Malignant pleural mesothelioma

Section editor
	Travis Osterman, DO, MS Vanderbilt University Nashville, TN TravisOsterman LinkedIn

19 regimens on this page 33 variants on this page

Guidelines

ASCO

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

ESMO

• 2015: Baas et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed

NCCN

• NCCN Guidelines - Malignant Pleural Mesothelioma

Advanced or metastatic disease, first-line therapy

Best supportive care

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Muers et al. 2008 (MS01)	Phase III (C)	1. MVP	Did not meet primary endpoint of OS
		2. Vinorelbine	Might have inferior OS

No antineoplastic treatment; used as a comparator arm and here for reference purposes only.

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 verified protocol link to PMC article PubMed

Carboplatin & Pemetrexed

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Variant #1, limited duration

Study	Evidence
Castagneto et al. 2007	Phase II

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 medications

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

21-day cycle for up to 9 cycles

Variant #2, indefinite

Study	Evidence
Ceresoli et al. 2006	Phase II

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 medications

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

21-day 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 verified protocol 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 verified protocol PubMed

Cisplatin monotherapy

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Variant #1, 75 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Vogelzang et al. 2003 (JMCH)	Phase III (C)	Cisplatin & Pemetrexed	Seems to have inferior OS

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

Chemotherapy

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

21-day cycles

Variant #2, 80 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
van Meerbeeck et al. 2005 (EORTC 08983/NCIC CTG BR.17)	Phase III (C)	Cisplatin & Raltitrexed	Seems to have inferior OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT 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. JMCH: 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 verified protocol PubMed
   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/NCIC CTG BR.17: van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G; European Organisation for Research and Treatment of Cancer Lung Cancer Group; National Cancer Institute of Canada. 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 verified protocol PubMed

Cisplatin & Gemcitabine

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Variant #1, 100/1000

Study	Evidence
Nowak et al. 2002	Phase II

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 medications

• Minimum of 3 liters of IV hydration for Cisplatin (Platinol), 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 (Platinol)

28-day cycle for up to 6 cycles

Variant #2, 80/1250

Study	Evidence
van Haarst et al. 2002	Phase II

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 medications

• Minimum of 2 liters of IV hydration for Cisplatin (Platinol)
• 5-HT3 antagonists before Cisplatin (Platinol)
• corticosteroids before Cisplatin (Platinol)

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 verified protocol 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 verified protocol link to PMC article PubMed

Cisplatin & Pemetrexed

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Regimen

FDA-recommended dose

Study	Evidence	Comparator	Comparative Efficacy
Vogelzang et al. 2003 (JMCH)	Phase III (E-RT-esc)	Cisplatin	Seems to have superior OS
Zalcman et al. 2016 (MAPS)	Phase III (C)	PCB	Seems to have inferior OS
Grosso et al. 2017 (LUME-Meso)	Phase II/III (C)	Cisplatin, Nintedanib, Pemetrexed	Did not meet primary endpoint of PFS (*)

Note: JMCH did not specify the total number of cycles and some patients did receive more than 6 cycles. Reported efficacy for LUME-Meso is based on the 2019 update.

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 medications

• Folic acid 350 to 1000 mcg PO once per day, starting 1 to 3 weeks before Pemetrexed (Alimta), to continue throughout therapy
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once 1 to 3 weeks before Pemetrexed (Alimta), 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 (Alimta)

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

References

1. JMCH: 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 verified protocol PubMed
   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; French Cooperative Thoracic Intergroup (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 protocol PubMed
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 verified protocol PubMed
   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

Cisplatin & Raltitrexed

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
van Meerbeeck et al. 2005 (EORTC 08983/NCIC CTG BR.17)	Phase III (E-esc)	Cisplatin	Seems to have superior OS

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/NCIC CTG BR.17: van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G; European Organisation for Research and Treatment of Cancer Lung Cancer Group; National Cancer Institute of Canada. 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 verified protocol PubMed

Cisplatin, Pemetrexed, Bevacizumab

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PCB: Pemetrexed, Cisplatin, Bevacizumab

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Zalcman et al. 2016 (MAPS)	Phase III (E-esc)	PC	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Pemetrexed (Alimta) 500 mg/m² IV once on day 1
• 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; French Cooperative Thoracic Intergroup (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 protocol PubMed

Pemetrexed monotherapy

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Regimen

Study	Evidence
Taylor et al. 2008	Phase II

Chemotherapy

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

Supportive medications

• 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 (Alimta)
• Cyanocobalamin (Vitamin B12) 1000 mcg IM once 1 to 2 weeks before Pemetrexed (Alimta), 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 (Alimta)

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 verified protocol PubMed

Vinorelbine monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Muers et al. 2008 (MS01)	Phase III (E-esc)	1. Best supportive care	Might have superior OS
		2. MVP	Did not meet primary endpoint of OS

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 verified protocol link to PMC article PubMed

Maintenance after first line therapy

Best supportive care

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Buikhuisen et al. 2013 (NVALT 5)	Phase III (C)	Thalidomide	Did not meet primary endpoint of TTP

No antineoplastic treatment after first-line therapy.

