Malignant pleural mesothelioma

Section editor
	Marjorie G. Zauderer, MD, MS, FACP Memorial Sloan Kettering Cancer Center New York, NY, USA

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19 regimens on this page 33 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.

ASCO

• 2018: Kindler et al. Treatment of malignant pleural mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline PubMed

ESMO

• 2021: Popat et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2015: Baas et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
  • 2010: Stahel et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2009: Stahel et al. Malignant pleural mesothelioma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: Stahel et al. Malignant pleural mesothelioma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Mesothelioma: Pleural
  • 2016: Ettinger et al. NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016 PubMed
  • 2012: Ettinger et al. Malignant pleural mesothelioma. PubMed

SITC

• 2022: Govindan et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma PubMed

Advanced or metastatic disease, first-line therapy

Carboplatin & Pemetrexed

Regimen variant #1, AUC 5/500 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Castagneto et al. 2007	2003-07 to 2005-03	Phase 2
Baas et al. 2021 (CheckMate 743)	2016-2018	Phase 3 (C)	Ipilimumab & Nivolumab	Inferior OS1
Chu et al. 2023 (IND227)	2017-01-31 to 2020-09-04	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab 1b. Cisplatin, Pemetrexed, Pembrolizumab	Seems to have inferior OS
Szlosarek et al. 2024 (ATOMIC-Meso)	2017-08-01 to 2021-08-15	Phase 3 (C)	1a. Carboplatin, Pegargimanse, Pemetrexed 1b. Cisplatin, Pegargimanse, Pemetrexed	Inferior OS (primary endpoint) Median OS: 7.7 vs 9.3 mo (HR 1.41, 95% CI 1.08-1.82)

¹Reported efficacy for CheckMate 743 is based on the 2022 update.

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second, 30 minutes after pemetrexed
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (varies depending on reference):
• Folic acid 350 to 600 mcg PO once per day, starting at least 1 week prior to pemetrexed, to continue throughout therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once at least 1 week prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) by one of the following:
  • 4 mg PO twice per day the day before, the day of, and day after pemetrexed
  • 8 mg IM once the day before, the day of, and day after pemetrexed
• No NSAIDs (nonsteroidal anti-inflammatory drugs) for 2 days (5 days for NSAIDs with longer half-lives) before or after pemetrexed

21-day cycle for 6 cycles

Regimen variant #2, AUC 5/500 x 9

Study	Dates of enrollment	Evidence
Castagneto et al. 2007	2003-07 to 2005-03	Phase 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second, 30 minutes after pemetrexed
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (varies depending on reference):
• Folic acid 350 to 600 mcg PO once per day, starting at least 1 week prior to pemetrexed, to continue throughout therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once at least 1 week prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) 4 mg PO twice per day the day before, the day of, and day after pemetrexed
  • Alternatively, Dexamethasone (Decadron) may be given 8 mg IM the day before, the day of, and day after pemetrexed
• No NSAIDs (nonsteroidal anti-inflammatory drugs) for 2 days (5 days for NSAIDs with longer half-lives) before or after pemetrexed

21-day cycle for up to 9 cycles

Regimen variant #3, AUC 5/500, indefinite

Study	Dates of enrollment	Evidence
Ceresoli et al. 2006	2002-11 to 2005-03	Phase 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second, 30 minutes after pemetrexed
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• (varies depending on reference):
• Folic acid 350 to 600 mcg PO once per day, starting at least 1 week prior to pemetrexed, to continue throughout therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once at least 1 week prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) 4 mg PO twice per day the day before, the day of, and day after pemetrexed
  • Alternatively, Dexamethasone (Decadron) may be given 8 mg IM the day before, the day of, and day after pemetrexed
• No NSAIDs (nonsteroidal anti-inflammatory drugs) for 2 days (5 days for NSAIDs with longer half-lives) before or after pemetrexed

21-day cycles

Regimen variant #4, AUC 6/500 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chu et al. 2023 (IND227)	2017-01-31 to 2020-09-04	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab 1b. Cisplatin, Pemetrexed, Pembrolizumab	Seems to have inferior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Supportive therapy

