"P" chemotherapy, "K" esophagus-Professor Guochun Cao: Combined immunotherapy is the new standard for first-line treatment of advanced esophageal cancer

Foreword Esophageal cancer is one of the most common malignant tumors in China.
New cases and deaths account for about one-half of the world's total.
There are obvious regional differences, treatment options are limited, and the mortality rate is high 1-2
.

As the PD-1 immune checkpoint inhibitor pembrolizumab combined with chemotherapy for the first-line treatment of unresectable locally advanced or metastatic esophageal cancer indications were approved in China in September this year, new treatment dawns for patients with advanced esophageal cancer in China
.

Yimaitong invited Professor Cao Guochun from Jiangsu Cancer Hospital to interpret the KEYNOTE-590 study and the clinical significance of the first-line treatment of esophageal cancer with pembrolizumab combined with chemotherapy
.

Expert profile Cao Guochun, doctor of internal medicine, Jiangsu Cancer Hospital, director of the ward, master's tutor, standing member of the Chinese Society of Clinical Oncology (CSCO) esophageal cancer expert committee, vice chairman of the Chinese Society of Clinical Oncology (CSCO) head and neck cancer expert committee, China Anticancer Member of the Society for Nasopharyngeal Cancer Committee, Vice Chairman of the Esophageal Cancer Committee of the Beijing Cancer Society Chairman, Chinese Society of Gerontology, Member of Tumor Rehabilitation Committee, Member of Chinese Society of Continuing Medical Education, Member of Abdominal Tumor Society Phase clinical studies included a total of 749 patients from 168 research centers in 26 countries around the world, of which the Chinese patient population accounted for 14.
2%3-4
.

This study aims to evaluate the efficacy of pembrolizumab combined with chemotherapy and placebo combined with chemotherapy for the first-line treatment of locally advanced or metastatic esophageal cancer (squamous cell carcinoma, adenocarcinoma and Siewert type I esophagogastric junction adenocarcinoma)
.

Figure 1.
KEYNOTE-590 study design 3KEYNOTE-590 is a very well-designed and sophisticated phase III clinical study, targeting ESCC with esophageal squamous cell carcinoma (ESCC), PD-L1 comprehensive positive score (CPS) ≥ 10 and overall The population, as well as the four groups of all populations, set up seven main research endpoints, including the overall survival (OS) of these four groups, and the overall population with ESCC, PD-L1 CPS≥10, and the overall population’s progression-free survival Period (PFS)
.

Secondary endpoints include objective response rate (ORR), duration of response (DOR), and safety and tolerability3
.

When a clinical study has up to seven research hypotheses, this requires a fine and reasonable allocation of the alpha value between the two primary endpoints of OS and PFS, so as to ensure that the overall alpha value of the study is controlled within the unilateral 0.
025 established in the study
.

 In the KEYNOTE-590 study, the alpha value of PFS was 0.
002 and the alpha value of OS was 0.
023
.

  Figure 2.
Statistical analysis of KEYNOTE-590: Allocation of α values ​​3 Professor Guochun Cao believes that such a design is very bold and shows the great confidence of the study designer in obtaining positive results from the first-line treatment of pembrolizumab combined with chemotherapy
.

An important conclusion can be drawn from multiple studies such as KEYNOTE-180 and KEYNOTE-181 in the second-line treatment of advanced esophageal cancer with pembrolizumab.
The efficacy of PD-L1 CPS≥10, esophageal squamous cell carcinoma, and Asian population is Advantageous populations of bolizumab have better therapeutic effects than those with PD-L1 negative expression, esophageal adenocarcinoma, and non-Asian populations
.

Professor Cao Guochun also pointed out that this is why the KEYNOTE-590 study included more than 50% of Asian patients with esophageal squamous cell carcinoma, and nearly 50% of the population with PD-L1 CPS≥10
.

Figure 3: Baseline situation 3 of the KEYNOTE-590 enrolled population shows that whether it is in the ITT population, ESCC, or ITT and ESCC population with PD-L1 CPS ≥ 10, pembrolizumab combined with chemotherapy is the first-line treatment in OS , PFS, ORR and DOR data show significant superiority compared with first-line chemotherapy alone, and safety data are comparable to standard chemotherapy3
.

Professor Guochun Cao pointed out that the seven main research hypothetical endpoints of the KEYNOTYE-590 study all got positive results, not only due to the sophisticated clinical research design, but also from its solid preliminary clinical research work
.

PK chemotherapy, immune combined chemotherapy to achieve new standards for advanced esophageal cancer In September this year, pembrolizumab combined with platinum and fluorouracil chemotherapy was approved by the National Food and Drug Administration (NMPA) for locally advanced unresectable or metastatic disease Pembrolizumab has become the first and currently the only PD-1 monoclonal antibody approved for the first-line treatment of esophageal cancer in the whole population of esophagus or gastroesophageal junction cancer
.

The approval of this indication is based on the results of the KEYNOTYE-590 study
.

The study randomly divided 749 patients into a treatment group (n=373) and a control group (n=376), and were given pembrolizumab + chemotherapy or placebo + chemotherapy, respectively
.

Research data shows that compared with placebo + chemotherapy, pembrolizumab + chemotherapy can significantly improve the OS of PD-L1 CPS ≥ 10 esophageal squamous cell carcinoma, PD-L1 CPS ≥ 10, esophageal squamous cell carcinoma, and OS of all random populations And PFS3
.

