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Alternating treatment fails to delay progression of advanced renal cell carcinoma
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An 8-week treatment rotation of pazopanib and everolimus failed to improve survival or quality of life in patients with advanced renal cell carcinoma, according to results from the multicenter, open-label, randomized phase 2 ROPETAR clinical trial.
Guidelines recommend treating renal cell carcinoma with VEGFR tyrosine kinase inhibitors followed by mTOR inhibitors or a different second-line VEGFR–TKI. However, treatment is limited by the development of drug resistance and disease progression.
Resistance is reversible in some patients after drug withdrawal. In addition, the rotation of two drug classifications may also improve efficacy and tolerability.
“Alternating two different agents with only partially overlapping toxic effect profiles and targeting different pathways may allow patients to recover from incurred toxic effects while being treated with another active agent,” Emile E. Voest, MD, PhD, professor of medical oncology and medical director of the Netherlands Cancer Institute, and colleagues wrote. “This may lead to improved quality of life and treatment compliance.”
The researchers randomly assigned 101 patients to a rotating treatment schedule (n = 52) — treatment with 8 weeks of 800mg daily pazopanib (Votrient, Novartis) followed by 8 weeks of 10mg/d of everolimus (Afinitor/Zortress, Novartis) — or continuous treatment (n = 49) with pazopanib until disease progression.
After progression, patients received a final rotation of either pazopanib or everolimus monotherapy if they were in the rotating-treatment arm, or initiated everolimus treatment if they were in the control arm.
Survival until first progression or death served as the primary endpoint. Secondary outcomes included time to second progression or death, toxic effects and quality of life.
Median survival until first progression or death was 7.4 months (95% CI, 5.6-18.4) among patients who underwent treatment rotation compared with 9.4 months (95% CI, 6.6-11.9) in the control arm.
However, the rotation arm demonstrated superior median time to second progression or death (20.2 vs. 14.5 months; HR = 1.02; 95% CI, 0.59-1.76).
Time between first and second progression was 4 months occurred in the rotating arm (95% CI, 1.8-9.2) compared with 3.3 months (95% CI, 1.9-7.9) in the control arm, which was not a significant difference.
Overall, 45% (95% CI, 33-60) of the rotating treatment group and 32% (95% CI, 21-49) of the control arm achieved 1-year PFS.
The rotating treatment arm had longer median OS (35 months; 95% CI, > 12.2 vs. 18.5 months; 95% CI, > 14.7), but there was no significant difference in OS between the arms (HR = 0.9; 95% CI, 0.51-1.58).
Adverse events in the rotation and control arms included mucositis (35% vs. 8%), anorexia (39% vs. 22%) and dizziness (16% vs. 2%).
Sixteen patients (31%) in the rotating arm switched to pazopanib monotherapy and four patients (8%) switched to everolimus monotherapy as second-line treatment, whereas 18 patients in the control arm received everolimus as second-line treatment and two patients continued on pazopanib despite disease progression.
No difference in quality of life was observed.
The researchers noted these results did not support their hypothesis and, therefore, questioned whether the interval of 2 months was optimal.
“It could be argued that pazopanib and everolimus induce similar resistance pathways, thereby, overriding the benefit of rotating drugs,” they added. “This requires further research.” – by Kristie L. Kahl
Disclosure: Voest reports consultant roles with Biogeneration Ventures and InteRNA; and research funding from AstraZeneca, GlaxoSmithKline, Novartis, Pfizer and Roche/Genentech. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Brian Rini
Although therapy targeted against the vascular endothelial growth factor (VEGF) receptor and mammalian target of rapamycin (mTOR) has achieved disease control and prolonged survival in metastatic renal cell carcinoma (mRCC), resistance to these therapies is universal. Several strategies to overcome this resistance have been tested in clinical trials largely without success.
Cirkel and colleagues published the results of a novel approach to the resistance problem, namely alternating therapy between a VEGF-R inhibitor and an mTOR inhibitor. Researchers randomly assigned 101 patients with treatment-naive mRCC to either alternating 8-week courses of pazopanib (Votrient, Novartis) followed by everolimus (Afinitor/Zortress, Novartis) or continuous pazopanib at standard dose and schedules. The researchers hypothesized — based on limited animal model data — rotating treatment would delay resistance and improve tolerability due to nonoverlapping toxicities.
Unfortunately, there were no significant differences in any of the clinical outcome measures, nor were tolerability or quality of life improved with a rotating schedule.
Several explanations are offered by the researchers for the negative results, but ultimately this clinical trial does not support such an approach or offer a strategy to overcoming targeted therapy resistance in mRCC. Other recent data look at a rotating schedule, albeit with periods on therapy — sunitinib (Sutent, Pfizer) — alternating with periods completely off drug. Although these data are from a single-arm trial and only demonstrate feasibility, clinical outcome appeared preserved. A larger randomized trial of this approach is in progress.
Additional active surveillance data in mRCC support a hypothesis that optimizing the benefit–risk of targeted therapy — and thus delaying resistance by delaying the start of therapy — in mRCC can be achieved in select patients with periods of time completely off systemic therapy.
Further, recent clinical data in VEGF–refractory mRCC with cabozantinib (Cometriq/Cabometyx, Exelixis), which inhibits c-MET and AXL receptors in addition to the VEGF receptor, supports that simultaneous targeting of additional receptors may have clinical advantages.
Looking forward, checkpoint inhibitors are being vigorously tested in mRCC both as monotherapy and increasingly in combination with targeted therapy. The optimal duration for each component of a combination therapy, especially in light of the potentially durable antitumor T-cell response generated by checkpoint inhibitors, will require careful prospective study.
Thus, at present, continuous targeted therapy remains a standard of care in mRCC. However, strategies to optimize benefit–risk including delayed start of therapy, intermittent drug holidays and inhibiting other targets are emerging. Further clinical trials to explore timing and rotation of therapy, as well as translational investigation to uncover mechanisms of resistance to targeted therapy are needed.
References:
Choueiri TK, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30107-3.
Ornstein MC, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.71.1184.
Rini BI, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30196-6.
Disclosure: Rini reports a consultant role with Exelixis, and a consultant role with and research funding from Pfizer.
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