• (varies depending on reference):
• Folic acid 350 to 600 mcg PO once per day, starting at least 1 week prior to pemetrexed, to continue throughout therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once at least 1 week prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) 4 mg PO twice per day the day before, the day of, and day after pemetrexed
  • Alternatively, Dexamethasone (Decadron) may be given 8 mg IM the day before, the day of, and day after pemetrexed
• No NSAIDs (nonsteroidal anti-inflammatory drugs) for 2 days (5 days for NSAIDs with longer half-lives) before or after pemetrexed

21-day cycle for 6 cycles

References

1. Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Marangolo M, Parra HJ, Santoro A. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006 Mar 20;24(9):1443-8. link to original article contains dosing details in manuscript PubMed
2. Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, Serra M, Muzio A, Carbone R, Buosi R, Galbusera V, Piccolini E, Giaretto L, Rebella L, Mencoboni M. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008 Feb;19(2):370-3. Epub 2007 Dec 20. link to original article contains dosing details in manuscript PubMed
3. CheckMate 743: Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, Mansfield AS, Popat S, Jahan T, Antonia S, Oulkhouir Y, Bautista Y, Cornelissen R, Greillier L, Grossi F, Kowalski D, Rodríguez-Cid J, Aanur P, Oukessou A, Baudelet C, Zalcman G. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021 Jan 30;397(10272):375-386. Epub 2021 Jan 21. link to original article contains dosing details in abstract PubMed NCT02899299
   1. Update: Peters S, Scherpereel A, Cornelissen R, Oulkhouir Y, Greillier L, Kaplan MA, Talbot T, Monnet I, Hiret S, Baas P, Nowak AK, Fujimoto N, Tsao AS, Mansfield AS, Popat S, Zhang X, Hu N, Balli D, Spires T, Zalcman G. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. 2022 May;33(5):488-499. Epub 2022 Feb 3. link to original article PubMed
4. IND227: Chu Q, Perrone F, Greillier L, Tu W, Piccirillo MC, Grosso F, Lo Russo G, Florescu M, Mencoboni M, Morabito A, Cecere FL, Ceresoli GL, Dawe DE, Zucali PA, Pagano M, Goffin JR, Sanchez ML, Gridelli C, Zalcman G, Quantin X, Westeel V, Gargiulo P, Delfanti S, Tu D, Lee CW, Leighl N, Sederias J, Brown-Walker P, Luo Y, Lantuejoul S, Tsao MS, Scherpereel A, Bradbury P, Laurie SA, Seymour L. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023 Dec 16;402(10419):2295-2306. Epub 2023 Nov 3. link to original article contains dosing details in manuscript PubMed NCT02784171
5. ATOMIC-Meso: Szlosarek PW, Creelan BC, Sarkodie T, Nolan L, Taylor P, Olevsky O, Grosso F, Cortinovis D, Chitnis M, Roy A, Gilligan D, Kindler H, Papadatos-Pastos D, Ceresoli GL, Mansfield AS, Tsao A, O'Byrne KJ, Nowak AK, Steele J, Sheaff M, Shiu CF, Kuo CL, Johnston A, Bomalaski J, Zauderer MG, Fennell DA; ATOMIC-Meso Study Group. Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. JAMA Oncol. 2024 Apr 1;10(4):475-483. link to original article contains dosing details in abstract link to PMC article PubMed NCT02709512

Carboplatin, Pemetrexed, Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (BEAT-meso)	2019-ongoing	Phase 3 (C)	ABCP	TBD if different primary endpoint of 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

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 4 up to 6: AUC 5 IV once on day 1
• Pemetrexed (Alimta) as follows:
  • Cycles 1 to 4 up to 6: 500 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. BEAT-meso: NCT03762018

Carboplatin, Pemetrexed, Pembrolizumab

Regimen variant #1, AUC 5

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chu et al. 2023 (IND227)	2017-01-31 to 2020-09-04	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Seems to have superior OS (primary endpoint) Median OS: 17.3 vs 16.1 mo (HR 0.79, 95% CI 0.64-0.98)

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 5 IV once on day 1
• Pemetrexed (Alimta) as follows:
  • Cycles 1 to 6: 500 mg/m² IV once on day 1

Immunotherapy

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

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

Regimen variant #2, AUC 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chu et al. 2023 (IND227)	2017-01-31 to 2020-09-04	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Seems to have superior OS (primary endpoint) Median OS: 17.3 vs 16.1 mo (HR 0.79, 95% CI 0.64-0.98)

