Esophageal squamous cell carcinoma

Section editor
	Travis Zack, MD, PhD University of California San Francisco San Francisco, CA, USA LinkedIn

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.

45 regimens on this page 66 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

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Esophageal and Esophagogastric Junction Cancers.

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

• Cisplatin (Platinol) 80 mg/m² IV over 4 hours once on day 1
• Etoposide (Vepesid) 100 mg/m² IV over 2 hours once per day on days 1 & 2, then 200 mg/m² PO once per day on days 3 & 5

21-day cycle for 2 to 4 cycles

Subsequent treatment

• Surgery

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

• Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

21-day cycle for 2 cycles

Subsequent treatment

• Surgery

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

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

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

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 2 cycles

Subsequent treatment

• Surgery

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

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 3 cycles

Subsequent treatment

• Surgery

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

• Cisplatin (Platinol) 75 mg/m² IV over 3 hours once per day on days 1 & 22
• Vinorelbine (Navelbine) 25 mg/m² IV bolus once per day on days 1, 8, 22, 29

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)

6-week course

Subsequent treatment

• Surgery

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

• Cisplatin (Platinol) 25 mg/m² IV over 2 hours once per day on days 1 to 4, 22 to 26
• Vinorelbine (Navelbine) 25 mg/m² IV bolus once per day on days 1, 8, 22, 29

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)

6-week course

Subsequent treatment

• Surgery

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

• Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion over 33 days, started on day 1 (total dose: 7425 mg/m²)
• Oxaliplatin (Eloxatin) 45 mg/m² IV over 2 hours once per day on days 1, 8, 15, 22, 29

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

• Surgery

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

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

• Capecitabine (Xeloda)
• Cisplatin (Platinol)

Radiotherapy

• Concurrent radiation therapy

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

• Cisplatin (Platinol) 80 mg/m² IV once per day on days 1 & 22
• Docetaxel (Taxotere) 60 mg/m² IV once per day on days 1 & 22

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

• Cisplatin (Platinol)
• Fluorouracil (5-FU)

Radiotherapy

• Concurrent radiation therapy

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

• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 3, 29 to 31
• Paclitaxel (Taxol) 135 mg/m² IV once per day on days 1 & 29

Radiotherapy

• Concurrent radiation therapy

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

• Cisplatin (Platinol) 25 mg/m² IV once per day on days 1 to 3, 22 to 24
• Paclitaxel (Taxol) 135 mg/m² IV once per day on days 1 & 22

Radiotherapy

• Concurrent radiation therapy 5040 cGy in 28 fractions

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

• Fluorouracil (5-FU) 1000 mg/m²/day (maximum dose of 1800 mg/day) IV continuous infusion over 96 hours, started on days 2 & 28 (total dose: 8000 mg/m²)
• Mitomycin (Mutamycin) 10 mg/m² (maximum dose of 18 mg) IV bolus once on day 2

Radiotherapy

• Concurrent radiation therapy

One course

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 contains dosing details in manuscript 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

• Fluorouracil & Paclitaxel consolidation

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

• Definitive 5-FU, Paclitaxel, RT

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m²)
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

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

• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Cisplatin (Platinol) 70 mg/m² IV over 60 minutes once on day 1
• Docetaxel (Taxotere) 70 mg/m² IV over 60 minutes once on day 1, given 3 hours before cisplatin

Supportive therapy

• Dexamethasone (Decadron) 8 mg PO twice per day x 1 day, starting 1 day prior to docetaxel administration
• At least 3 liters hydration (with mannitol, magnesium, and potassium chloride)
• "Antiemetic treatment"

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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)

21-day cycles

Regimen variant #2, 80/3200 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2024 (GEMSTONE-304)	2019-12-19 to 2021-12-23	Phase 3 (C)	CF & Sugemalimab	Inferior PFS/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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m²)

21-day cycle for up to 6 cycles

Regimen variant #3, 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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycles

Regimen variant #4, 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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

28-day cycles

Regimen variant #5, 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

• Standard antiemetic prophylaxis
• Pre- and post-cisplatin hydration

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
   1. Update: Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Makino T, Blum Murphy M, Amaya-Chanaga C, Patel A, Hu N, Matsumura Y, Kitagawa Y, Ajani J. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024 May;13(9):e7235. link to original article link to PMC article PubMed
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. GEMSTONE-304: Li J, Chen Z, Bai Y, Liu B, Li Q, Zhang J, Zhou J, Deng T, Zhou F, Gao S, Yang S, Ye F, Chen L, Bai W, Yin X, Cang S, Liu L, Pan Y, Luo H, Ji Y, Zhang Z, Wang J, Yang Q, Li N, Huang R, Qu C, Ni J, Wang B, Xu Y, Hu J, Shi Q, Yang J. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med. 2024 Mar;30(3):740-748. Epub 2024 Feb 1. link to original article contains dosing details in abstract PubMed NCT04187352

