Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma

• Published in: Annals of oncology Vol. 26; no. 2; pp. 378 - 385
• Main Authors: Elaidi, R., Harbaoui, A., Beuselinck, B., Eymard, J.-C., Bamias, A., De Guillebon, E., Porta, C., Vano, Y., Linassier, C., Debruyne, P.R., Gross-Goupil, M., Ravaud, A., Aitelhaj, M., Marret, G., Oudard, S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2015
• Subjects: Aged; Antineoplastic Agents - therapeutic use; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - mortality; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; kidney cancer; Male; mammalian target of rapamycin (mTOR); Middle Aged; Proportional Hazards Models; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Retrospective Studies; Salvage Therapy - methods; sequence; TOR Serine-Threonine Kinases - antagonists & inhibitors; Treatment Outcome; tyrosine kinase inhibitor; kidney cancer; mammalian target of rapamycin (mTOR); sequence; tyrosine kinase inhibitor
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdu552

In a comparison of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) in patients with metastatic clear-cell renal cell carcinoma who received a 1st-line TKI for at least 6 months, the TKI-TKI sequence was favored over the TKI-mTORi. Long-term 2nd-line responders were more likely to have received a second TKI and to have been long-term responders to a 1st-line TKI. 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). 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). 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. 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.