Preceding treatment

• Pemetrexed-containing chemotherapy x 4

References

1. NVALT 5: Buikhuisen WA, Burgers JA, Vincent AD, Korse CM, van Klaveren RJ, Schramel FM, Pavlakis N, Nowak AK, Custers FL, Schouwink JH, Gans SJ, Groen HJ, Strankinga WF, Baas P. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2013 May;14(6):543-51. Epub 2013 Apr 12. link to original article PubMed

Advanced or metastatic disease, subsequent lines of therapy

Best supportive care

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Jassem et al. 2008	Phase III (C)	Pemetrexed	Seems to have inferior PFS
Maio et al. 2017 (DETERMINE)	Randomized Phase IIb (C)	Tremelimumab	Did not meet primary endpoint of OS

No antineoplastic treatment; used as a comparator arm and here for reference purposes only.

References

1. 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 verified protocol PubMed
2. DETERMINE: Maio M, Scherpereel A, Calabrò L, Aerts J, Cedres Perez S, Bearz A, Nackaerts K, Fennell DA, Kowalski D, Tsao AS, Taylor P, Grosso F, Antonia SJ, Nowak AK, Taboada M, Puglisi M, Stockman PK, Kindler HL. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017 Sep;18(9):1261-1273. Epub 2017 Jul 17. link to original article PubMed

Doxorubicin monotherapy

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Variant #1, 60 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Doxorubicin & NGR-hTNF	Did not meet primary endpoint of OS

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.

Chemotherapy

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

21-day cycle for up to 6 cycles

Variant #2, 75 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Doxorubicin & NGR-hTNF	Did not meet primary endpoint of OS

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.

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 protocol PubMed

Gemcitabine monotherapy

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

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Gemcitabine & NGR-hTNF	Did not meet primary endpoint of OS

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.

Chemotherapy

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

21-day cycle for up to 6 cycles

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

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

Chemotherapy

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

28-day cycles

Variant #3, 1250 mg/m², 2 out of 3 weeks

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Gemcitabine & NGR-hTNF	Did not meet primary endpoint of OS

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.

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 protocol 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 protocol PubMed

Gemcitabine & Vinorelbine

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Regimen

Study	Evidence
Zauderer et al. 2014meso	Retrospective, <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. contains protocol link to PMC article PubMed

Pemetrexed monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Jassem et al. 2008	Phase III (E-esc)	Best supportive care	Seems to have superior PFS

Chemotherapy

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

Supportive medications

• Folic acid 350 to 1000 mcg PO once per day, starting 1 to 2 weeks before Pemetrexed (Alimta), 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 before Pemetrexed (Alimta), 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 (Alimta)

21-day cycle for 8 or more cycles

References

1. 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 verified protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Krug et al. 2015 (VANTAGE-014)	Phase III (C)	Vorinostat	Did not meet primary endpoint of OS

No active antineoplastic treatment.

References

1. VANTAGE-014: Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Öhman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015 Apr;16(4):447-56. Epub 2015 Mar 20. Erratum in: Lancet Oncol. 2015 May;16(5):e199. link to original article PubMed

Vinorelbine monotherapy

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

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS

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

Chemotherapy

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

21-day cycle for up to 6 cycles

Variant #2, 25 mg/m² IV, weekly

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS

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

Chemotherapy

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

21-day cycle for 4 cycles

Variant #3, 30 mg/m²

Study	Evidence
Stebbing et al. 2008	Phase II

Chemotherapy

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

42-day cycles

Variant #4, 60 mg/m² PO, 2 weeks out of 3

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS

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

Chemotherapy

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

21-day cycle for up to 6 cycles

Variant #5, 60 mg/m² PO, weekly

Study	Evidence	Comparator	Comparative Efficacy
Gregorc et al. 2018 (NGR015)	Phase III (C)	Vinorelbine & NGR-hTNF	Did not meet primary endpoint of OS

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

Chemotherapy

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

21-day cycle for 4 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 verified protocol 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 protocol PubMed