Modifying sunitinib schedule in advanced kidney cancer patients: Reflections from the results of the renal EFFECT trial

The Renal EFFECT trial was a randomized phase II trial of sunitinib given to advanced renal cell carcinoma (RCC) patients, either according to the standard schedule (50 mg daily, 4 weeks on, 2 weeks off) or according to a modified schedule, with sunitinib given continuously at the reduced dose of 37.5 mg daily. Even though the declared primary end-point of the study was time to progression (TTP), and despite authors claimed that " this trial was not designed to be either a superiority or a noninferiority trial " (1), in practical terms the study was supposed to answer a completely different question, i.e., is the continuous dosing schedule equieffective, but safer, as compared to the standard schedule? Let's start to analyze the results of this study in terms of efficacy. Median TTP was 9.9 months for the classical schedule vs. 7.1 months for the continuous daily dose schedule; consistent with the TTP analysis, a longer progression-free survival (PFS) was observed in patients treated with the classical schedule: 8.5 vs. 7.0 months; overall survival, on the other hand, was almost superimposible between the two treatment arms (23.1 vs. 23.5 months) (1). As a whole, the observed better performance in terms of efficacy outcome measures (TTP and PFS) of the classical schedule is someway in agreement with a recent pharmacokinetic/pharmacodynamic meta-analysis aimed at investigating the relationship between sunitinib exposure and efficacy and tolerability endpoints (2); according to such meta-analysis, the importance of maintaining patients on a 50 mg dose of sunitinib and striving to avoid unscheduled dose titrations (as well as unscheduled treatment interruptions) during treatment, clearly emerged (2). Indeed, patients with the highest exposure to sunitinib displayed longer TTP, longer OS, a higher probability of a response, and greater tumor size decreases (2). Despite that, the absolute PFS values observed in the two treatment arms of the renal EFFECT trial (1) were someway disappointing; no one would infact consider the 8.5 months of PFS achieved by the standard arm a satisfactory outcome for first line sunitinib, irrespective of any statistical consideration. And indeed, all the efficacy figures reported in the renal EFFECT trial were lower than those accomplished by sunitinib (given according to the standard schedule) within the pivotal registration trial, as summarized in Table 1 (3). These results, however, are probably relatively easy to explain. Indeed, we agree with study investigators that " … is not an unusual observation, when …