R Elaidi1, A Harbaoui2, B Beuselinck3, J-C Eymard4, A Bamias5, E De Guillebon6, C Porta7, Y Vano8, C Linassier9, P R Debruyne10, M Gross-Goupil2, A Ravaud2, M Aitelhaj11, G Marret11, S Oudard12. 1. Department of Oncology, Georges Pompidou European Hospital, Paris Association Pour la Recherche de Thérapeutiques Innovantes en Cancérologie, Paris reza-thierry.elaidi@egp.aphp.fr. 2. St André Hospital, Bordeaux, France. 3. University Hospitals Leuven, Leuven, Belgium. 4. Department of Oncology, Centre Joliot Curie, Reims, France. 5. Department of Clinical Therapeutics, University of Athens, Athens, Greece. 6. Jean Bernard Hospital, Poitiers, France. 7. San Matteo University Hospital Foundation, Pavia, Italy. 8. Centre Antoine-Lacassagne, University of Nice-Sophia-Antipolis, Nice. 9. Department of Oncology, Bretonneau Hospital, Tours, France. 10. Kortrijk Cancer Center, Kortrijk, Belgium Center for Positive Ageing, University of Greenwich, London, UK. 11. Department of Oncology, Georges Pompidou European Hospital, Paris. 12. Department of Oncology, Georges Pompidou European Hospital, Paris René Descartes Faculty, Paris, France.
Abstract
BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
Authors: Carmine D'Aniello; Maria G Vitale; Azzurra Farnesi; Lorenzo Calvetti; Maria M Laterza; Carla Cavaliere; Chiara Della Pepa; Vincenza Conteduca; Anna Crispo; Ferdinando De Vita; Francesco Grillone; Enrico Ricevuto; Michele De Tursi; Rocco De Vivo; Marilena Di Napoli; Sabrina C Cecere; Gelsomina Iovane; Alfonso Amore; Raffaele Piscitelli; Giuseppe Quarto; Salvatore Pisconti; Gennaro Ciliberto; Piera Maiolino; Paolo Muto; Sisto Perdonà; Massimiliano Berretta; Emanuele Naglieri; Luca Galli; Giacomo Cartenì; Ugo De Giorgi; Sandro Pignata; Gaetano Facchini; Sabrina Rossetti Journal: Front Pharmacol Date: 2016-09-28 Impact factor: 5.810