Esophageal squamous cell carcinoma

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Travis Zack, MD, PhD
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Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens that were tested in unselected populations.

44 regimens on this page
64 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

NCCN

Neoadjuvant induction therapy

Cisplatin & Etoposide (EP)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Boonstra et al. 2011 1989-1996 Phase 3 (E-esc) Surgery alone Seems to have superior OS (primary endpoint)
Median OS: 16 vs 12 mo
(HR 0.71, 95% CI 0.51-0.98)

Chemotherapy

21-day cycle for 2 to 4 cycles

Subsequent treatment

References

  1. Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. link to original article contains dosing details in manuscript link to PMC article PubMed

Cisplatin & Fluorouracil (CF)

CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol (Cisplatin)

Regimen variant #1, 80/4000, 5 day 5-FU infusion

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ando et al. 2011 (JCOG 9907) 2000-2006 Phase 3 (E-switch-ic) Adjuvant CF Seems to have superior OS (secondary endpoint)
OS60: 55% vs 43%
(HR 0.73, 95% CI 0.54-0.99)

Might have superior PFS (primary endpoint)

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 100/5000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ancona et al. 2001 (CNR-012809) 1992-1997 Phase 3 (E-esc) Surgery alone Did not meet primary endpoint of OS

Note: it is not entirely clear from Ancona et al. 2001 whether this was a 96-hour or 120-hour infusion; there was option to proceed after the 2nd cycle. This is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment

  • Surgery, performed 3 to 4 weeks after the last cycle of chemotherapy

References

  1. CNR-012809: Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, Bonavina L, Peracchia A. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001 Jun 1;91(11):2165-74. link to original article contains partial protocol PubMed NCT00002897
  2. JCOG 9907: Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. link to original article contains dosing details in manuscript PubMed NCT00190554

Cisplatin & Paclitaxel

Regimen variant #1, 2 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tang et al. 2023 (CMISG1701) 2017-01-01 to 2019-12-31 Randomized (C) Cisplatin, Paclitaxel, RT Did not meet primary endpoint of OS36

Note: the CT.gov record reports a paclitaxel dose of 135 mg/m2, whereas the manuscript reports 175 mg/m2. The authors have been contacted to resolve this discrepancy.

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment


Regimen variant #2, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (HCHTOG1909) 2020-ongoing Phase 3 (C) Cisplatin, Paclitaxel, Toripalimab TBD if different primary endpoint of DFS

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

References

  1. CMISG1701: Tang H, Wang H, Fang Y, Zhu JY, Yin J, Shen YX, Zeng ZC, Jiang DX, Li WF, Hou YY, Du M, Lian CH, Zhao Q, Jiang HJ, Gong L, Li ZG, Liu J, Xie DY, Chen C, Zheng B, Chen KN, Dai L, Liao YD, Li K, Li HC, Zhao NQ, Tan LJ. Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial. Ann Oncol. 2023 Feb;34(2):163-172. Epub 2022 Nov 15. link to original article contains dosing details in manuscript PubMed NCT03001596
  2. HCHTOG1909: Contains dosing details on CT.gov NCT04280822

Neoadjuvant chemoradiotherapy

Note: while these regimens are listed as neoadjuvant (pre-operative), in some cases they are also used as definitive therapy in patients that are not surgical candidates.

Cisplatin, Vinorelbine, RT

Cisplatin, Vinorelbine, RT: Cisplatin, Vinorelbine, Radiation Therapy

Regimen variant #1, standard cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2018 (NEOCRTEC5010) 2007-2014 Phase 3 (E-esc) No neoadjuvant therapy Seems to have superior OS1 (primary endpoint)
OS60: 59.9% vs 49.1%
(HR 0.74, 95% CI 0.57-0.97)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 (20 fractions, for a total dose of 4000 cGy)

4-week course

Subsequent treatment


Regimen variant #2, split-dose cisplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2018 (NEOCRTEC5010) 2007-2014 Phase 3 (E-esc) No neoadjuvant therapy Seems to have superior OS1 (primary endpoint)
OS60: 59.9% vs 49.1%
(HR 0.74, 95% CI 0.57-0.97)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26 (20 fractions, for a total dose of 4000 cGy)

4-week course

Subsequent treatment

References

  1. NEOCRTEC5010: Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. Epub 2018 Aug 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01216527
    1. Update: Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J. Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg. 2021 Aug 1;156(8):721-729. link to original article link to PMC article PubMed

