The Time To Progression Ratio: a new individualized volumetric parameter for early detection of clinical benefit of targeted therapies
Menée sur 43 patients atteints d'un cancer métastatique traité par évérolimus, cette étude évalue l'association entre le rapport "vitesse de croissance tumorale avant traitement / vitesse de croissance tumorale sous traitement" et la survie globale des patients
Background : Early signs of efficacy are critical in drug development. Response Evaluation Criteria In Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST however, emphasizes the value of tumor shrinkage, whilst many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a Time To Progression (TTP) endpoint based on prospective volumetric measurements and an intra-patient control, the TTP ratio.
Patients and Methods : Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pre-treatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined.
Results : Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (N=43) of treated patients. The inter-observer agreement for volumetric progression was 0.78 (95%CI 0.70-0.87) (Krippendorff's
α-coefficient). Using RECIST, 35 patients (59%) had Stable Disease (SD) and one patient demonstrated a Partial Response (PR), while only 21 patients (36%) met the prespecified criteria for treatment efficacy using TTP ratio. Treatment response according to TTP ratio and RECIST (SD+PR) both correlated with Overall Survival (OS) (P(log-rank)<0.001). The TTP ratio however, was also able to differentiate which patients had a better OS within the RECIST SD group (P(log-rank)=0.0496).
Conclusion
:
The TTP ratio had a high inter-observer agreement, correlated to OS, and identified which patients within the RECIST SD group had a longer OS.
ClinicalTrials.gov identifier NCT01566279
Annals of Oncology , résumé, 2016