Results from the first prospective trial of systemic treatment for von Hippel-Lindau (VHL) disease show that the antiangiogenic agent pazopanib (Votrient, Novartis) could offer a "realistic option" to surgical resection in patients with this rare, inherited cancer syndrome, say researchers.
The single-arm, nonrandomized phase 2 trial was conducted in 31 patients with VHL disease. It showed that pazopanib was associated with activity in renal cell carcinomas and pancreatic serous cystadenomas and demonstrated potential signs of activity in central nervous system (CNS) and retinal hemangioblastomas.
The study, led by Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, in Houston, was published online September 17 in the Lancet Oncology.
"The data from this study are potentially practice-changing for patients with von Hippel-Lindau disease because they provide an alternative approach to surgical intervention in the management of growing lesions," the authors write. There is no established systemic therapy for this disease, they note.
The autosomal dominant tumor predisposition disorder, caused by germline mutations in the VHL gene, affects approximately 1 in 35,000 live births each year.
It is characterized by a variety of highly angiogenic lesions that can be benign or malignant. Patients with VHL disease develop retinal, cerebellar, and spinal hemangioblastomas, renal cysts, clear cell renal cell carcinomas, pancreatic cysts, pancreatic neuroendocrine tumors, pheochromocytomas, endolymphatic sac tumors of the middle ear, and epidydimal or round ligament cysts.
Meningiomas, lung cancer, and testicular tumors have also been observed in VHL disease, although much less frequently.
Currently, VHL disease is managed with lifelong surveillance and surgery. Although life expectancy is good, patients' quality of life can be negatively affected by tumor-related symptoms, the side effects of treatment, and psychosocial factors.
Data from the phase 2 trial demonstrate a partial response to systemic pazopanib in 13 of 31 (42%) patients with genetically confirmed VHL disease or clinical symptoms of VHL disease. There was a response in 31 of 59 (52%) renal cell carcinomas, 9 of 17 (53%) pancreatic lesions, and 2 of 49 (4%) CNS hemangioblastomas.
The remaining 18 patients (58%) showed stable disease as the best response. Notably, stabilization of retinal hemangioblastomas could be good news for patients with declining visual acuity who are not eligible for standard treatment options, the researchers comment.
No patient had a complete response or experienced progressive disease, the study showed.
Side effects, such as fatigue, diarrhea, or transaminitis, were largely consistent with those seen in phase 3 clinical trials of pazopanib in patients with metastatic renal cell carcinoma, the researchers say. Serious treatment-related adverse events included one case each of appendicitis and gastritis and a fatal CNS bleed in one patient.
More research into the safety and activity of pazopanib is needed, they point out, but the drug offers the first systemic therapy for VHL disease.
At present, the disease is managed surgically after lesions have grown.
Renal cell carcinomas or neuroendocrine tumors larger than 3 cm can become metastatic, and symptomatic hemangioblastomas must be surgically removed to reduce the risk for permanent neurologic consequences, the team points out. Patients with retinal hemangioblastomas must undergo laser or thermal ablation to prevent irreversible retinal damage.
"The overall effect that these multiple tests and interventions have on the patient is substantial," the authors say. "Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients."
Ultimately, the hope is to delay progression of disease-related lesions so that patients are not faced with multiple surgeries, Jonasch told Medscape Medical News. Larger studies and longer follow-up are needed to assess any survival improvement, he said.
"Although the number of patients treated in this study is small, the findings are encouraging and suggest that pazopanib is a potential option for individuals with von Hippel Lindau disease who are harboring these lesions. We hope that as systemic therapies improve and surveillance strategies become more sophisticated, we can improve the lives of people living with von Hippel-Lindau disease by decreasing the burdens induced by both surveillance and intervention."
In an accompanying editorial, Rachel H. Giles, PhD, of the University Medical Center Utrecht, the Netherlands, and Sven Gläsker, MD, of the Universitair Ziekenhuis Brussel, Brussels, Belgium, confirm that this trial presents exciting new management options for patients with VHL disease. They note that data from the Dutch patient registry indicate that by age 60 years, most patients with VHL disease have been treated for seven tumors.
"This study carries the potential to reduce disease burden for patients with von Hippel-Lindau disease, particularly individuals who do not have standard treatment options available but do have a confirmed DNA diagnosis and small or no CNS hemangioblastomas," the editorialists write.
They note that, like sunitinib (Sutent, Pfizer), pazopanib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors. Both agents are indicated as first-line systemic therapy in select patients with clear cell renal cell carcinoma, as is another similar agent, sunitinib (Sutent, Pfizer), Giles and Gläsker note.
Hemorrhage is a known side effect of pazopanib, they point out. In a systematic review of targeted therapies for metastatic renal cell carcinoma, treatment-related hemorrhage accounted for 9% to 14% of reported all-grade bleeding events.
Although intracranial hemorrhage is rare in patients with VHL disease with CNS hemangioblastomas, "this risk might mitigate enthusiasm for treating a patient with pancreatic involvement, for example, if they also had hemangioblastomas with large solid components," Giles and Gläsker say.
The editorialists emphasize that because VHL disease is often assocaited with multiple comorbidities, "decision making within a multidisciplinary team in a specialist centre is highly recommended." Team members might include an oncologist, a neurosurgeon, an interventional neuroradiologist, a radiotherapist, an ophthalmologist, an otorhinolaryngologist, a nephrologist, a urologist, an endocrinologist, and a geneticist.
For the study, 31 of 32 patients recruited from the University of Texas MD Anderson Cancer Center received pazopanib (800 mg orally daily) for 24 weeks with the option of continuing treatment after that time. Radiographic assessments were conducted at baseline and every 12 weeks.
The study population consisted of 18 women and 14 men (median age at enrollment, 38 years). A total of 28 patients had either genetically confirmed VHL disease or a clinical diagnosis of disease and a strong family history.
All 31 patients who underwent treatment received a median of six cycles of therapy. The median follow-up was 12 months. For renal cell carcinoma, the median time to response, as determined using the Evaluation Criteria in Solid Tumors (RECIST), was 3 months. For hemangioblastomas and pancreatic lesions, the median time to RECIST response was 6 months.
Seven of 31 patients (23%) chose to continue treatment after 24 weeks. In many patients with renal cell carcinomas, there was no evidence of tumor regrowth. In others in whom initial shrinkage had occurred, slow regrowth was eventually treated with surgical resection, the researchers say.
Several patients with pancreatic serous cystadenomas chose to continue treatment and showed benefit after several years. Although not cancerous, these pancreatic lesions can be extensive in VHL disease and require resection, the authors point out.
Four patients who had negative results on VHL gene testing and multiple CNS or retinal hemangioblastomas did not respond to therapy.
Four patients (13%) withdrew because of grade 3 or 4 transaminitis. Three patients (10%) chose to discontinue treatment after 6 months because of grade 1 and 2 side effects. Although modest, these side effects resulted in a decline in quality of life that patients said was intolerable.
As of September 1, 2018, the longest time on treatment was 60 months.
Funding for the study was provided by Novartis Inc and the National Cancer Institute of the National Institutes of Health. Dr Janisch reported a relationship with Novartis. All other authors have disclosed no relevant financial interests. Dr Giles has disclosed relationships with Novartis, Roche, Pfizer, BMS, Eisai, Merck MSD, Ipsen, and Exelixis. Dr Gläsker has disclosed no relevant financial relationships.
Medscape Medical News © 2018
Cite this: Pazopanib Shows Promise in Rare Cancer Syndrome - Medscape - Oct 01, 2018.