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6: AUC 6 IV once on day 1
• Pemetrexed (Alimta) as follows:
  • Cycles 1 to 6: 500 mg/m² IV once on day 1

Immunotherapy

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

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

References

1. IND227: Chu Q, Perrone F, Greillier L, Tu W, Piccirillo MC, Grosso F, Lo Russo G, Florescu M, Mencoboni M, Morabito A, Cecere FL, Ceresoli GL, Dawe DE, Zucali PA, Pagano M, Goffin JR, Sanchez ML, Gridelli C, Zalcman G, Quantin X, Westeel V, Gargiulo P, Delfanti S, Tu D, Lee CW, Leighl N, Sederias J, Brown-Walker P, Luo Y, Lantuejoul S, Tsao MS, Scherpereel A, Bradbury P, Laurie SA, Seymour L. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023 Dec 16;402(10419):2295-2306. Epub 2023 Nov 3. link to original article contains dosing details in manuscript PubMed NCT02784171

Cisplatin monotherapy

Regimen variant #1, 75 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Vogelzang et al. 2003 (EMPHACIS)	1999-2001	Phase 3 (C)	Cisplatin & Pemetrexed	Seems to have 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.

Chemotherapy

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

21-day cycles

Regimen variant #2, 80 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van Meerbeeck et al. 2005 (EORTC 08983)	2000-2003	Phase 3 (C)	Cisplatin & Raltitrexed	Seems to have 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.

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 1 to 2 hours once on day 1

21-day cycles

References

1. EMPHACIS: Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. link to original article contains dosing details in manuscript PubMed NCT00005636
   1. Update: Manegold C, Symanowski J, Gatzemeier U, Reck M, von Pawel J, Kortsik C, Nackaerts K, Lianes P, Vogelzang NJ. Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol. 2005 Jun;16(6):923-7. Epub 2005 Apr 11. link to original article PubMed
2. EORTC 08983: van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G; EORTC Lung Cancer Group; National Cancer Institute of Canada Clinical Trials Group. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol. 2005 Oct 1;23(28):6881-9. link to original article contains dosing details in manuscript PubMed NCT00004920

Cisplatin & Gemcitabine (GC)

Regimen variant #1, 100/1000

Study	Evidence
Nowak et al. 2002	Phase 2

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 60 minutes once on day 1, given first
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1, 8, 15, given second

Supportive therapy

• Minimum of 3 liters of IV hydration for [cisplatin, with magnesium supplementation
• 5-HT3 antagonists & Dexamethasone (Decadron) IV once per day on days 1, 8, 15, prior to chemotherapy
• 5-HT3 antagonists, Dexamethasone (Decadron), and/or phenothiazines for antiemesis PO or by rectal suppository for 3 to 5 days after cisplatin

28-day cycle for up to 6 cycles

Regimen variant #2, 80/1250

Study	Evidence
van Haarst et al. 2002	Phase 2

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 3 hours once on day 1, given second
• Gemcitabine (Gemzar) 1250 mg/m² IV over 30 minutes once per day on days 1 & 8, given first

Supportive therapy

• Minimum of 2 liters of IV hydration for cisplatin
• 5-HT3 antagonists prior to cisplatin
• corticosteroids prior to cisplatin

21-day cycle for up to 6 cycles

References

1. van Haarst JM, Baas P, Manegold Ch, Schouwink JH, Burgers JA, de Bruin HG, Mooi WJ, van Klaveren RJ, de Jonge MJ, van Meerbeeck JP. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer. 2002 Feb 1;86(3):342-5. link to original article contains dosing details in manuscript link to PMC article PubMed content property of HemOnc.org
2. Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Fielding D, Mitchell P, Musk AW, Robinson BW. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer. 2002 Aug 27;87(5):491-6. link to original article contains dosing details in manuscript link to PMC article PubMed

