SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.
More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.
Dr. John J. Bissler
Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.
"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.
"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.
The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."
Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.
Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.
The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.
The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.
Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.
Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.
Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).
Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.
There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.
Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.