Fluorouracil, Oxaliplatin, RT

Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, Radiation Therapy

Regimen variant #1, 4500 cGy

Study Dates of enrollment Evidence
Lorenzen et al. 2008 2003-2005 Phase 1/2

Note: Patients had 100% squamous cell etiology, 65% poor differentiated or undifferentiated

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)

5-week course

Subsequent treatment

  • Surgery, 4 to 6 weeks after finishing chemoradiation

References

  1. Lorenzen S, Brücher B, Zimmermann F, Geinitz H, Riera J, Schuster T, Roethling N, Höfler H, Ott K, Peschel C, Siewert JR, Molls M, Lordick F. Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer. 2008 Oct 7;99(7):1020-6. Epub 2008 Sep 16. link to original article contains dosing details in manuscript link to PMC article PubMed

Adjuvant therapy

Cisplatin & Fluorouracil (CF)

CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ando et al. 2003 (JCOG 9204) 1992-1997 Phase 3 (E-esc) Observation Seems to have superior DFS
Ando et al. 2011 (JCOG 9907) 2000-2006 Phase 3 (C) Neoadjuvant CF Seems to have inferior OS

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. JCOG 9204: Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, Takiyama W, Watanabe H, Isono K, Aoyama N, Makuuchi H, Tanaka O, Yamana H, Ikeuchi S, Kabuto T, Nagai K, Shimada Y, Kinjo Y, Fukuda H; JCOG. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204. J Clin Oncol. 2003 Dec 15;21(24):4592-6. link to original article contains dosing details in manuscript PubMed
  2. JCOG 9907: Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012 Jan;19(1):68-74. Epub 2011 Aug 31. link to original article contains dosing details in manuscript PubMed NCT00190554

Definitive therapy

Capecitabine & Cisplatin (CX) & RT

CX & RT: Cisplatin, Xeloda (Capecitabine), Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (KUNLUN) 2020-2025 Phase 3 (C) 1a. CX, Durvalumab, RT
1b. CF, Durvalumab, RT
To be determined

Chemotherapy

Radiotherapy

References

  1. KUNLUN: NCT04550260

Cisplatin, Docetaxel, RT

DC & RT: Docetaxel, Cisplatin, Radiation Therapy

Regimen variant #1, 80/60 x 2

Study Dates of enrollment Evidence
Li et al. 2009 2004-2007 Phase 2

Note: Patients had 5% gastroesophageal junction site. 44% of patients had stage IV disease.

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 10 mg IV or PO once per day on days -1 & 21, then once per day on days 1 & 22; 30 minutes prior to docetaxel, then once per day on days 2 & 23
  • Diphenhydramine (Benadryl) 40 mg IV once per day on days 1 & 22, prior to chemotherapy
  • Cimetidine (Tagamet) 40 mg IV once per day on days 1 & 22, prior to chemotherapy
  • Granisetron 2 mg IV once per day on days 1 & 22, prior to chemotherapy
  • 1.5 to 2 liters fluids prior to cisplatin

Radiotherapy

  • Concurrent radiation therapy 1.8 to 200 cGy fractions, to start within 24 hours of the start of chemotherapy
    • Patients with stage I to III disease received a total dose of 60 to 6400 cGy over 4 to 6 weeks
    • Patients with stage IV disease (lymph node only) received a total dose of 50 to 5600 cGy

Note, dose reductions were permitted, see article for specifications One course

References

  1. Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010 Apr;23(3):253-9. Epub 2009 Aug 28. link to original article contains dosing details in manuscript PubMed

Cisplatin & Fluorouracil (CF) & RT

CF & RT: Cisplatin, Fluorouracil, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (KUNLUN) 2020-2025 Phase 3 (C) 1a. CX, Durvalumab, RT
1b. CF, Durvalumab, RT
To be determined

Chemotherapy

Radiotherapy

References

  1. KUNLUN: NCT04550260

Cisplatin, Paclitaxel, RT

TP & RT: Taxol (Paclitaxel), Platinol (Cisplatin), Radiation Therapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wu et al. 2018 (Shixiu - 1) 2007-2015 Phase 3 (C) Cisplatin, Paclitaxel, Erlotinib, ENI Seems to have inferior OS

Chemotherapy

Radiotherapy


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (RATIONALE 311) 2019-ongoing Phase 3 (C) Cisplatin, Paclitaxel, Tislelizumab, RT To be determined

