Current Status of Checkpoint Inhibitors in the Treatment of Esophageal and Gastric Tumors – Overview of Studies

Česká verzia

Authors: David Vrána; Marcel Matzenauer; Bohuslav Melichar
Authors place of work: Onkologická klinika LF UP a FN Olomouc
Published in the journal: Klin Onkol 2018; 31(1): 35-39
Category: Přehled
doi: https://doi.org/10.14735/amko201835

Summary

Background:
Despite recent advances in oncological treatment, gastric and esophageal cancer remain neoplastic diseases with poor prognoses. The only potential curative treatment is surgical resection with adjuvant or neoadjuvant chemotherapy/chemoradiotherapy. Targeted therapy of metastatic disease unfortunately does not provide better outcomes than for other tumor types, with the exception of trastuzumab and ramucirumab, which have relatively limited efficacy. Immunotherapy is a rapidly evolving treatment that has influenced the treatment guidelines for many tumors. In the present review, we summarize clinical trials of checkpoint inhibitors for the treatment of gastric and esophageal cancer, including published results and the perspectives of ongoing trials.

Results and Discussion:
Gastric and esophageal cancer are tumors with high mutation loads that have attracted considerable attention since the beginning of interest in immunotherapy. Phase I clinical trials (Keynote 012, Javelin, KEYNOTE 028) have demonstrated efficacy and acceptable toxicity. These studies were followed by phase II clinical trials (KEYNOTE 059, CheckMate 032, JapicCTI-No.142422), which showed about a 10–30% overall tumor response rate and confirmed the predictive role of PD-L1 expression. Ongoing phase III clinical trials (CheckMate 648, KEYNOTE 181, KEYNOTE 590, CheckMate 577) should finally confirm whether checkpoint inhibitors have a role to play in a palliative and adjuvant setting.

Conclusion:
Checkpoint inhibitors are perspective treatment modalities for gastric and esophageal tumors.

Key words:
stomach neoplasms – esophageal neoplasms – immunotherapy

Submitted:
19. 9. 2017

Accepted:
22. 10. 2017

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Zdroje

1. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376 (9742): 687–697. doi: 10.1016/S0140-6736 (10) 61121-X.

2. Wilke H, Muro K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; 15 (11): 1224–1235. doi: 10.1016/S1470-2045 (14) 70420-6.

3. Dutton SJ, Ferry DR, Blazeby JM et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 2014; 15 (8): 894–904. doi: 10.1016/S1470-2045 (14) 70024-5.

4. Alexandrov LB, Nik-Zainal S, Wedge DC et al. Signatures of mutational processes in human cancer. Nature 2013; 500 (7463): 415–421. doi: 10.1038/nature12477.

5. Rizvi NA, Hellmann MD, Snyder A et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348 (6230): 124–128. doi: 10.1126/science.aaa1348.

6. Champiat S, Dercle L, Ammari S et al. Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res 2017; 23 (8): 1920–1928. doi: 10.1158/1078-0432.CCR-16-1741.

7. Toomey PG, Vohra NA, Ghansah T et al. Immunotherapy for gastrointestinal malignancies. Cancer control 2013; 20 (1): 32–42. doi: 10.1177/107327481302000106.

8. Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1. J Gastrointest Oncol 2016; 7 (5): 771–788. doi: 10.21037/jgo.2016.08.06.

9. 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. doi: 10.1016/S1470-2045 (16) 00175-3.

10. Chung HC, Arkenau HT, Wyrwicz L et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced gastric or gastroesophageal junction cancer from JAVELIN solid tumor phase Ib trial: Analysis of safety and clinical activity. J Clin Oncol 2016; 34 (Suppl 15): abstr. 4009.

11. Fuchs CS, Doi T, Jang RW et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 2017; 35 (Suppl 15): abstr. 4003.

12. 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 (Suppl 15): abstr. 4012.

13. Janjigian YY, Bendell JC, Calvo E et al. CheckMate-032: Phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol 2016; 34 (Suppl 15): abstr. 4010.

14. Kang YK, Satoh T, Ryu MH et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastroesophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol 2017; 35 (Suppl 4): abstr. 2.

15. Perioperative chemo and pembrolizumab in gastric cancer. ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/record/NCT02918162.

16. Doi T, Piha-Paul SA, Jalal SI et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). J Clin Oncol 2016; 34: (Suppl 4): abstr. 7.

17. 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. doi: 10.1016/S1470-2045 (17) 30181-X.

18. An investigational immuno-therapy study of nivolumab or placebo in patients with resected esophageal or gastroesophageal junction cancer (CheckMate 577). ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/record/NCT02743494.

19. Adjuvant durvalumab for esophageal cancer. ClinicalTrials.gov. [online]. Bethesda (MD): National Library of Medicine (US). Available from: https: //clinicaltrials.gov/ct2/show/NCT02520453.

20. PDL-1 targeting in resectable oesophageal cancer (PERFECT). ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/record/NCT03087864.

21. Pembrolizumab with locally delivered radiation therapy for the treatment of metastatic esophageal cancers. ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT02642809.

22. Demaria S, Ng B, Devitt ML et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58 (3): 862–870. doi: 10.1016/j.ijrobp.2003.09.012.

23. First-line esophageal carcinoma study with chemo vs. chemo plus pembrolizumab (MK-3475-590/KEYNOTE-590). ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT03189719.

24. Phase II trial of pembrolizumab with trastuzumab and chemotherapy in advanced HER2 positive esophagogastric (EG) cancer. ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/record/NCT02954536.

25. Study of pembrolizumab (MK-3475) versus investigator‘s choice standard therapy for participants with advanced esophageal/esophagogastric junction carcinoma that progressed after first-line therapy (MK-3475-181/KEYNOTE-181). ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT02564263.

26. A study to evaluate efficacy in subjects with esophageal cancer treated with nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin (CheckMate 648). ClinicalTrials.gov. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT03143153.