Pemetrexed in Thoracic Malignancies

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Pemetrexed in Thoracic Malignancies

• Mike Martin
• 12.15.06
• Grand Rounds

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Pemetrexed

• Approved 2004
• Multi-targeted anti-folate anti-metabolite
• Thymidylate synthase
• Dihydrofolate reductase
• Glycinamide ribonucleotide formyltransferase
• Enters cells via folate carrier and membrane
  proteins
• In vitro activity in tumor cell lines resistant
  to methotrexate and 5-FU

Cohen MH, et al. The Oncologist. 2005 10 363-8
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Glycinamide Ribonucleotide Formyltransferase
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Methods

• MeSH terms
• Pemetrexed
• Esophageal neoplasm
• Lung neoplasm
• Thymoma
• Mesothelioma

Robinson KA, Dickersin KO.. Int J Epidemiol.
200231 (1) 150-3.
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Methods

• Inclusion
• Pemetrexed
• MPM, Thymoma, SCLC, NSCLC
• End-points
• As defined in the studies
• QOL, OS, PFS, etc
• Narrative description

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Robinson BWS, Lake RA. NEJM. 2005 353 1591
603.
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MPM

• Cisplatin was standard of care for unresectable
  disease
• 1988 study of 35 persons
• 14.3 PRs
• 7.5m OS

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MPM

• Phase II monotherapy trial showed activity
• 64 pts
• 14.1 RR
• 10.7m OS

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MPM
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MPM
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MPM
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MPM
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MPM

• Phase III
• 456 patients
• Cisplatin 75mg/m2 vs cisplatin Pemetrexed q21
  days
• Variably supplemented

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MPM
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MPM
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MPM
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MPM
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MPM

• Other Phase II trials
• Also given with Carbo Gem
• Gem data immature
• Neoadjuvant c cisplatin immature

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MPM

• RR of 18.6

Compared with pemetrexed cisplatin? RR 41.3,
TTP 5.7m, OS 12.1m
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MPM
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MPM conclusions?
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Thymoma Thymic CA

• 27 heavily pretreated patients
• Stage IVA or IVB disease
• 500mg/m2 vitamins

Loehrer PJ, Yiannoutsos CT, Dropcho S, et al.
2006 ASCO Annual Meeting Proceedings7079
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Thymoma Thymic CA

• 23 evaluable
• 2 PR, 2 CR ORR 17
• OS not reached
• TTP of 45 weeks
• No grade 4 toxicity
• Grade 3 toxcities in 11/27
• dyspnea, infections, fatigue, abnormal
  chemistries, and neutropenia
• 2/27 Dcd Rx due to AEs

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Thymoma Thymic CA

• Context?
• Hampered by rarity (16-30pts)
• First line chemo-sensitive
• Cisplatin/doxorubicin/ cyclophosphamide ORR 50
• Cisplatin/etoposide ORR 56
• Salvage regimens

Fornasiero A, Daniele O, Ghiotto C, et al.
Cancer. 1998 68 30 - 3.
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Thymoma Salvage

• 5 patients tandem autos (3 long CRs)
• IL-2 success, then failure
• Re-excision
• XRT
• Retreatment (2 patient series)
• Octreotide prednisone (1 patient)

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Thymoma Conclusions?
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ES-SCLC
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ES-SCLC

• Many options
• Goal to palliate without adverse effects
• Phase II trial with vitamins

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ES-SCLC
Socinski MA, Weissman C, Hart LL, et al. JCO
2006 24 4840 4847.
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ES-SCLC
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ES-SCLC
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ES-SCLC

• Active
• Well-tolerated
• Need phase III trials

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www.adjuvantonline.com
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NSCLC
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NSCLC monotherapy

• Elderly and poor performance status

• Vinorelbine ORR 31 OS 8.3
• Paclitaxel ORR 21 24 OS 6.8
• Docetaxel ORR 13 38 OS 6.0
• Gemcitabine ORR 20 33 OS 7.0

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NSCLC doublets

• 36 patients
• IIIB or IV
• Cisplatin 75mg/m2 Pemetrexed 500mg/m2 c dex
• 39 PR
• 10.9 OS
• 59 Grade ¾ Neutropenia

• 31 patients
• IIIB or IV
• Cisplatin 75mg/m2 Pemetrexed 500mg/m2 c dex
• 45 PR
• 8.9 OS
• 36 Grade ¾ Neutropenia

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NSCLC doublets
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NSCLC doublets

• 41 pts
• Oxaliplatin
• 26.8 RR
• 10.5m OS
• 7.3 neutropenia

• 39 pts
• Carboplatin
• 31.6 RR
• 10.5m OS
• 25.6 neutropenia

Similar results with vinorelbine doublet
Ongoing trial of carbo pemetrexed bevacizumab
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NSCLC gem doublets

• 58pts IIIB/IV
• D8 pemetrexed c vitamins
• D1 and 8 gem
• 15 PR
• 10.1 OS
• 17 febrile neutropenia

• 34pts IIIB/IV
• Same regimen
• 44 PR
• NR OS
• 12 febrile neutropenia

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NSCLC gem doublets

• Ma et al. 3 schedules
• A Pemetrexed followed by Gem D1, Gem D8
• B Gem followed by pemetrexed D1, Gem D8
• C Gem D1, pemetrexed followed by Gem D8

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NSCLC gem doublets
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NSCLC gem doublets
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NSCLC gem doublets
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NSCLC second-line

• Phase III trial
• Pemetrexed 500mg/m2 vitamins vs. docetaxel
  75mg/m2

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NSCLC second-line
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NSCLC second-line
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NSCLC second-line
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NSCLC second-line
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NSCLC conclusions?
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