TKI Treatment Breaks May Be Feasible For Advanced RCC Patients

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: A drug-free interval strategy (DFIS) may offer an alternative to continuous treatment for patients with a new diagnosis of advanced clear cell renal cell carcinoma (RCC) who require tyrosine kinase inhibitor (TKI) therapy, the STAR investigators have reported at the ESMO Congress 2021. 

Although the trial did not meet the prespecified statistical criteria for the co-primary endpoint of noninferior overall survival (OS), presenter Janet Brown, from the University of Sheffield in the UK, said that the study showed “treatment breaks were acceptable to patients and clinicians, were not detrimental to overall survival or quality of life and had significant cost savings.” 

The phase II/III trial was initiated following the approval of sunitinib for first-line treatment of metastatic RCC and had a “pragmatic design” so that the participants were “representative of the UK [metastatic] RCC population at the time of recruitment”, the presenter explained. 

The 919 patients in the phase III part of the trial were given 24 weeks of treatment with sunitinib or pazopanib before being randomly assigned to a DFIS (n=458), with a treatment break until radiological evidence of disease progression, or to receive a conventional continuous strategy (CCS, n=461), without a treatment break, until disease progression on imaging. 

After week 24, 56.3% of patients assigned to the DFIS arm continued with the trial. At least one treatment break was mandated in the DFIS arm and this was achieved by 94.0% of the group; one break was achieved by 51.2% of patients, 15.3% had two breaks and 27.4% had at least three breaks, with a maximum of nine permitted. The median duration of treatment break was 87 days. 

The DFIS and CCS arms received a similar number of 6-week treatment cycles (median 4 vs 5) and were followed up for a median of 58 months. 

In the intention-to-treat population, OS was a median 27 months with DFIS and 28 months with CCS, giving a nonsignificant hazard ratio (HR) of 0.97 with a lower bound of the 95% confidence interval of 0.83 that was above the threshold of 0.812 required to demonstrate noninferiority. 

While the median OS durations were the same in the per protocol population, the HR of 0.94 had a lower bound of 0.80 and was therefore below the threshold required to demonstrate a 7.5% or smaller difference in OS between the treatment arms. 

However, Janet Brown explained that the trial was “slightly unpowered” because the study stopped before the number of survival events required to meet 80% statistical power had occurred.  

“This is because of the improvement in survival which is also welcome news during the period of this trial, in that there were less survival events, and the power is around 0.77 and we know that we can certainly say that it equates to less than 7.7% survival difference in the [per protocol] arm”, explained Janet Brown. 

In addition, the co-primary endpoint of noninferior quality-adjusted life years, assessed using the EQ-5D utility index, was met in both intention-to-treat and per protocol analyses, with the cost effectiveness of DFIS endpoint estimated to be met at 2 years, the presenter said. 

DFIS was superior to CCS for the secondary endpoints of strategy failure (time to death, disease progression or receipt of a new systematic therapy) and summative progression-free interval (interval accounting for disease response following a treatment break), with significant HRs of 0.75 and 0.77, respectively. 

Turning to safety, Janet Brown reported that DFIS-treated patients had fewer serious adverse events related to TKI therapy from week 24 onwards than their CCS counterparts (9.4 vs 11.7%). Of the 59 such events reported, just 39.0% occurred in the DFIS arm. 

The presenter concluded that “47.2% of patients in the DFIS arm who continued post week-24 had multiple treatment breaks” and these will be an “important group” for exploratory analysis assessing the characteristics of patients who benefited from a treatment break. 

Janet Brown observed that while immunotherapy is now used in the first line, “TKIs remained the most appropriate treatment for some patients in the first-line setting, and many others second-line.” 

Reference  

LBA28 - Brown JE, Royle K, Ralph C, et al. STAR: A randomised multi-stage phase II/III trial of standard first-line therapy (sunitinib or pazopanib) comparing temporary cessation with allowing continuation, in the treatment of locally advanced and/or metastatic renal cancer (RCC). Ann Oncol 2021;32(suppl_5): S1283–S1346. doi:10.1016/annonc/annonc741