Cisplatin & Pemetrexed

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Vogelzang et al. 2003 (EMPHACIS)	1999-2001	Phase 3 (E-RT-esc)	Cisplatin	Seems to have superior OS (primary endpoint) Median OS: 12.1 vs 9.3 mo (HR 0.77)
Zalcman et al. 2016 (MAPS)	2008-2014	Phase 3 (C)	PCB	Seems to have inferior OS
Grosso et al. 2017 (LUME-Meso)	2013-09 to 2014-12	Phase 2/3 (C)	Cisplatin, Nintedanib, Pemetrexed	Did not meet primary endpoint of PFS1
Baas et al. 2021 (CheckMate 743)	2016-2018	Phase 3 (C)	Ipilimumab & Nivolumab	Inferior OS2
Chu et al. 2023 (IND227)	2017-01-31 to 2020-09-04	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Pembrolizumab 1b. Cisplatin, Pemetrexed, Pembrolizumab	Seems to have inferior OS
Szlosarek et al. 2024 (ATOMIC-Meso)	2017-08-01 to 2021-08-15	Phase 3 (C)	1a. Carboplatin, Pegargimanse, Pemetrexed 1b. Cisplatin, Pegargimanse, Pemetrexed	Inferior OS (primary endpoint) Median OS: 7.7 vs 9.3 mo (HR 1.41, 95% CI 1.08-1.82)
Awaiting publication (DREAM3R)	2021-ongoing	Phase 3 (C)	1a. Carboplatin, Pemetrexed, Durvalumab 1b. Cisplatin, Pemetrexed, Durvalumab	TBD if different primary endpoint of OS

¹Reported efficacy for LUME-Meso is based on the 2019 update.
²Reported efficacy for CheckMate 743 is based on the 2022 update.
Note: EMPHACIS (aka JMCH) did not specify the total number of cycles and some patients did receive more than 6 cycles.

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 2 hours once on day 1, given second, 30 minutes after pemetrexed
• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1, given first

Supportive therapy

• Folic acid 350 to 1000 mcg PO once per day, starting 1 to 3 weeks prior to pemetrexed, to continue throughout therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once 1 to 3 weeks prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) (dose not specified by reference) the day before, the day of, and day after pemetrexed

21-day cycle for up to 6 cycles (see note)

References

1. EMPHACIS: Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. link to original article contains dosing details in manuscript PubMed NCT00005636
   1. Update: Manegold C, Symanowski J, Gatzemeier U, Reck M, von Pawel J, Kortsik C, Nackaerts K, Lianes P, Vogelzang NJ. Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol. 2005 Jun;16(6):923-7. Epub 2005 Apr 11. link to original article PubMed
2. MAPS: Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Rivière F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A; IFCT. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Apr 2;387(10026):1405-14. Epub 2015 Dec 21. Erratum in: Lancet. 2016 Apr 2;387(10026):e24. link to original article contains dosing details in abstract PubMed NCT00651456
3. LUME-Meso: Grosso F, Steele N, Novello S, Nowak AK, Popat S, Greillier L, John T, Leighl NB, Reck M, Taylor P, Planchard D, Sørensen JB, Socinski MA, von Wangenheim U, Loembé AB, Barrueco J, Morsli N, Scagliotti G. Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: Phase II results from the randomized, placebo-controlled LUME-Meso trial. J Clin Oncol. 2017 Nov 1;35(31):3591-3600. Epub 2017 Sep 11. link to original article contains dosing details in manuscript PubMed NCT01907100
   1. Update: Scagliotti GV, Gaafar R, Nowak AK, Nakano T, van Meerbeeck J, Popat S, Vogelzang NJ, Grosso F, Aboelhassan R, Jakopovic M, Ceresoli GL, Taylor P, Orlandi F, Fennell DA, Novello S, Scherpereel A, Kuribayashi K, Cedres S, Sørensen JB, Pavlakis N, Reck M, Velema D, von Wangenheim U, Kim M, Barrueco J, Tsao AS. Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2019 Jul;7(7):569-580. Epub 2019 May 15. link to original article PubMed
4. CheckMate 743: Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, Mansfield AS, Popat S, Jahan T, Antonia S, Oulkhouir Y, Bautista Y, Cornelissen R, Greillier L, Grossi F, Kowalski D, Rodríguez-Cid J, Aanur P, Oukessou A, Baudelet C, Zalcman G. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021 Jan 30;397(10272):375-386. Epub 2021 Jan 21. link to original article contains dosing details in abstract PubMed NCT02899299
   1. Update: Peters S, Scherpereel A, Cornelissen R, Oulkhouir Y, Greillier L, Kaplan MA, Talbot T, Monnet I, Hiret S, Baas P, Nowak AK, Fujimoto N, Tsao AS, Mansfield AS, Popat S, Zhang X, Hu N, Balli D, Spires T, Zalcman G. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. 2022 May;33(5):488-499. Epub 2022 Feb 3. link to original article PubMed
5. IND227: Chu Q, Perrone F, Greillier L, Tu W, Piccirillo MC, Grosso F, Lo Russo G, Florescu M, Mencoboni M, Morabito A, Cecere FL, Ceresoli GL, Dawe DE, Zucali PA, Pagano M, Goffin JR, Sanchez ML, Gridelli C, Zalcman G, Quantin X, Westeel V, Gargiulo P, Delfanti S, Tu D, Lee CW, Leighl N, Sederias J, Brown-Walker P, Luo Y, Lantuejoul S, Tsao MS, Scherpereel A, Bradbury P, Laurie SA, Seymour L. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023 Dec 16;402(10419):2295-2306. Epub 2023 Nov 3. link to original article contains dosing details in manuscript PubMed NCT02784171
6. ATOMIC-Meso: Szlosarek PW, Creelan BC, Sarkodie T, Nolan L, Taylor P, Olevsky O, Grosso F, Cortinovis D, Chitnis M, Roy A, Gilligan D, Kindler H, Papadatos-Pastos D, Ceresoli GL, Mansfield AS, Tsao A, O'Byrne KJ, Nowak AK, Steele J, Sheaff M, Shiu CF, Kuo CL, Johnston A, Bomalaski J, Zauderer MG, Fennell DA; ATOMIC-Meso Study Group. Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. JAMA Oncol. 2024 Apr 1;10(4):475-483. link to original article contains dosing details in abstract link to PMC article PubMed NCT02709512
7. DREAM3R: NCT04334759