Chemotherapy

Radiotherapy

6-week course

References

  1. Shixiu - 1: Wu SX, Wang LH, Luo HL, Xie CY, Zhang XB, Hu W, Zheng AP, Li DJ, Zhang HY, Xie CH, Lian XL, Du DX, Chen M, Bian XH, Tan BX, Jiang H, Zhang HB, Wang JH, Jing Z, Xia B, Zhang N, Zhang P, Li WF, Zhao FJ, Tian ZF, Liu H, Huang KW, Hu J, Xie RF, Du L, Li G. Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer. Eur J Cancer. 2018 Apr;93:99-107. Epub 2018 Mar 20. link to original article contains dosing details in abstract PubMed NCT00686114
    1. Update: Xie C, Jing Z, Luo H, Jiang W, Ma L, Hu W, Zheng A, Li D, Ding L, Zhang H, Xie C, Lian X, Du D, Chen M, Bian X, Tan B, Xia B, Xie R, Liu Q, Wang L, Wu S. Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial. Br J Cancer. 2020 Nov;123(11):1616-1624. Epub 2020 Sep 22. link to original article link to PMC article PubMed
  2. KEYSTONE-002: NCT04807673
  3. RATIONALE 311: contains dosing details on CT.gov NCT03957590
  4. SHR-1210-III-323: NCT04426955

Fluorouracil, Mitomycin, RT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. (ECOG E1282) 1982-07 to 1988-07 Randomized (E-esc) RT Seems to have superior OS
Median OS: 14.8 vs 9.2 mo

Chemotherapy

Radiotherapy

References

  1. ECOG E1282: Smith TJ, Ryan LM, Douglass HO Jr, Haller DG, Dayal Y, Kirkwood J, Tormey DC, Schutt AJ, Hinson J, Sischy B. Combined chemoradiotherapy vs radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):269-76. link to original article PubMed

Fluorouracil, Paclitaxel, RT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chen et al. 2019 (ESO-Shanghai1) 2012-2015 Phase 3 (E-switch-ic) Cisplatin, Flourouracil, RT Did not meet primary endpoint of OS36

Note: The total dose of 5-FU for this portion of the protocol is unclear in the manuscript; dosing here is as clarified by the authors.

Eligibility criteria

  • Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated.

Chemotherapy

  • Fluorouracil (5-FU) 75 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22, 29 (total dose: 1800 mg/m2)
  • Paclitaxel (Taxol) 50 mg/m2 IV once per day on days 1, 8, 15, 22, 29

Radiotherapy

  • Concurrent radiation therapy, 180 cGy fractions x 34 fractions, for a total dose of 6120 cGy

7-week course

Subsequent treatment

References

  1. ESO-Shanghai1: Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01591135

S-1 & RT

S-1 & RT: S-1 & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2023 (3JECROG-P01) 2017-03 to 2020-04 Phase 3 (E-esc) RT x 6000 cGy Seems to have superior OS (primary endpoint)
OS24: 46.2% vs 33.9%

Eligibility criteria

  • 70 years old or older

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
    • Less than 1.25 m2: 40 mg PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38
    • Between 1.25 m2 and 1.5 m2: 50 mg PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38
    • 1.5 m2 or more: 60 mg PO twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38

Radiotherapy

  • External beam radiotherapy SIB 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (28 fractions for a total dose of 5040 cGy)

6-week course

Subsequent treatment

  • S-1 consolidation

References

  1. 3JECROG-P01: Wang X, Han W, Zhang W, Wang X, Ge X, Lin Y, Zhou H, Hu M, Wang W, Liu K, Lu J, Qie S, Zhang J, Deng W, Wang L, Han C, Li M, Zhang K, Li L, Wang Q, Shi H, Yu Z, Zhao Y, Sun X, Shi Y, Pang Q, Zhou Z, Liang J, Chen D, Feng Q, Bi N, Zhang T, Deng L, Wang W, Liu W, Wang J, Zhai Y, Wang J, Chen W, Chen J, Xiao Z; Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG). Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2312625. link to original article link to PMC article contains partial dosing details in manuscript PubMed NCT02979691

Consolidation after definitive therapy

Fluorouracil & Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chen et al. 2019 (ESO-Shanghai1) 2012-2015 Phase 3 (E-switch-ic) Cisplatin & Flourouracil Did not meet primary endpoint of OS36

Eligibility criteria

  • Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated

Preceding treatment

Chemotherapy

28-day cycle for 2 cycles

References

  1. ESO-Shanghai1: Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01591135

Metastatic or locally advanced disease, first-line

Capecitabine & Cisplatin (CX)

CX: Cisplatin & Xeloda (Capecitabine)

Regimen variant #1, 60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of cisplatin dosing.

