Further, our prior study showed that even a few days off sorafenib appeared to be sufficient to restore sensitivity of RCC xenografts to sorafenib as measured by induction of tumor Quizartinib necrosis. These observations are also supported by clinical data that suggests restored sensitivity to VEGFR TKI including the rechallenge with the same agent following a drug holiday. These data may have direct clinical relevance. Other VEGFR pathway inhibitors have demonstrated similar schedule issues. As recently reported, the EFFECT trial showed that sunitinib given at 50 mg day for 4 weeks fol lowed by a 2 week break was more active than sunitinib 37. 5 mg daily with the higher dose intermittent regimen showing a 9. 9 month PFS vs a 7. 1 month PFS for the lower dose continuous regimen.
Furthermore, tivoza nib is administered at 1. 5 mg kg qd for 3 weeks out of 4 and has produced at response rate 30% and a median PFS of 15 months in patients with clear cell histology who had undergone a nephrectomy. A recent dose escalation study in RCC patients showed that increasing the dose of sorafenib while maintaining the continuous dosing schedule was not feasible due to toxicities. However, the patients in whom the dose could be escalated appeared to have greater clinical benefit with longer PFS and greater response rates. Our data suggest that dose escalation in addition to schedule alteration may improve efficacy with less toxicity. The concept that a higher dose may be more effective is also consistent with a study by Houk et al which showed that in patients treated with sunitinib, higher blood levels of the drug correlated with longer PFS and overall survival.
It is likely that the higher dose in our study achieved a higher blood level in the mice. The notion that higher drug levels may correlate with better efficacy is further supported by the finding that hyper tension, thought to be an independent pharmacody namic marker of VEGFR inhibition, correlated with response in a retrospective study of patients treated with first or second line sunitinib. Patients with systolic BP 140 had a 12. 5 month PFS and patients with no systolic hypertension had only a 2. 5 month PFS. Thus, as with other VEGFR pathway inhibitors, sorafe nibs overall effect may be enhanced at higher doses, likely leading to higher blood levels, and more effective inhibition of VEGFR.
This results in improved antian giogenic activity and improved efficacy. The finding that the high dose showed similar activity at either an intermittent or continuous schedule would support the practice of allowing patients a break from therapy to recover from toxicities. While this data requires valida tion, it suggests that the therapeutic index for VEGFR TKI therapy of RCC may be maximal with higher dose intermittent therapy.