Cisplatin & Raltitrexed

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van Meerbeeck et al. 2005 (EORTC 08983)	2000-2003	Phase 3 (E-esc)	Cisplatin	Seems to have superior OS (primary endpoint) Median OS: 11.4 vs 8.8 mo (HR 0.76, 95% CI 0.58-1.00)

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 1 to 2 hours once on day 1, given second
• Raltitrexed (Tomudex) 3 mg/m² IV over 15 minutes once on day 1, given first

21-day cycles

References

1. EORTC 08983: van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G; EORTC Lung Cancer Group; National Cancer Institute of Canada Clinical Trials Group. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol. 2005 Oct 1;23(28):6881-9. link to original article contains dosing details in manuscript PubMed NCT00004920

Cisplatin, Pemetrexed, Bevacizumab

PCB: Pemetrexed, Cisplatin, Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zalcman et al. 2016 (MAPS)	2008-2014	Phase 3 (E-esc)	PC	Superior OS (primary endpoint) Median OS: 18.8 vs 16.1 mo (HR 0.77, 95% CI 0.62-0.95)

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

References

1. MAPS: Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Rivière F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A; IFCT. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Apr 2;387(10026):1405-14. Epub 2015 Dec 21. Erratum in: Lancet. 2016 Apr 2;387(10026):e24. link to original article contains dosing details in abstract PubMed NCT00651456

Cisplatin, Pemetrexed, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chu et al. 2023 (IND227)	2017-01-31 to 2020-09-04	Phase 3 (E-esc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Seems to have superior OS (primary endpoint) Median OS: 17.3 vs 16.1 mo (HR 0.79, 95% CI 0.64-0.98)

Chemotherapy

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 6: 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) as follows:
  • Cycles 1 to 6: 500 mg/m² IV once on day 1

Immunotherapy

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

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

References

1. IND227: Chu Q, Perrone F, Greillier L, Tu W, Piccirillo MC, Grosso F, Lo Russo G, Florescu M, Mencoboni M, Morabito A, Cecere FL, Ceresoli GL, Dawe DE, Zucali PA, Pagano M, Goffin JR, Sanchez ML, Gridelli C, Zalcman G, Quantin X, Westeel V, Gargiulo P, Delfanti S, Tu D, Lee CW, Leighl N, Sederias J, Brown-Walker P, Luo Y, Lantuejoul S, Tsao MS, Scherpereel A, Bradbury P, Laurie SA, Seymour L. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023 Dec 16;402(10419):2295-2306. Epub 2023 Nov 3. link to original article contains dosing details in manuscript PubMed NCT02784171

