention and Treatment Expert Committee, Director of Beijing Xisike Clinical Oncology Research Foundation, Beijing Chaoyang District Youth Federation Member, "Chinese Colorectal Member of the editorial board of the Electronic Journal of Diseases and the Journal of Cancer Progress, Associate Editor of the Chinese Journal of Biochemical Medicine