EVEROLIMUS FOR LYMPHOMA

June 16, 2009 (Berlin, Germany) — Everolimus has shown single-agent activity in patients with relapsed non-Hodgkin's lymphoma and Hodgkin's disease in a proof-of-concept phase 2 trial. The results show that the drug's novel mechanism of action — the inhibition of mTOR kinase — is clinically relevant in these diseases, and further research along these lines might eventually lead to a new class of agents for a broad range of lymphomas, say researchers.

The results, reported here at the 14th Congress of the European Hematology Association, have already prompted the manufacturer, Novartis, to initiate a phase 3 trial in patients with diffuse large B-cell lymphoma.

Everolimus was recently launched as Afinitor for use in kidney cancer in the United States, and is awaiting approval for this indication in Europe. The drug is also being investigated in a number of other cancers, including breast, gastric, and hepatocellular carcinoma.

Sound Rationale for This Mode of Action

"There was sound rationale to test the mTOR inhibitors in lymphoma," said principal investigator Thomas Witzig, MD, from the Mayo Clinic in Rochester, Minnesota. He explained to Medscape Oncology that mTOR kinase is a key regulator of the PI3K signal transduction pathway, which is important to the growth and survival of cancer cells. It is also involved in Akt activation in diffuse large B-cell lymphoma and in cyclin D translation in mantle cell lymphoma.

The trial was conducted in 145 patients with relapsed lymphoma. They include 77 patients with aggressive non-Hodgkin's lymphoma, 41 with indolent lymphoma, 8 with T-cell non-Hodgkin's lymphoma, and 17 with Hodgkin's disease.

Patients received oral everolimus 10 mg daily and were evaluated monthly. They could remain on the drug until their disease progressed or until they developed toxicity.

The overall response rate was 33%, although the responses varied by disease subgroup. The best responses (53%) were seen in patients with Hodgkin's disease, Dr. Witzig noted.

"We were pleased to see responses in patients with heavily pretreated, relapsed lymphoma," he explained. In such a patient population "anything over 20% is considered of interest and worthy of further study," he said. The 33% seen in the trial is "a modest response rate and in line with other new agents, such as bortezemib," he added.

"The side effects were tolerable. Patients were able to stay on the drug for an extended period of time — some as long as nearly 3 years," he said.

"Although we are encouraged by the modest single-agent response to everolimus, we are not satisfied with 33%," Dr. Witzig added. His team has recently completed a phase 1 study that combined everolimus with another signal transduction inhibitor, sorafenib, which has a different mechanism of action.

The team hopes to achieve even higher responses by blocking 2 different pathways. "I am certain there will be other studies and combinations in the future," Dr. Witzig said, adding: "I believe that this will offer patients a new class of drugs for a broad range of lymphomas."

Phase 3 Study Already Begun

The phase 2 study was initiated by Mayo Clinic investigators, but Novartis supplied the drug and provided "a modest amount of money to support data collection, etc," Dr. Witzig told Medscape Oncology.

The results have prompted Novartis to initiate a larger, worldwide phase 3 study. This will be conducted in poor-risk patients with diffuse large B-cell lymphoma who have achieved a complete remission with the combination of first-line rituximab and chemotherapy. About 50% of such patients relapse, but there is no approved therapy for this group; this represents an unmet medical need, the company noted in a press release. The trial will evaluate the potential of everolimus to extend disease-free survival in these patients.

Dr. Witzig reports having been on advisory boards for Novartis, but was uncompensated (honoraria went to the Mayo Clinic).

14th Congress of the European Hematology Association: Abstract 1081. Presented June 8, 2009.