Chemotherapy

21-day cycles


Regimen variant #2, 80

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of cisplatin dosing.

Chemotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Capecitabine & Cisplatin (CX) & Tislelizumab

CX & Tislelizumab: Cisplatin, Xeloda (Capecitabine), Tislelizumab

Regimen variant #1, 60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the lower bound of cisplatin dosing.

Chemotherapy

Immunotherapy

21-day cycles


Regimen variant #2, 80

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the upper bound of cisplatin dosing.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

CapeOx

CapeOx: Capecitabine & Oxaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Capecitabine & Oxaliplatin (CapeOx) & Tislelizumab

CapeOx & Tislelizumab: Capecitabine, Oxaliplatin, Tislelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Cisplatin & Docetaxel (DC)

DC: Docetaxel, Cisplatin
TC: Taxotere (Docetaxel), Cisplatin

Regimen

Study Dates of enrollment Evidence
Kim et al. 2009 2004-2007 Phase 2

Note: 5% of patients had ECOG PS of 2.

Chemotherapy

Supportive therapy

21-day cycle for up to 6 cycles

References

  1. Kim JY, Do YR, Park KU, Kim MK, Lee KH, Bae SH, Ryoo HM, Baek JH, Song HS. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010 May;66(1):31-6. Epub 2009 Sep 18. link to original article contains dosing details in manuscript PubMed

Cisplatin & Fluorouracil (CF)

CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol

Regimen variant #1, 60/3750

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of cisplatin AND 5-FU.

Chemotherapy

21-day cycles


Regimen variant #2, 80/4000, 4-day infusion, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moehler et al. 2019 (POWER) 2012-2015 Phase 3 (C) CFP Did not meet primary endpoint of OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the dosing after a mid-protocol amendment.

Chemotherapy

28-day cycles


Regimen variant #3, 80/4000, 5-day infusion, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Doki et al. 2022 (CheckMate 648) 2017-2019 Phase 3 (C) 1. CF & Nivolumab
2. Ipilimumab & Nivolumab
Inferior OS1
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

1Reported efficacy for CheckMate 648 is for the overall randomized population.
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of cisplatin AND 5-FU in RATIONALE-306.

Chemotherapy

28-day cycles


Regimen variant #4, 100/5000 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lorenzen et al. 2009 2004-2006 Randomized Phase 2 (C) CF & Cetuximab Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. 87% of patients had metastatic disease. No patients with ECOG PS greater than 1.

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 5000 mg/m2)

Supportive therapy

29-day cycle for up to 6 cycles

References

  1. Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains dosing details in manuscript PubMed
  2. POWER: Moehler M, Maderer A, Thuss-Patience PC, Brenner B, Meiler J, Ettrich TJ, Hofheinz RD, Al-Batran SE, Vogel A, Mueller L, Lutz MP, Lordick F, Alsina M, Borchert K, Greil R, Eisterer W, Schad A, Slotta-Huspenina J, Van Cutsem E, Lorenzen S. Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER). Ann Oncol. 2020 Feb;31(2):228-235. Epub 2019 Dec 16. link to original article contains dosing details in manuscript PubMed NCT01627379
  3. CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains dosing details in manuscript PubMed NCT03143153
  4. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Cisplatin & Fluorouracil (CF) & Cetuximab

CF-C: Cisplatin, Fluorouracil, Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lorenzen et al. 2009 2004-2006 Randomized Phase 2 (E-esc) CF Did not meet primary endpoint of ORR

Note: 87% patients had metastatic disease. No patients with ECOG PS greater than 1.

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22
    • Cycles 2 to 6: 250 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive therapy

29-day cycle for up to 6 cycles

References

  1. Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains dosing details in manuscript PubMed

Cisplatin & Fluorouracil (CF) & Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Doki et al. 2022 (CheckMate 648) 2017-2019 Phase 3 (E-RT-esc) 1. CF Superior OS1 (co-primary endpoint)
Median OS: 13.2 vs 10.7 mo
(HR 0.74, 99.1% CI 0.58-0.96)
2. Ipilimumab & Nivolumab Not reported

1Reported efficacy is for the overall randomized population.

