Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial

Charting the Path to Systemic Therapy De-escalation—Oligometastatic Kidney Cancer as a Paradigm

“…In one of the first case reports about this topic, Barney and Churchill described in 1939 nephrectomy and the resection of a solitary lung metastasis, reporting rendering the patient into remission 5 years after MDT. Since then, phase 2 trials have investigated systemic therapy de-escalation for indolent and unselected populations of patients with metastatic kidney cancer by using serial MDT, defined systemic therapy breaks, and surveillance imaging alone . The only reported phase 3 study to investigate systemic therapy de-escalation was the STAR trial, which randomized patients undergoing tyrosine kinase monotherapy regimes to continuous systemic therapy (control arm) vs a planned drug-free interval (experimental arm).…”

“…Since then, phase 2 trials have investigated systemic therapy de-escalation for indolent and unselected populations of patients with metastatic kidney cancer by using serial MDT, defined systemic therapy breaks, and surveillance imaging alone . The only reported phase 3 study to investigate systemic therapy de-escalation was the STAR trial, which randomized patients undergoing tyrosine kinase monotherapy regimes to continuous systemic therapy (control arm) vs a planned drug-free interval (experimental arm). Unfortunately, this trial used tyrosine kinase monotherapies, which are no longer routinely used in the frontline metastatic setting and was ultimately hindered by accrual challenges leading to an inconclusive signal for its primary end point .…”

“…The only reported phase 3 study to investigate systemic therapy de-escalation was the STAR trial, which randomized patients undergoing tyrosine kinase monotherapy regimes to continuous systemic therapy (control arm) vs a planned drug-free interval (experimental arm). Unfortunately, this trial used tyrosine kinase monotherapies, which are no longer routinely used in the frontline metastatic setting and was ultimately hindered by accrual challenges leading to an inconclusive signal for its primary end point . A limited number of recently activated RCTs are now investigating treatment strategies that would prolong time before frontline systemic therapy initiation.…”

Evolutionary Dynamics and Intermittent Therapy for Metastatic Cancers

“…First, intermittent therapy typically begins with an induction period of prolonged drug administration at MTD. In the study by Brown et al 5 , the induction period was 24 weeks, and in the study of continuous versus intermitted ADT in prostate cancer, induction ADT was administered at MTD for 7 months. Mathematical analysis of this prolonged induction period demonstrates reductions in the size of the treatment-sensitive population so that it is ineffective in its evolutionary role of suppressing proliferation of resistant cells during the off cycle (Fig 1).…”

“…3 In a large trial, Hussain et al, 4 found that intermittent therapy using androgen deprivation therapy (ADT) in men with metastatic castrate-sensitive prostate cancer produced no significant benefit compared with standard dosing. Most recently, Brown et al 5 reported a randomized phase II/III trial for patients with metastatic clear cell renal cell cancer comparing cessation versus continuous sunitinib or pazopanib after 24 weeks of therapy on the basis of initial response. Cessation therapy proved to be feasible, safe, cost-effective, and without a significant decline in life expectancy in comparison with continuous drug dosing.…”