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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

1486 - Bcl-2 proteins expression and response to Navitoclax in platinum resistant/refractory recurrent ovarian cancer (PROC)

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Topics

Cytotoxic Therapy

Tumour Site

Ovarian Cancer

Presenters

Pierre Emmanuel Brachet

Citation

Annals of Oncology (2018) 29 (suppl_8): viii332-viii358. 10.1093/annonc/mdy285

Authors

P.E. Brachet1, F. Joly Lobbedez2, M. Fabbro3, A. Leary4, J. Medioni5, P. Follana6, A.F. Lesoin7, J. Frenel8, S. Abadie Lacourtoisie9, A. Floquet10, L. Gladieff11, B. You12, C. Gavoille13, E. Kalbacher14, M. Briand15, P.A. Just16, C. Blanc-Fournier17, F. Giffard18, B. Clarisse19, L. Poulain20

Author affiliations

  • 1 Clinical research, UNICANCER Centre Francois Baclesse and INSERM U1086 “ANTICIPE” (Interdisciplinary Research Unit for Cancers Prevention and Treatment, Axis BioTICLA “Biology and Innovative Therapeutics for Ovarian Cancers”) and GINEGEPS, GINECO Group on Early Phase Studie, 14076 - Caen/FR
  • 2 Clinical research, UNICANCER Centre Francois Baclesse and INSERM U1086 “ANTICIPE” (Interdisciplinary Research Unit for Cancers Prevention and Treatment, Axis BioTICLA “Biology and Innovative Therapeutics for Ovarian Cancers”), 14076 - Caen/FR
  • 3 Oncology Department, UNICANCER ICM Regional Cancer Institute of Montpellier, 34298 - Montpellier/FR
  • 4 Gynecological Unit, UNICANCER Gustave Roussy Cancer Center, INSERM U981, and Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and GINEGEPS, GINECO Group on Early Phase Studies, 94800 - Villejuif/FR
  • 5 Medical Oncology Department, AP-HP Hôpital Européen Georges Pompidou, 75015 - Paris/FR
  • 6 Medical Oncology, UNICANCER Centre Anticancer Antoine Lacassagne, 6100 - Nice/FR
  • 7 Oncology Department, UNICANCER Centre Oscar Lambret, 59020 - Lille/FR
  • 8 Oncology Department, UNICANCER ICO Institut de Cancerologie de l'Ouest René Gauducheau, 44805 - Saint-Herblain/FR
  • 9 Oncology Department, UNICANCER Institut de Cancérologie de l’Ouest, Site Angers, 49100 - Angers/FR
  • 10 Oncologie Médicale, UNICANCER Institute Bergonié, 33076 - Bordeaux/FR
  • 11 Oncology Department, UNICANCER, Institut Claudius Regaud- IUCT-Oncopole, 31059 - Toulouse/FR
  • 12 Oncology Department, Centre Hospitalier Lyon Sud and GINEGEPS, GINECO Group on Early Phase Studies, Paris, 69495 - Pierre Bénite/FR
  • 13 Oncology Department, UNICANCER Institut de Cancérologie de Lorraine - Alexis Vautrin, 54519 - Vandoeuvre les Nancy/FR
  • 14 Oncology Department, CHU Besançon, Hôpital Jean Minjoz, 25030 - Besançon/FR
  • 15 Anticipe Bioticla, UNICAEN, INSERM U1086 “ANTICIPE” (Interdisciplinary Research Unit for Cancers Prevention and Treatment, Axis BioTICLA “Biology and Innovative Therapeutics for Ovarian Cancers”), Centre François Baclesse, 14076 - Caen/FR
  • 16 Anatomo-pathology, AP-HP Hôpital Cochin and GINEGEPS, GINECO Group on Early Phase Studies, 75014 - Paris/FR
  • 17 Anatomo-pathology, UNICANCER, Centre François Baclesse and INSERM U1086 “ANTICIPE” (Interdisciplinary Research Unit for Cancers Prevention and Treatment, Axis BioTICLA “Biology and Innovative Therapeutics for Ovarian Cancers”),, 14076 - Caen/FR
  • 18 Inserm U1086 “anticipe” (interdisciplinary Research Unit For Cancers Prevention And Treatment, Axis Bioticla “biology And Innovative Therapeutics For Ovarian Cancers”, Centre Francois Baclesse and INSERM U1086 “ANTICIPE” (Interdisciplinary Research Unit for Cancers Prevention and Treatment, Axis BioTICLA “Biology and Innovative Therapeutics for Ovarian Cancers”), 14076 - Caen/FR
  • 19 Clinical research, UNICANCER Centre Francois Baclesse, 14076 - Caen/FR
  • 20 Inserm U1086 “anticipe” (interdisciplinary Research Unit For Cancers Prevention And Treatment, Axis Bioticla “biology And Innovative Therapeutics For Ovarian Cancers”),, Centre Francois Baclesse, 14076 - Caen/FR
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Resources

Abstract 1486

Background

Here is no convincing active treatment for patients with PROC. Anti-apoptotic bcl-2 proteins have been implicated in chemotherapy (CT) resistance. In preclinical studies, we demonstrated promising activity of Navitoclax, an anti-apoptotic inhibitor of Bcl-2 family, in ROC tumors, suggesting a potential action in platinum resistant pts. We conducted a multicentric phase II trial of Navitoclax monotherapy and reported modest efficacy (ESMO 2017, abstract #2269). Here we aimed to describe the relationship between Bcl-2 protein expression and response to Navitoclax; we also reported response to subsequent line of CT.

Methods

Pts (N = 46) with high grade serous PROC received oral Navitoclax (150 mg daily for 7 days followed by 250 mg daily) until disease progression or toxicity. All pts had a biopsy of relapsed disease before navitoclax initiation to assess the expression level of Bcl-2 proteins by histoimmunochemistry (IHC), as low, medium or high. We first evaluated the efficacy of Navitoclax for pts with high BIM level, then with high BIM expression combined with low Mcl-1 and/or phospho-ERK. Response to subsequent CT was also described.

Results

44 pts (with median of 4 prior lines) were assessable for efficacy: PFS was 50 days [6-234] with 1 partial response (PR), 15 stable diseases (SD). IHC data were available for 35 pts. BIM was highly expressed in 9 pts, 4 of them with PR/SD (p = 0.68). Among them, 7 had a low expression of Mcl-1 and/or phospho-ERK, of whom 4 with PR/SD, showing no evidence of relation with clinical response. After Navitoclax, 32 pts were retreated with CT: 4PR and 9SD were noted, including 11 pts with long response (6-13 months). Median delay from previous platinum-based treatment to subsequent CT was 9 months [2-23] for PR/SD pts. Especially, 12 pts received platinum after Navitoclax with high response rate (3PR/4SD, 58%), median delay from previous platinum-CT was 18 months.

Conclusions

BIM expression, alone or combined with Mcl-1 and/or pERK, is not predictive of Navitoclax benefit. High proportion of PROC pts response to platinum rechallenge; the potential implication of Navitoclax needs further explorations. Other Bcl-2 family proteins (activator BH3-only BID and PUMA) expression may be more relevant. This trial is granted by the French Cancer Research Hospital Program in 2011 and the Mariapia Bressan award in GINEGEPS 2014.

Clinical trial identification

Eudract: 2015-000193-35.

Legal entity responsible for the study

Centre François Baclesse.

Funding

Abbvie.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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