Chemotherapy

Immunotherapy

28-day cycles

References

  1. CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains dosing details in manuscript PubMed NCT03143153

Cisplatin & Fluorouracil (CF) & Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (LEAP-014) 2021-ongoing Phase 3 (C) 1a. FP, Lenvatinib, Pembrolizumab
1b. TP, Lenvatinib, Pembrolizumab
1c. mFOLFOX6, Lenvatinib, Pembrolizumab
TBD if different co-primary endpoints of PFS/OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. There is no doubt that the 5-FU is given as a continuous infusion, but these details are not provided on CT.gov.

Chemotherapy

Immunotherapy

42-day cycle for up to 18 cycles (2 years)

References

  1. LEAP-014: contains dosing details on CT.gov NCT04949256

Cisplatin & Fluorouracil (CF) & Sintilimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2022 (ORIENT-15) 2018-2021 Phase 3 (E-esc) 1a. CF
1b. Cisplatin & Paclitaxel
Superior OS1 (co-primary endpoint)
Median OS: 17.2 vs 13.6 mo
(HR 0.64, 95% CI 0.48-0.85)

1Reported efficacy is for the population with tumors having CPS of 10 or more.

Chemotherapy

  • Cisplatin (Platinol) as follows:
    • Cycles 1 to 6: 75 mg/m2 IV once on day 1
  • Fluorouracil (5-FU) as follows:
    • Cycles 1 to 6: 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)

Immunotherapy

  • Sintilimab (Tyvyt) by the following weight-based criteria:
    • Less than 60 kg: 3 mg/kg IV once on day 1
    • 60 kg or more: 200 mg IV once on day 1

28-day cycle for up to 26 cycles (2 years)

References

  1. ORIENT-15: Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03748134

Cisplatin & Fluorouracil (CF) & Tislelizumab

CF & Tislelizumab: Cisplatin, Fluorouracil, Tislelizumab

Regimen variant #1, 60/3750

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the lower bound of cisplatin AND 5-FU dosing.

Chemotherapy

Immunotherapy

21-day cycles


Regimen variant #2, 80/4000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the upper bound of cisplatin AND 5-FU dosing.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Cisplatin & Paclitaxel

Regimen variant #1, 60/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of cisplatin dosing.

Chemotherapy

21-day cycles


Regimen variant #2, 75/175 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Luo et al. 2021 (ESCORT-1st) 2018-2020 Phase 3 (C) Cisplatin, Paclitaxel, Camrelizumab Inferior OS
Wang et al. 2022 (JUPITER-06) 2019-01-28 to 2020-11-30 Phase 3 (C) Cisplatin, Paclitaxel, Toripalimab Inferior OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #3, 75/175; indefinite

Study Dates of enrollment Evidence
Zhang et al. 2008 2001-07 to 2006-04 Phase 2

Note: Patients had 100% squamous cell carcinoma with advanced or metastatic disease. 18% ECOG PS of 2.

Chemotherapy

21-day cycles


Regimen variant #4, 80/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of cisplatin dosing.

Chemotherapy

21-day cycles

References

  1. Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29-33. link to original article contains dosing details in abstract PubMed
  2. ESCORT-1st: Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. link to original article contains dosing details in abstract link to PMC article PubMed NCT03691090
  3. JUPITER-06: Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, Zhang Y, Zhang Y, Chen X, Dai G, He J, Li J, Li G, Liu Y, Liu Z, Yuan X, Zhang J, Fu Z, He Y, Ju F, Liu Z, Tang P, Wang T, Wang W, Zhang J, Luo X, Tang X, May R, Feng H, Yao S, Keegan P, Xu RH, Wang F. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 2022 Mar 14;40(3):277-288.e3. Epub 2022 Mar 3. link to original article contains dosing details in manuscript PubMed NCT03829969
  4. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442
  5. SKYSCRAPER-08: NCT04540211

Cisplatin, Paclitaxel, Camrelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Luo et al. 2021 (ESCORT-1st) 2018-2020 Phase 3 (E-esc) Cisplatin & Paclitaxel Superior OS (co-primary endpoint)
Median OS: 15.3 vs 12 mo
(HR 0.70, 95% CI 0.56-0.88)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. ESCORT-1st: Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. link to original article contains dosing details in abstract link to PMC article PubMed NCT03691090

Cisplatin, Paclitaxel, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (LEAP-014) 2021-ongoing Phase 3 (C) 1a. FP, Lenvatinib, Pembrolizumab
1b. TP, Lenvatinib, Pembrolizumab
1c. mFOLFOX6, Lenvatinib, Pembrolizumab
TBD if different co-primary endpoints of PFS/OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Immunotherapy

