title: Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma.
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).
  
  
  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).
  
  
  METHODS
  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.affiliation: Department of Oncology, Georges Pompidou European Hospital, Paris Association Pour la Recherche de Thérapeutiques Innovantes en Cancérologie, Paris reza-thierry.elaidi@egp.aphp.fr.
authors.forename: R
authors.initials: R
authors.lastname: Elaidi
authors.affiliation: St André Hospital, Bordeaux, France.
authors.forename: A
authors.initials: A
authors.lastname: Harbaoui
authors.affiliation: University Hospitals Leuven, Leuven, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Beuselinck
authors.affiliation: Department of Oncology, Centre Joliot Curie, Reims, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Eymard
authors.affiliation: Department of Clinical Therapeutics, University of Athens, Athens, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Bamias
authors.affiliation: Jean Bernard Hospital, Poitiers, France.
authors.forename: E
authors.initials: E
authors.lastname: De Guillebon
authors.affiliation: San Matteo University Hospital Foundation, Pavia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Porta
authors.affiliation: Centre Antoine-Lacassagne, University of Nice-Sophia-Antipolis, Nice.
authors.forename: Y
authors.initials: Y
authors.lastname: Vano
authors.affiliation: Department of Oncology, Bretonneau Hospital, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Linassier
authors.affiliation: Kortrijk Cancer Center, Kortrijk, Belgium Center for Positive Ageing, University of Greenwich, London, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Debruyne
authors.affiliation: St André Hospital, Bordeaux, France.
authors.forename: M
authors.initials: M
authors.lastname: Gross-Goupil
authors.affiliation: St André Hospital, Bordeaux, France.
authors.forename: A
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: Department of Oncology, Georges Pompidou European Hospital, Paris.
authors.forename: M
authors.initials: M
authors.lastname: Aitelhaj
authors.affiliation: Department of Oncology, Georges Pompidou European Hospital, Paris.
authors.forename: G
authors.initials: G
authors.lastname: Marret
authors.affiliation: Department of Oncology, Georges Pompidou European Hospital, Paris René Descartes Faculty, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Oudard
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D016879:Salvage Therapy / Q000379:methods*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D011505:Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases
keywords: kidney cancer; mammalian target of rapamycin (mTOR); sequence; tyrosine kinase inhibitor