Cisplatin, Pemetrexed, TTFields

Regimen

Study	Dates of enrollment	Evidence
Ceresoli et al. 2019 (STELLAR)	2015-2017	Phase 2

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Tumor treating fields

• NovoTTF-100A system (Optune)

References

1. STELLAR: Ceresoli GL, Aerts JG, Dziadziuszko R, Ramlau R, Cedres S, van Meerbeeck JP, Mencoboni M, Planchard D, Chella A, Crinò L, Krzakowski M, Rüssel J, Maconi A, Gianoncelli L, Grosso F. Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial. Lancet Oncol. 2019 Dec;20(12):1702-1709. Epub 2019 Oct 15. link to original article PubMed NCT02397928

Ipilimumab & Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baas et al. 2021 (CheckMate 743)	2016-2018	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin & Pemetrexed 1b. Cisplatin & Pemetrexed	Superior OS1 (primary endpoint) Median OS: 18.1 vs 14.1 mo (HR 0.73, 95% CI 0.61-0.87)

¹Reported efficacy is based on the 2022 update.

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 18 cycles (2 years)

References

1. CheckMate 743: Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, Mansfield AS, Popat S, Jahan T, Antonia S, Oulkhouir Y, Bautista Y, Cornelissen R, Greillier L, Grossi F, Kowalski D, Rodríguez-Cid J, Aanur P, Oukessou A, Baudelet C, Zalcman G. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021 Jan 30;397(10272):375-386. Epub 2021 Jan 21. link to original article contains dosing details in abstract PubMed NCT02899299
   1. Update: Peters S, Scherpereel A, Cornelissen R, Oulkhouir Y, Greillier L, Kaplan MA, Talbot T, Monnet I, Hiret S, Baas P, Nowak AK, Fujimoto N, Tsao AS, Mansfield AS, Popat S, Zhang X, Hu N, Balli D, Spires T, Zalcman G. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. 2022 May;33(5):488-499. Epub 2022 Feb 3. link to original article PubMed

Pemetrexed monotherapy

Regimen

Study	Evidence
Taylor et al. 2008	Phase 2

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive therapy

• Folic acid 350 to 600 mcg PO once per day, starting 1 to 2 weeks before pemetrexed, to continue throughout therapy and at least 3 weeks after the last dose of pemetrexed
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once 1 to 2 weeks prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) 4 mg PO twice per day the day before, the day of, and day after pemetrexed

21-day cycles

References

1. Taylor P, Castagneto B, Dark G, Marangolo M, Scagliotti GV, van Klaveren RJ, Labianca R, Serke M, Schuette W, van Meerbeeck JP, Heigener D, Liu Y, Adachi S, Blatter J, von Pawel J. Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. J Thorac Oncol. 2008 Jul;3(7):764-71. link to original article contains dosing details in manuscript PubMed

Vinorelbine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Muers et al. 2008 (MS01)	2001-2006	Phase 3 (E-esc)	1. Best supportive care	Might have superior OS (primary endpoint) Median OS: 9.5 vs 7.6 mo (HR 0.80, 95% CI 0.63-1.02)
			2. MVP	Not directly compared

Note: Some guidelines list the dosage as 25 to 30 mg/m². No primary reference could be found for the 25 mg/m² dosage. Note also that it is not clear from the reference whether 11 or 12 doses were given.

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15, 22, 29, 36

7-week cycle for 2 cycles

References

1. MS01: Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, Nicholson AG, O'Brien M, Peake M, Rudd R, Snee M, Steele J, Girling DJ, Nankivell M, Pugh C, Parmar MK; MS01 Trial Management Group. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet. 2008 May 17;371(9625):1685-94. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00075699

Advanced or metastatic disease, subsequent lines of therapy

Doxorubicin monotherapy

Regimen variant #1, 60 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)

Note: this is the lower bound of dosing used in NGR015. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Prior treatment criteria

• NGR015: One prior pemetrexed-containing regimen

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #2, 75 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)

Note: this is the upper bound of dosing used in NGR015. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Prior treatment criteria