42-day cycle for up to 18 cycles (2 years)

References

  1. LEAP-014: contains dosing details on CT.gov NCT04949256

Cisplatin, Paclitaxel, Sintilimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2022 (ORIENT-15) 2018-2021 Phase 3 (E-esc) 1a. CF
1b. Cisplatin & Paclitaxel
Superior OS1 (co-primary endpoint)
Median OS: 17.2 vs 13.6 mo
(HR 0.64, 95% CI 0.48-0.85)

1Reported efficacy is for the population having tumors with CPS of 10 or more.

Chemotherapy

  • Cisplatin (Platinol) as follows:
    • Cycles 1 to 6: 75 mg/m2 IV once on day 1
  • Paclitaxel (Taxol) as follows:
    • Cycle 1: 87.5 mg/m2 IV once per day on days 1 & 8
    • Cycles 2 to 6: 175 mg/m2/day IV once on day 1

Immunotherapy

  • Sintilimab (Tyvyt) by the following weight-based criteria:
    • Less than 60 kg: 3 mg/kg IV once on day 1
    • 60 kg or more: 200 mg IV once on day 1

28-day cycle for up to 26 cycles (2 years)

References

  1. ORIENT-15: Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03748134

Cisplatin, Paclitaxel, Tislelizumab

Regimen variant #1, 60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the lower bound of cisplatin dosing.

Chemotherapy

Immunotherapy

21-day cycles


Regimen variant #2, 80

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the upper bound of cisplatin dosing.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Cisplatin, Paclitaxel, Toripalimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2022 (JUPITER-06) 2019-01-28 to 2020-11-30 Phase 3 (E-esc) Cisplatin & Paclitaxel Superior OS (co-primary endpoint)
Median OS: 17 vs 11 mo
(HR 0.58, 95% CI 0.43-0.78)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. JUPITER-06: Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, Zhang Y, Zhang Y, Chen X, Dai G, He J, Li J, Li G, Liu Y, Liu Z, Yuan X, Zhang J, Fu Z, He Y, Ju F, Liu Z, Tang P, Wang T, Wang W, Zhang J, Luo X, Tang X, May R, Feng H, Yao S, Keegan P, Xu RH, Wang F. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 2022 Mar 14;40(3):277-288.e3. Epub 2022 Mar 3. link to original article contains dosing details in manuscript PubMed NCT03829969

Etoposide monotherapy

Regimen

Study Dates of enrollment Evidence
Harstrick et al. 1992 1989-02 to NR Phase 2

Note: this is higher than the dose usually employed in modern settings. Patients had metastatic 100% squamous cell carcinoma of the esophagus, with ECOG PS range 1-2.

Chemotherapy

21-day cycles

References

  1. Harstrick A, Bokemeyer C, Preusser P, Köhne-Wömpner CH, Meyer HJ, Stahl M, Knipp H, Schmoll HJ, Wilke H. Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus. Cancer Chemother Pharmacol. 1992;29(4):321-2. link to original article contains dosing details in abstract PubMed

FUOX

FUOX: 5-FU & OXaliplatin

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the lower bound of 5-FU dosing.

Chemotherapy

21-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This was the upper bound of 5-FU dosing.

Chemotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Fluorouracil & Oxaliplatin (FUOX) & Tislelizumab

FUOX & Tislelizumab: 5-FU, OXaliplatin, Tislelizumab

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the lower bound of 5-FU dosing.

Chemotherapy

Immunotherapy

21-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Note: this was the upper bound of 5-FU dosing.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

mFOLFOX6 & Pembrolizumab

mFOLFOX6 & Pembrolizumab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (LEAP-014) 2021-ongoing Phase 3 (C) 1a. FP, Lenvatinib, Pembrolizumab
1b. TP, Lenvatinib, Pembrolizumab
1c. mFOLFOX6, Lenvatinib, Pembrolizumab
TBD if different co-primary endpoints of PFS/OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

  • Fluorouracil (5-FU) as follows:
    • Cycles 1 up to 2: 400 mg/m2 IV bolus once per day on days 1, 15, 29, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 8400 mg/m2)
  • Leucovorin (Folinic acid) as follows:
    • Cycles 1 up to 2: 400 mg/m2 IV once per day on days 1, 15, 29
  • Oxaliplatin (Eloxatin) as follows:
    • Cycles 1 up to 2: 85 mg/m2 IV once per day on days 1, 15, 29

