Esophageal squamous cell carcinoma

Section editor transclusions Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens.

45 regimens on this page 66 variants on this page

Neoadjuvant induction therapy

Cisplatin & Etoposide (EP)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Boonstra et al. 2011	1989-1996	Phase 3 (E-esc)	Surgery alone	Seems to have superior OS

Note: Patients had 100% squamous cell histology

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 & Paclitaxel

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (HCHTOG1909)	2020-ongoing	Phase 3 (C)	Cisplatin, Paclitaxel, Toripalimab	TBD

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. 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.

Fluorouracil, Oxaliplatin, RT

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

Regimen variant #1, 45 Gy

Study	Evidence
Lorenzen et al. 2008	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, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy

35-day 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

Definitive therapy

Capecitabine & Cisplatin (CX) & RT

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ongoing (KUNLUN)	2020-ongoing	Phase 3 (C)	1. CX, Durvalumab, RT 2. 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	Evidence
Li et al. 2009	Phase 2

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

Chemotherapy

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

Supportive therapy

• Dexamethasone (Decadron) 10 mg IV or PO once on day -1, then once on day 1; 30 minutes prior to Docetaxel (Taxotere), then once on day 2
• Diphenhydramine (Benadryl) 40 mg IV once on day 1, prior to chemotherapy
• Cimetidine (Tagamet) 40 mg IV once on day 1, prior to chemotherapy
• Granisetron 2 mg IV once on day 1, prior to chemotherapy
• 1.5 to 2 liters fluids before Cisplatin (Platinol)

21-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy, 1.8 to 2 Gy 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 64 Gy over 4 to 6 weeks
  • Patients with stage IV disease (lymph node only) received a total dose of 50 to 56 Gy

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ongoing (KUNLUN)	2020-ongoing	Phase 3 (C)	1. CX, Durvalumab, RT 2. 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	Years 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
• Paclitaxel (Taxol) 135 mg/m² IV once on day 1

28-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy

Regimen variant #2

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

21-day cycle for 2 cycles

Radiotherapy

• Concurrent radiation therapy 50.4 Gy in 28 fractions

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, Paclitaxel, RT

Regimen

Study	Years 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 day 1 (total dose per cycle: 300 mg/m²)
• Paclitaxel (Taxol) 50 mg/m² IV once on day 1

7-day cycle for 5 cycles

Radiotherapy

• Concurrent radiation therapy, 1.8 Gy fractions x 34 fractions, for a total dose of 61.2 Gy

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 PubMed NCT01591135

Consolidation after definitive therapy

Fluorouracil & Paclitaxel

Regimen

Study	Years 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

• 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 PubMed NCT01591135

Metastatic or locally advanced disease, first-line

Cisplatin & Docetaxel (DC)

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

Regimen

Study	Evidence
Kim et al. 2009	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 before Docetaxel (Taxotere) 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, 80/4000, 4-day infusion, indefinite

Study	Years 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: 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 #2, 80/4000, 5-day infusion, indefinite

Study	Years 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

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)

28-day cycles

Regimen variant #3, 100/5000 x 6

Study	Years 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: 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 and pre- and post- Cisplatin (Platinol) 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

Cisplatin & Fluorouracil (CF) & Cetuximab

CF-C: Cisplatin, Fluorouracil, Cetuximab

Regimen

Study	Years 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 and pre- and post- Cisplatin (Platinol) 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Doki et al. 2022 (CheckMate 648)	2017-2019	Phase 3 (E-RT-esc)	1. CF	Superior OS1 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

Cisplatin & Fluorouracil (CF) & Pembrolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (LEAP-014)	2021-ongoing	Phase 3 (C)	1. FP, Lenvatinib, Pembrolizumab 2. TP, Lenvatinib, Pembrolizumab 3. mFOLFOX6, Lenvatinib, Pembrolizumab	TBD

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lu et al. 2022 (ORIENT-15)	2018-2021	Phase 3 (E-esc)	1. CF 2. Cisplatin & Paclitaxel	Superior OS1 Median OS: 17.2 vs 13.6 mo (HR 0.64, 95% CI 0.48-0.85)

¹Reported efficacy is for the primary efficacy population (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:
  • Weight less than 60 kg: 3 mg/kg IV once on day 1
  • Weight 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 PubMed NCT03748134

Cisplatin & Paclitaxel

Regimen variant #1, 6 cycles

Study	Years 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)	2019-2020	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 #2, indefinite

Study	Evidence
Zhang et al. 2008	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

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 to 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. BGB-A317-306: NCT03783442
5. SKYSCRAPER-08: NCT04540211

Cisplatin, Paclitaxel, Camrelizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Luo et al. 2021 (ESCORT-1st)	2018-2020	Phase 3 (E-esc)	Cisplatin & Paclitaxel	Superior OS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (LEAP-014)	2021-ongoing	Phase 3 (C)	1. FP, Lenvatinib, Pembrolizumab 2. TP, Lenvatinib, Pembrolizumab 3. mFOLFOX6, Lenvatinib, Pembrolizumab	TBD