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

• Standard antiemetic prophylaxis
• Pre- and post-cisplatin hydration"

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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

Immunotherapy

• Nivolumab (Opdivo) as follows:
  • Cycle 1 up to 26: 240 mg IV once per day on days 1 & 15

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
   1. Update: Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Makino T, Blum Murphy M, Amaya-Chanaga C, Patel A, Hu N, Matsumura Y, Kitagawa Y, Ajani J. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024 May;13(9):e7235. link to original article link to PMC article PubMed

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

• Cisplatin (Platinol) as follows:
  • Cycles 1 up to 3: 80 mg/m² IV once per day on days 1 & 22
• Fluorouracil (5-FU) 4000 mg/m² IV once per day on days 1 & 22

Immunotherapy

• Pembrolizumab (Keytruda) 400 mg IV once on day 1

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) & Sugemalimab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2024 (GEMSTONE-304)	2019-12-19 to 2021-12-23	Phase 3 (E-esc)	CF	Superior OS (co-primary endpoint) Median OS: 15.3 vs 11.5 mo (HR 0.70, 95% CI 0.55-0.90) Superior PFS (co-primary endpoint) Median PFS: 6.2 vs 5.4 mo (HR 0.67, 95% CI 0.54-0.82)

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 6: 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) as follows:
  • Cycles 1 to 6: 800 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m²)

Immunotherapy

• Sugemalimab (Cejemly) 1200 mg IV once on day 1

21-day cycles

References

1. GEMSTONE-304: Li J, Chen Z, Bai Y, Liu B, Li Q, Zhang J, Zhou J, Deng T, Zhou F, Gao S, Yang S, Ye F, Chen L, Bai W, Yin X, Cang S, Liu L, Pan Y, Luo H, Ji Y, Zhang Z, Wang J, Yang Q, Li N, Huang R, Qu C, Ni J, Wang B, Xu Y, Hu J, Shi Q, Yang J. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med. 2024 Mar;30(3):740-748. Epub 2024 Feb 1. link to original article contains dosing details in abstract PubMed NCT04187352

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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Cisplatin (Platinol) 75 mg/m² IV over 2 hours once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Cisplatin (Platinol) as follows:
  • Cycles 1 up to 6: 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 up to 6: 175 mg/m² IV once on day 1

Immunotherapy

• Camrelizumab (AiRuiKa) 200 mg IV once on day 1

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

• Cisplatin (Platinol) as follows:
  • Cycles 1 up to 3: 75 mg/m² IV once per day on days 1 & 22
• Paclitaxel (Taxol) as follows:
  • Cycles 1 up to 3: 175 mg/m² IV once per day on days 1 & 22

Immunotherapy

• Pembrolizumab (Keytruda) 400 mg IV once on day 1

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 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

• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Cisplatin (Platinol) as follows:
  • Cycles 1 up to 6: 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycle 1 up to 6: 175 mg/m² IV once on day 1

Immunotherapy

• Toripalimab (Loqtorzi) 240 mg IV once on day 1

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

• Etoposide (Vepesid) 200 mg/m² (route not specified) once per day on days 1 to 3

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

• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Fluorouracil (5-FU) 800 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m²)
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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

• Pembrolizumab (Keytruda) 400 mg IV once on day 1

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

• Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
• Nivolumab (Opdivo) 3 mg/kg IV once per day on days 1, 15, 29

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
   1. Update: Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Makino T, Blum Murphy M, Amaya-Chanaga C, Patel A, Hu N, Matsumura Y, Kitagawa Y, Ajani J. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. 2024 May;13(9):e7235. link to original article link to PMC article PubMed

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

• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Immunotherapy

• Tislelizumab (Baizean) 200 mg IV once on day 1

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)	Investigator's choice of: 1a. Docetaxel 1b. Irinotecan	Superior OS (primary endpoint) Median OS: 8 vs 6 mo (HR 0.71, 95% CI 0.57-0.87)

Immunotherapy

• Camrelizumab (AiRuiKa) 200 mg IV once on day 1

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

• Docetaxel (Taxotere) 70 mg/m² IV over 60 minutes once on day 1

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

• Docetaxel (Taxotere) 75 mg/m² IV over at least 60 minutes once on day 1

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

• Irinotecan (Camptosar) 180 mg/m² IV once on day 1

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

• Irinotecan (Camptosar) 125 mg/m² IV once per day on days 1 & 8

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

• Nivolumab (Opdivo) 240 mg IV over 30 minutes once on day 1

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

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

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

• Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15

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

• Paclitaxel (Taxol) 135 mg/m² IV once on day 1

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

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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

• Tislelizumab (Baizean) 200 mg IV once on day 1

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