Immunotherapy

42-day cycle for up to 18 cycles (2 years)

References

  1. LEAP-014: contains dosing details on CT.gov NCT04949256

Ipilimumab & Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Doki et al. 2022 (CheckMate 648) 2017-2019 Phase 3 (E-RT-switch-ooc) 1. CF Superior OS (co-primary endpoint)
Median OS: 12.7 vs 10.7 mo
(HR 0.78, 98.2% CI 0.62-0.98)
2. CF & Nivolumab Not compared

Immunotherapy

42-day cycle for up to 17 cycles (2 years)

References

  1. CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains dosing details in manuscript PubMed NCT03143153

Oxaliplatin & Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (C) 1a. CF & Tislelizumab
1b. CX & Tislelizumab
1c. Cisplatin, Paclitaxel, Tislelizumab
1d. FUOX & Tislelizumab
1e. CapeOx & Tislelizumab
1f. Oxaliplatin, Paclitaxel, Tislelizumab
Inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Oxaliplatin, Paclitaxel, Tislelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Xu et al. 2023 (RATIONALE-306) 2018-12-12 to 2020-11-24 Phase 3 (E-esc) 1a. CF
1b. CX
1c. Cisplatin & Paclitaxel
1d. FUOX
1e. CapeOx
1f. Oxaliplatin & Paclitaxel
Superior OS (primary endpoint)
Median OS: 17.2 vs 10.6 mo
(sHR 0.66, 95% CI 0.54-0.80)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE-306: Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, Park SR, Ping L, Jiang Y, Zhang J, Wu X, Yao Y, Shen L, Kojima T, Gotovkin E, Ishihara R, Wyrwicz L, Van Cutsem E, Jimenez-Fonseca P, Lin CY, Wang L, Shi J, Li L, Yoon HH. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023 May;24(5):483-495. Epub 2023 Apr 17. link to original article contains dosing details in abstract PubMed NCT0378442

Metastatic or locally advanced disease, subsequent lines of therapy

Camrelizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Huang et al. 2020 (ESCORT) 2017-05-10 to 2018-07-24 Phase 3 (E-switch-ooc) 1a. Docetaxel
1b. Irinotecan
Superior OS (primary endpoint)
Median OS: 8 vs 6 mo
(HR 0.71, 95% CI 0.57-0.87)

Immunotherapy

14-day cycles

References

  1. ESCORT: Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Zeng M, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z, Shen L, Shu Y, Zhang T, Yang Q, Zou J; ESCORT Study Group. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020 Jun;21(6):832-842. Epub 2020 May 13. link to original article contains dosing details in abstract PubMed NCT03099382

Docetaxel monotherapy

Regimen variant #1, 70 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (C) Tislelizumab Inferior OS

Note: this is Japanese dosing.

Prior treatment criteria

  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Chemotherapy

21-day cycles


Regimen variant #2, 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase 3 (C) Pembrolizumab Inferior OS1
Kato et al. 2019 (ATTRACTION-3) 2016-01-07 to 2017-05-25 Phase 3 (C) Nivolumab Seems to have inferior OS
Huang et al. 2020 (ESCORT) 2017-05-10 to 2018-07-24 Phase 3 (C) Camrelizumab Inferior OS
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (C) Tislelizumab Inferior OS

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.

Prior treatment criteria

  • KEYNOTE-181: One prior line of standard therapy
  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Chemotherapy

21-day cycles

References

  1. ATTRACTION-3: Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1506-1517. Epub 2019 Sep 30. link to original article contains dosing details in abstract PubMed NCT02569242
  2. ESCORT: Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Zeng M, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z, Shen L, Shu Y, Zhang T, Yang Q, Zou J; ESCORT Study Group. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020 Jun;21(6):832-842. Epub 2020 May 13. link to original article contains dosing details in abstract PubMed NCT03099382
  3. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263
  4. RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03430843

Irinotecan monotherapy

Regimen variant #1, 14-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase 3 (C) Pembrolizumab Inferior OS1
Huang et al. 2020 (ESCORT) 2017-05-10 to 2018-07-24 Phase 3 (C) Camrelizumab Inferior OS

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.