Figure 4: KEYNOTE-590 study overall population, ESCC, PD-L1 CPS ≥ 10 ITT and ESCC population OS3 Figure 5: KEYNOTE-590 study overall population, ESCC, PD-L1 CPS ≥ 10 ITT PFS3 chemotherapy is China The main treatment plan for patients with advanced metastatic esophageal cancer, but its curative effect is limited.
Pembrolizumab + chemotherapy has also broken the treatment dilemma of advanced metastatic esophageal cancer in China and brought the hope of treatment for patients
.

In this year's American Society of Clinical Oncology (ASCO) annual meeting, the KEYNOTE-590 study published data on the Chinese subgroup of patients
.

The results of the study showed that compared with chemotherapy, pembrolizumab + chemotherapy prolonged the median OS by 2.
5 months and reduced the risk of death by 49% (HR, 0.
51; 95% CI, 0.
32-0.
81)
.

Figure 6.
KEYNOTE-590 study Chinese population study data 4 The median PFS of the Chinese subgroup treatment group and control group were 6.
2 months and 4.
6 months, respectively (HR=0.
60, 95% CI: 0.
39-0.
92), disease progression or The risk of death is reduced by 40%
.

Figure 7: KEYNOTE-590 Chinese subgroup PFS data 4 Although compared with chemotherapy, pembrolizumab + chemotherapy extended the median OS of the Chinese subgroup by 2.
5 months (10.
5 vs 8.
0), but compared with the overall The median OS of the population is still slightly different (12.
4 vs 9.
8)
.

Prof.
Guochun Cao analyzed that compared with the overall population, the Eastern Cooperative Oncology Group Score (ECOG)=1 for the Chinese subgroup is more common, with a ratio of 81.
1%, far exceeding 59.
8% of the overall population
.

In addition, the age of onset of the Chinese subgroup of patients is relatively low, and their physical status and immune status are relatively poor
.

Therefore, it is reasonable that the ORR level of the Chinese subgroup is lower than the overall population
.

Figure 8.
Baseline characteristics of the Chinese population enrolled in KEYNOTE-590 From the perspective of ORR improvement, pembrolizumab + chemotherapy increased the ORR of the Chinese subgroup by 17.
3%, and showed good and controllable safety
.

Professor Cao Guochun believes that whether it is to improve the patient’s short-term effective rate, prolong OS, and improve the quality of life of patients, pembrolizumab + chemotherapy is an ideal treatment plan, which provides long-term survival hope for patients with advanced esophageal cancer.
And it will surely become the new standard of first-line treatment for this patient group
.

Neoadjuvant therapy, the next "strategic fortress" in the diagnosis and treatment of esophageal cancer.
Neoadjuvant therapy is a hot topic in the diagnosis and treatment of esophageal cancer.
Both the National Comprehensive Cancer Network (NCCN) and the Chinese Society of Clinical Oncology (CSCO) guidelines for esophageal cancer diagnosis and treatment Neoadjuvant therapy is given to patients with locally advanced esophageal cancer
.

Previous neoadjuvant concurrent radiotherapy and chemotherapy can increase the rate of complete local pathological remission (pCR), but the risk of distant metastasis is still high
.

Can you find a better solution that simultaneously controls local progress and distant metastasis? Immunotherapy gives amazing answers
.

Professor Guochun Cao shared that the neoadjuvant therapy of immunization combination emerged in this year's ASCO conference
.

From the existing research, the pCR rate of neoadjuvant therapy combined with immunity is close to 40%, and it does not increase the difficulty of surgery
.

Therefore, the neoadjuvant treatment of immune combination is more favored by surgeons
.

In addition, for the neoadjuvant treatment plan of immunotherapy combined with chemotherapy, Professor Cao Guochun believes that the combination of treatment plan, medication order and medication cycle are all worthy of further exploration by researchers to provide patients with neoadjuvant therapy with better curative effect
.

To promote MDT, the director of Bo Zhongjia provides better diagnosis and treatment for patients with esophageal cancer.
Multidisciplinary diagnosis and treatment (MDT) is a favorable guarantee for the treatment of esophageal cancer
.

Professor Cao Guochun said that MDT brings together experts from many departments such as surgery, radiotherapy, and internal medicine to provide patients with personalized and standardized diagnosis and treatment plans based on their own conditions
.

Therefore, we should implement the MDT model, boast the strengths of the public, and provide patients with scientific and effective diagnosis and treatment plans, reduce the time and cost of diagnosis and treatment, and avoid potential diagnosis and treatment risks
.

In addition, due to the increased availability of PD-1/PD-L1 monoclonal antibodies, the number of users of PD-1/PD-L1 monoclonal antibodies is gradually increasing, and adverse reactions will follow
.

Professor Cao Guochun called for the standardized use of PD-1/PD-L1 monoclonal antibodies, and hoped that the cardiology, respiratory, and gastroenterology departments would jointly establish an immunotoxic side reaction MDT to provide patients with more standardized and timely treatment of side effects in immunotherapy
.

References: 1.
https://gco.
iarc.
fr/2, Guidelines for Diagnosis and Treatment of Esophageal Cancer (2018 Edition) [J].
Chinese Journal of Digestive Diseases and Imaging (Electronic Edition), 2019, 9(04): 158-192.
3 , Sun JM, Shen L, Shah MA, et al.
Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.
Lancet.
2021;398 (10302):759-771.
4, Li Z, Sun Y, Ye F, et al.
First-Line Pembrolizumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Esophageal Cancer: China Subgroup Analysis of KEYNOTE-590.
Journal of Clinical Oncology 39, no .
15_suppl (May 20, 2021) 4049-4049.