Progress of clinical trials for immunotherapy drugs in advanced esophageal cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LENG Xuefeng , LUO Qiyu ,  HAN Yongtao

Division of Thoracic Surgery, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, P.R.China;

Corresponding author：

HAN Yongtao, Email: hanyongt@aliyun.com

Keywords：

Esophageal cancer; immunotherapy; clinical trials; clinical guidelines; review

DOI：

10.7507/1007-4848.201908070

Video：

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Early and mid-stage esophageal cancer can achieve a particular effect through surgeries or comprehensive treatment based on surgery. Once the esophageal cancer progresses to the advanced stage, it is still lack of effective remedy for the disease, and the patient's prognosis is poor. Immunotherapy has developed rapidly in recent years, bringing dawn to patients with advanced esophageal cancer. On July 31, 2019, the US Food and Drug Administration (FDA) approved KEYTRUDA (Merck) for the treatment of esophageal squamous cell carcinoma, and it became the first milestone drug for esophageal squamous cell carcinoma. In the paper, we will review the progress of immunotherapy in the treatment of advanced esophageal cancer on the basis of current clinical researches, which might provide ideas for further studies in the immunotherapy for esophageal cancer.

Citation： LENG Xuefeng, LUO Qiyu, HAN Yongtao. Progress of clinical trials for immunotherapy drugs in advanced esophageal cancer. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2020, 27(7): 834-839. doi: 10.7507/1007-4848.201908070 Copy

1.	NCCN. National Comprehensive Cancer Network: NCCN clinical practice guidelines in oncology: esophageal and esophagogastric junction cancers, version 2, 2019. Available at: www.nccn.org/patients.
2.	Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phaseⅢKEYNOTE-181 study. J Clin Oncol, 2019, 37(4): 2.
3.	Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol, 2018, 4(5): e180013.
4.	Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26): 2509-2520.
5.	Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol, 2019, 5(4): 546-550.
6.	Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol, 2016, 17(6): 717-726.
7.	Bang YJ, Muro K, Fuchs CS, et al. KEYNOTE-059 cohort 2: safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol, 2017, 35(15): 4012-4012.
8.	Catenacci DV, Wainberg Z, Fuchs CS, et al. LBA-009KEYNOTE-059 cohort 3: safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients (pts) with PD-L1-positive advanced gastric/gastroesophageal (G/GEJ) cancer. Ann Oncol, 2017, 28(3): 153.
9.	Kato K, Shah MA, Enzinger P, et al. KEYNOTE-590: phase Ⅲ study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol, 2019, 15(10): 1057-1066.
10.	Shitara K, Ozguroglu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet, 2018, 392(10142): 123-133.
11.	Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol, 2018, 36(1): 61-67.
12.	Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol, 2017, 18(5): 631-639.
13.	Janjigian YY, Bendell J, Calvo E, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol, 2018, 36(28): 2836-2844.
14.	Bang YJ, Cho JY, Kim YH, et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res, 2017, 23(19): 5671-5678.
15.	Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 390(10111): 2461-2471.
16.	Kitagawa Y, Doki Y, Kato K, et al. Two year survival and safety update for esophageal squamous cell carcinoma treated with nivolumab (ATTRACTION-01/ONO-4538-07). Ann Oncol, 2017, 28(5): 369.
17.	Moehler MH, JanjigianYY, Adenis A, et al. CheckMate 649: A randomized, multicenter, open-label, phase Ⅲ study of nivolumab (NIVO) + ipilimumab (IPI) or nivo + chemotherapy (CTX) versus CTX alone in patients with previously untreated advanced (Adv) gastric (G) or gastroesophageal junction (GEJ) cancer. J Clin Oncol, 2018, 36(4): 213.
18.	ONO Pharmaceutical Co, Ltd. Opdivo (Nivolumab) demonstrates a significant extension in overall survival versus chemotherapy in patients with unresectable advanced or recurrent esophageal cancer in phase Ⅲ clinical study. https://www.ono.co.jp/eng/news/pdf/sm_cn190109.pdf.
19.	Bang YJ, Ruiz EY, Van Cutsem E, et al. Phase Ⅲ, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol, 2018, 29(10): 2052-2060.
20.	Moehler M, Ryu MH, Dvorkin M, et al. Maintenance avelumabversus continuation of first-line chemotherapy in gastric cancer: JAVELIN Gastric 100 study design. Future Oncol, 2019, 15(6): 567-577.

1. NCCN. National Comprehensive Cancer Network: NCCN clinical practice guidelines in oncology: esophageal and esophagogastric junction cancers, version 2, 2019. Available at: www.nccn.org/patients.
2. Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phaseⅢKEYNOTE-181 study. J Clin Oncol, 2019, 37(4): 2.
3. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol, 2018, 4(5): e180013.
4. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26): 2509-2520.
5. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol, 2019, 5(4): 546-550.
6. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol, 2016, 17(6): 717-726.
7. Bang YJ, Muro K, Fuchs CS, et al. KEYNOTE-059 cohort 2: safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol, 2017, 35(15): 4012-4012.
8. Catenacci DV, Wainberg Z, Fuchs CS, et al. LBA-009KEYNOTE-059 cohort 3: safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients (pts) with PD-L1-positive advanced gastric/gastroesophageal (G/GEJ) cancer. Ann Oncol, 2017, 28(3): 153.
9. Kato K, Shah MA, Enzinger P, et al. KEYNOTE-590: phase Ⅲ study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol, 2019, 15(10): 1057-1066.
10. Shitara K, Ozguroglu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet, 2018, 392(10142): 123-133.
11. Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol, 2018, 36(1): 61-67.
12. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol, 2017, 18(5): 631-639.
13. Janjigian YY, Bendell J, Calvo E, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol, 2018, 36(28): 2836-2844.
14. Bang YJ, Cho JY, Kim YH, et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res, 2017, 23(19): 5671-5678.
15. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 390(10111): 2461-2471.
16. Kitagawa Y, Doki Y, Kato K, et al. Two year survival and safety update for esophageal squamous cell carcinoma treated with nivolumab (ATTRACTION-01/ONO-4538-07). Ann Oncol, 2017, 28(5): 369.
17. Moehler MH, JanjigianYY, Adenis A, et al. CheckMate 649: A randomized, multicenter, open-label, phase Ⅲ study of nivolumab (NIVO) + ipilimumab (IPI) or nivo + chemotherapy (CTX) versus CTX alone in patients with previously untreated advanced (Adv) gastric (G) or gastroesophageal junction (GEJ) cancer. J Clin Oncol, 2018, 36(4): 213.
18. ONO Pharmaceutical Co, Ltd. Opdivo (Nivolumab) demonstrates a significant extension in overall survival versus chemotherapy in patients with unresectable advanced or recurrent esophageal cancer in phase Ⅲ clinical study. https://www.ono.co.jp/eng/news/pdf/sm_cn190109.pdf.
19. Bang YJ, Ruiz EY, Van Cutsem E, et al. Phase Ⅲ, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol, 2018, 29(10): 2052-2060.
20. Moehler M, Ryu MH, Dvorkin M, et al. Maintenance avelumabversus continuation of first-line chemotherapy in gastric cancer: JAVELIN Gastric 100 study design. Future Oncol, 2019, 15(6): 567-577.

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