Prior treatment criteria

  • One prior line of standard therapy

Chemotherapy

14-day cycles


Regimen variant #2, 21-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (C) Tislelizumab Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Prior treatment criteria

  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Chemotherapy

21-day cycles

References

  1. ESCORT: Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Zeng M, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z, Shen L, Shu Y, Zhang T, Yang Q, Zou J; ESCORT Study Group. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020 Jun;21(6):832-842. Epub 2020 May 13. link to original article contains dosing details in abstract PubMed NCT03099382
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263
  3. RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03430843

Nivolumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3) 2016-01-07 to 2017-05-25 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Docetaxel
1b. Paclitaxel
Seems to have superior OS (primary endpoint)
Median OS: 11 vs 8 mo
(HR 0.77, 95% CI 0.62-0.96)

Eligibility criteria

  • Unresectable advanced or recurrent esophageal SCC regardless of PDL1 expression, ECOG 0-1, refractory or intolerance to one prior 5-FU or platinum-based chemotherapy

Immunotherapy

14-day cycles

References

  1. ATTRACTION-3: Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1506-1517. Epub 2019 Sep 30. link to original article contains dosing details in abstract PubMed NCT02569242

Paclitaxel monotherapy

Regimen variant #1, 80 mg/m2, 3 out of 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase 3 (C) Pembrolizumab Inferior OS1

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
This is the lower bound of dosing specified in KEYNOTE-181.

Prior treatment criteria

  • One prior line of standard therapy

Chemotherapy

28-day cycles


Regimen variant #2, 100 mg/m2, 3 out of 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase 3 (C) Pembrolizumab Inferior OS1

1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
This is the upper bound of dosing specified in the protocol.

Prior treatment criteria

  • One prior line of standard therapy

Chemotherapy

28-day cycles


Regimen variant #3, 100 mg/m2, 6 out of 7 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3) 2016-01-07 to 2017-05-25 Phase 3 (C) Nivolumab Seems to have inferior OS
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (C) Tislelizumab Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Prior treatment criteria

  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Chemotherapy

  • Paclitaxel (Taxol) 100 mg/m2 IV over at least 60 minutes once per day on days 1, 8, 15, 22, 29, 36

49-day cycles


Regimen variant #4, 135 mg/m2, 21-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (C) Tislelizumab Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This is the lower bound of q3wk dosing in the protocol.

Prior treatment criteria

  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Chemotherapy

21-day cycles


Regimen variant #5, 175 mg/m2, 21-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (C) Tislelizumab Inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. This is the upper bound of q3wk dosing in the protocol.

Prior treatment criteria

  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Chemotherapy

21-day cycles

References

  1. ATTRACTION-3: Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1506-1517. Epub 2019 Sep 30. link to original article contains dosing details in abstract PubMed NCT02569242
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263
  3. RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03430843

Pembrolizumab monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181) 2015-2017 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Docetaxel
1b. Irinotecan
1c. Paclitaxel
Superior OS1 (co-primary endpoint)
Median OS: 9.3 vs 6.7 mo
(HR 0.69, 95% CI, 0.52-0.93)
Shah et al. 2019 (KEYNOTE-180) 2016-2017 Phase 2 (RT)

1Reported efficacy in KEYNOTE-181 is for patients with PD-L1 combined positive score of at least 10; in all patients the experimental arm might have superior OS.
Patients in KEYNOTE-180 had 100% squamous histology.

Prior treatment criteria

  • KEYNOTE-181: One prior line of standard therapy
  • KEYNOTE-180: 2 or more lines of therapy

Biomarker eligibility criteria

  • PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-180: Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, Lordick F, Kim SB, Tajika M, Kim HT, Lockhart AC, Arkenau HT, El-Hajbi F, Gupta M, Pfeiffer P, Liu Q, Lunceford J, Kang SP, Bhagia P, Kato K. 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 Apr 1;5(4):546-550. link to original article link to PMC article PubMed NCT02559687
  2. KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263

Tislelizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shen et al. 2022 (RATIONALE 302) 2018-2020 Phase 3 (E-switch-ooc) Investigator's choice of:
1a. Docetaxel
1b. Irinotecan
1c. Paclitaxel
Superior OS (primary endpoint)
Median OS: 8.6 vs 6.3 mo
(HR 0.70, 95% CI 0.57-0.85)

Prior treatment criteria

  • RATIONALE 302: Advanced or metastatic disease with progression after first-line systemic treatment or tumor progression within 6 months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy

Immunotherapy

21-day cycles

References

  1. RATIONALE 302: Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. Epub 2022 Apr 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03430843