• NGR015: One prior pemetrexed-containing regimen

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

References

1. NGR015: Gregorc V, Gaafar RM, Favaretto A, Grossi F, Jassem J, Polychronis A, Bidoli P, Tiseo M, Shah R, Taylor P, Novello S, Muzio A, Bearz A, Greillier L, Fontana F, Salini G, Lambiase A, O'Brien M. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2018 Jun;19(6):799-811. Epub 2018 May 9. link to original article contains dosing details in abstract PubMed NCT01098266

Gemcitabine monotherapy

Regimen variant #1, 1000 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)
Popat et al. 2020 (PROMISE-meso)	2017-09 to 2018-08	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of PFS

Note: this is the lower bound of dosing used in NGR015. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Prior treatment criteria

• NGR015: One prior pemetrexed-containing regimen
• PROMISE-meso: Failure of platinum-based chemotherapy

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 1000 mg/m², 3 out of 4 weeks

Study	Evidence
Zauderer et al. 2014meso	Retrospective, fewer than 20 pts

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 1250 mg/m², 2 out of 3 weeks

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)

Note: this is the upper bound of dosing used in NGR015. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Prior treatment criteria

• NGR015: One prior pemetrexed-containing regimen

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. Retrospective: Zauderer MG, Kass SL, Woo K, Sima CS, Ginsberg MS, Krug LM. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer. 2014 Jun;84(3):271-4. Epub 2014 Mar 14. link to original article contains dosing details in abstract link to PMC article PubMed
2. NGR015: Gregorc V, Gaafar RM, Favaretto A, Grossi F, Jassem J, Polychronis A, Bidoli P, Tiseo M, Shah R, Taylor P, Novello S, Muzio A, Bearz A, Greillier L, Fontana F, Salini G, Lambiase A, O'Brien M. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2018 Jun;19(6):799-811. Epub 2018 May 9. link to original article contains dosing details in abstract PubMed NCT01098266
3. PROMISE-meso: Popat S, Curioni-Fontecedro A, Dafni U, Shah R, O'Brien M, Pope A, Fisher P, Spicer J, Roy A, Gilligan D, Gautschi O, Nadal E, Janthur WD, López Castro R, García Campelo R, Rusakiewicz S, Letovanec I, Polydoropoulou V, Roschitzki-Voser H, Ruepp B, Gasca-Ruchti A, Peters S, Stahel RA. A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol. 2020 Dec;31(12):1734-1745. Epub 2020 Sep 22. link to original article contains dosing details in manuscript PubMed NCT02991482

Gemcitabine & Vinorelbine

Regimen

Study	Evidence
Zauderer et al. 2014meso	Retrospective, fewer than 20 pts

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Retrospective: Zauderer MG, Kass SL, Woo K, Sima CS, Ginsberg MS, Krug LM. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer. 2014 Jun;84(3):271-4. Epub 2014 Mar 14. link to original article contains dosing details in abstract link to PMC article PubMed

Nivolumab monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fennell et al. 2021 (CONFIRMmeso)	2017-2020	Phase 3 (E-esc)	Placebo	Superior OS (co-primary endpoint) Median OS: 10.2 vs 6.9 mo (HR 0.69, 95% CI 0.52-0.91)

Note: this trial should not be confused with the one by the same name in breast cancer.

Prior treatment criteria

• Failure of first-line platinum-based chemotherapy

Immunotherapy

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

14-day cycle for up to 26 cycles (1 year)

References

1. CONFIRM_meso: Fennell DA, Ewings S, Ottensmeier C, Califano R, Hanna GG, Hill K, Danson S, Steele N, Nye M, Johnson L, Lord J, Middleton C, Szlosarek P, Chan S, Gaba A, Darlison L, Wells-Jordan P, Richards C, Poile C, Lester JF, Griffiths G; CONFIRM trial investigators. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1530-1540. Epub 2021 Oct 14. link to original article contains dosing details in abstract link to PMC article PubMed NCT03063450

Pemetrexed monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jassem et al. 2008 (JMEW)	2001-2004	Phase 3 (E-esc)	Best supportive care	Did not meet primary endpoint of OS Median OS: 9.7 vs 8.4 mo