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lu et al. 2022 (ORIENT-15)	2018-2021	Phase 3 (E-esc)	1. CF 2. Cisplatin & Paclitaxel	Superior OS1 Median OS: 17.2 vs 13.6 mo (HR 0.64, 95% CI 0.48-0.85)

¹Reported efficacy is for the primary efficacy population (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:
  • Weight less than 60 kg: 3 mg/kg IV once on day 1
  • Weight 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 PubMed NCT03748134

Cisplatin, Paclitaxel, Toripalimab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2022 (JUPITER-06)	2019-2020	Phase 3 (E-esc)	Cisplatin & Paclitaxel	Superior OS 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/day IV once on day 1

Immunotherapy

• Toripalimab (Tuoyi) 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	Evidence
Harstrick et al. 1992	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

Ipilimumab & Nivolumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Doki et al. 2022 (CheckMate 648)	2017-2019	Phase 3 (E-RT-switch-ooc)	1. CF	Superior OS 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

mFOLFOX6 & Pembrolizumab

mFOLFOX6 & Pembrolizumab: modified FOLinic acid, Fluorouracil, OXaliplatin, Pembrolizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (LEAP-014)	2021-ongoing	Phase 3 (C)	1. FP, Lenvatinib, Pembrolizumab 2. TP, Lenvatinib, Pembrolizumab 3. mFOLFOX6, Lenvatinib, Pembrolizumab	TBD

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)
• Folinic acid (Leucovorin) 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

Metastatic or locally advanced disease, subsequent lines of therapy

Camrelizumab monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Huang et al. 2020 (ESCORT)	2017-2018	Phase 3 (E-switch-ooc)	1. Docetaxel 2. Irinotecan	Superior OS Median OS: 8 mo 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;21(6):832-842. link to original article contains dosing details in abstract PubMed NCT03099382

Docetaxel monotherapy

Regimen variant #1, 70 mg/m²

Study	Years 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) 75 mg/m² IV over 60 minutes once on day 1

21-day cycles

Regimen variant #2, 75 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017	Phase 3 (C)	Pembrolizumab	Inferior OS1
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 60 minutes once on day 1

21-day cycles

Regimen variant #3, 100 mg/m²

Study	Years of enrollment	Evidence
Albertsson et al. 2007	1997-2003	Phase 2

Note: patients had squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycles

References

1. Albertsson M, Johansson B, Friesland S, Kadar L, Letocha H, Frykholm G, Wagenius G. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24(4):407-12. link to original article contains dosing details in abstract PubMed
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 PubMed NCT03430843

Irinotecan monotherapy

Regimen variant #1, 14-day cycles

Study	Years 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.

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	Years 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

Regimen variant #3, 4 out of 6 weeks

Study	Years of enrollment	Evidence
Mühr-Wilkenshoff et al. 2003	1999-2000	Phase 2, <20 patients

Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m² IV once per day on days 1 & 8, with 21-day cycles. Ten patients had esophageal squamous cell carcinoma, three had esophageal adenocarcinoma

Chemotherapy

• Irinotecan (Camptosar) 125 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

42-day cycles

References

1. Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, Scherübl H. A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis. 2003 Jul;18(4):330-4. Epub 2003 Feb 1. link to original article PubMed
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 PubMed NCT03430843

Nivolumab monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kato et al. 2019 (ATTRACTION-3)	2016-2017	Phase 3 (E-RT-switch-ooc)	1. Docetaxel 2. Paclitaxel	Seems to have superior OS Median OS: 11 mo 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 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 PubMed NCT02569242

Paclitaxel monotherapy

Regimen variant #1, weekly

Study	Years of enrollment	Evidence
Ilson et al. 2007	1998-2000	Phase 2

Note: Patients had 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15, 22

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to Paclitaxel (Taxol)
• Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to Paclitaxel (Taxol)
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to Paclitaxel (Taxol)

28-day cycles

Regimen variant #2, 80 mg/m², 3 out of 4 weeks

Study	Years 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 #3, 100 mg/m², 3 out of 4 weeks

Study	Years 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 #4, 100 mg/m², 6 out of 7 weeks

Study	Years 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 a Japanese dosing approach.

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 once per day on days 1, 8, 15, 22, 29, 36

49-day cycles

Regimen variant #5, 135 mg/m², 21-day cycles

Study	Years 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 #6, 175 mg/m², 21-day cycles

Study	Years 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. Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. link to original article contains dosing details in manuscript PubMed
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 PubMed NCT03430843

Pembrolizumab monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kojima et al. 2020 (KEYNOTE-181)	2015-2017	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1. Docetaxel 2. Irinotecan 3. Paclitaxel	Superior OS1
Shah et al. 2019 (KEYNOTE-180)	2016-2017	Phase 2 (RT)

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 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
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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shen et al. 2022 (RATIONALE 302)	2018-2020	Phase 3 (E-switch-ooc)	Investigator's choice of: 1. Docetaxel 2. Irinotecan 3. Paclitaxel	Superior OS 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 (BGB-A317) 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 PubMed NCT03430843