Benign Kidney Tumors Shrink With mTOR Inhibitor

Most patients with a nonmalignant form of kidney tumor had significant tumor shrinkage with the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor), a small multicenter clinical trial showed.

Within 4 months after the start of treatment for angiomyolipomas, tumor volume had shrunk by at least 25% in 10 of 18 evaluable patients. By 6 months, 10 of 14 patients had at least a 25% decrease in tumor. Median shrinkage at both time points was almost 60%.

Already approved for angiomyolipomas associated with tuberous sclerosis complex (TSC), everolimus demonstrated the potential to shrink tumors that arise sporadically. However, the clinical efficacy came with a toxicity tradeoff, as four patients discontinued the study because of protocol-defined toxicities, and eight others asked to be withdrawn because of toxicity, according to the study online in the Journal of Urology.

“The thought was that, if a tumor was big enough to treat and we could shrink it with this medication, maybe we could keep it at a smaller size and watch it, and maybe it will never have to be treated surgically,” Robert Uzzo, MD, of Fox Chase Cancer Center in Philadelphia, told MedPage Today. “The tumors shrunk on average by about 50%, but there were some toxicities to the medication, even though we were giving patients low doses.”

Background of Fatty Kidney Tumors

Angiomyolipomas are the most common type of benign kidney tumors. The most troubling risk posed by untreated angiomyolipomas is spontaneous rupture and bleeding, a risk that increases with the size of the lesion. In addition to being painful, angiomyolipoma rupture occasionally leads to acute life-threatening hemorrhage.

Surveillance, percutaneous embolization, percutaneous ablation, and surgical excision are accepted options for managing patients with a higher risk of hemorrhage (TSC, women of childbearing age), Uzzo and colleagues noted in their background information. Historically, clinicians have used a cutoff of ≥4 cm to guide decision making for surgical or percutaneous interventions. Both surgery and minimally invasive interventions confer some risk, including loss of renal parenchyma in the affected kidney and a long-term risk of chronic kidney disease.

Bilateral multifocal angiomyolipomas have a strong association with TSC and exhibit activation of mTOR. In a phase III, placebo-controlled trial involving 118 patients with TSC and one or more angiomyolipomas ≥3 cm, everolimus led to ≥50% reduction in target angiomyolipomas in 53.6% of patients versus 0% for placebo and had an acceptable safety profile. The results led to FDA approval of everolimus for angiomyolipomas associated with TSC.

Activation of mTOR also occurs in some sporadic angiomyolipomas, suggesting a role for mTOR inhibition in at least a subset of patients. Case reports documented mTOR inhibitor use in advanced angiomyolipomas and lesion progression after angioembolization, no prospective trials had assessed growth inhibition and outcomes in sporadic angiomyolipomas.

To inform the issue, investigators at five centers enrolled 20 adult patients with radiographically confirmed angiomyolipomas ≥3 cm, eligible for active surveillance, surgery, or percutaneous intervention. Patients were not tested for the mutation associated with TSC.

The trial had an accrual goal of 43 patients, with an early stopping point for interim safety and efficacy analysis after 20 patients. The investigators defined response as ≥25% reduction in tumor volume with everolimus and defined clinically interesting activity as a response rate of at least 25%.

Balancing Safety, Efficacy

The protocol specified early termination of the trial if three or more of the first 20 patients enrolled withdrew because of protocol-defined adverse events: any grade of noninfectious pneumonitis, grade ≥3 hyperglycemia or hyperlipidemia, grade ≥3 transaminitis, and any grade 4 event.

“Since this is a benign tumor, we really lowered the stopping rules for toxicity,” said Uzzo. “We did not want patients with benign tumors to suffer any adverse events that they shouldn’t have to endure.”

Patients received everolimus daily for four 28-day cycles, after which magnetic resonance imaging (MRI) was performed to assess tumor volume. Patients whose angiomyolipomas decreased by at least 25% after the first four cycles of therapy received an additional two cycles, followed by another MRI assessment. Treatment ended at four cycles for patients who had a 25% decrease in tumor volume.

The 20 patients had a combined total of 21 angiomyolipomas. Median age was 68, women accounted for 75% of the total study population, and median baseline tumor volume was 47.3 cc.

The median number of days on treatment was 64. Ten patients completed four cycles of everolimus and seven completed six cycles. Withdrawals because of protocol-defined toxicities consisted of two cases of pneumonitis and one each of mucositis and hyperglycemia.

All 10 responding patients met the response criteria after four cycles of therapy. The median tumor volume reduction was 58.5% at 4 months and 58.2% at 6 months. Five of 10 patients who underwent MRI at 12 months continued to meet response criteria (median volume reduction of 37.9%). Investigators noted volumetric regrowth in four of 10 patients at 4 months (mean 16.4%), increasing to a mean of 37.3% at 12 months in five of 10 patients who had MRI assessments.

All patients had at least one adverse event, most of which were grade 1/2 in severity. No grade 4 events occurred. The most commonly reported adverse events were consistent with the known safety profile of everolimus: oral mucositis, elevated transaminases, anemia, fatigue, hypercholesterolemia, and maculopapular skin lesions.

Whether everolimus becomes an accepted treatment for sporadic angiomyolipomas remains to be seen, said Uzzo, noting that the medication is FDA approved. The trial also left some key questions unanswered, most notably whether patients have to continue treatment long term or indefinitely to control tumor growth.