Prior treatment criteria

• One prior systemic chemotherapy regimen, not including pemetrexed

Chemotherapy

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

Supportive therapy

• Folic acid 350 to 1000 mcg PO once per day, starting 1 to 2 weeks prior to pemetrexed, to continue throughout therapy and at least 3 weeks after the last dose of pemetrexed
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once 1 to 2 weeks prior to pemetrexed, then 1000 mcg IM once every 9 weeks
• Dexamethasone (Decadron) 4 mg PO twice per day the day before, the day of, and day after pemetrexed

21-day cycle for 8 or more cycles

References

1. JMEW: Jassem J, Ramlau R, Santoro A, Schuette W, Chemaissani A, Hong S, Blatter J, Adachi S, Hanauske A, Manegold C. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol. 2008 Apr 1;26(10):1698-704. link to original article contains dosing details in manuscript PubMed NCT00190762

Vinorelbine monotherapy

Regimen variant #1, 25 mg/m² IV, 2 weeks out of 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)

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

• NGR015: One prior pemetrexed-containing regimen

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

Regimen variant #2, 25 mg/m² IV, weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)

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

• NGR015: One prior pemetrexed-containing regimen

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Regimen variant #3, 30 mg/m² IV, 2 weeks out of 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Popat et al. 2020 (PROMISE-meso)	2017-09 to 2018-08	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of PFS

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

• PROMISE-meso: Failure of platinum-based chemotherapy

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #4, 30 mg/m² IV, weekly

Study	Evidence
Stebbing et al. 2008	Phase 2

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² (maximum dose of 60 mg) IV over 5 minutes once per day on days 1, 8, 15, 22, 29, 36

42-day cycles

Regimen variant #5, 60 mg/m² PO, 2 weeks out of 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)
Popat et al. 2020 (PROMISE-meso)	2017-09 to 2018-08	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of PFS

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

• NGR015: One prior pemetrexed-containing regimen
• PROMISE-meso: Failure of platinum-based chemotherapy

Chemotherapy

• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1 & 8

21-day cycles

Regimen variant #6, 60 mg/m² PO, weekly

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	2010-2013	Phase 3 (C)	Investigator's choice of: 1a. Doxorubicin & NGR-hTNF 1b. Gemcitabine & NGR-hTNF 1c. Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS Median OS: 8 vs 8.5 mo (HR 1.06, 95% CI 0.85-1.33)

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

• NGR015: One prior pemetrexed-containing regimen

Chemotherapy

• Vinorelbine (Navelbine) 60 mg/m² PO once per day on days 1, 8, 15

21-day cycle for 4 cycles

Regimen variant #7, 80 mg/m² PO, 2 weeks out of 3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Popat et al. 2020 (PROMISE-meso)	2017-09 to 2018-08	Phase 3 (C)	Pembrolizumab	Did not meet primary endpoint of PFS

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

• PROMISE-meso: Failure of platinum-based chemotherapy

Chemotherapy

• Vinorelbine (Navelbine) 80 mg/m² PO once per day on days 1 & 8

21-day cycles

References

1. Stebbing J, Powles T, McPherson K, Shamash J, Wells P, Sheaff MT, Slater S, Rudd RM, Fennell D, Steele JP. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer. 2009 Jan;63(1):94-7. Epub 2008 May 16. link to original article contains dosing details in manuscript PubMed
2. NGR015: Gregorc V, Gaafar RM, Favaretto A, Grossi F, Jassem J, Polychronis A, Bidoli P, Tiseo M, Shah R, Taylor P, Novello S, Muzio A, Bearz A, Greillier L, Fontana F, Salini G, Lambiase A, O'Brien M. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2018 Jun;19(6):799-811. Epub 2018 May 9. link to original article contains dosing details in abstract PubMed NCT01098266
3. PROMISE-meso: Popat S, Curioni-Fontecedro A, Dafni U, Shah R, O'Brien M, Pope A, Fisher P, Spicer J, Roy A, Gilligan D, Gautschi O, Nadal E, Janthur WD, López Castro R, García Campelo R, Rusakiewicz S, Letovanec I, Polydoropoulou V, Roschitzki-Voser H, Ruepp B, Gasca-Ruchti A, Peters S, Stahel RA. A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol. 2020 Dec;31(12):1734-1745. Epub 2020 Sep 22. link to original article contains dosing details in manuscript PubMed NCT02991482