Novartis' Afinitor Goes To Panel Review With Trouble Areas For FDA

The Oncology Drugs Advisory Committee will review everolimus for certain advanced neuroendocrine tumors on April 12; the pivotal trial used progression-free survival and a crossover design, both areas that FDA has critiqued.

The use of a crossover trial design in a pivotal trial for Novartis' Afinitor (everolimus) may be an issue when it comes up for FDA advisory committee review on April 12.

FDA's Oncologic Drugs Advisory Committee will review the application for advanced neuroendocrine tumors of gastroinstestinal, lung or pancreatic origin. The panel will also consider Pfizer's Sutent (sunitinib) for unresectable pancreatic neuroendocrine tumors on the same day

In the Afinitor trial, patients who progressed while on placebo in the Phase III trial were allowed to switch to the active arm, for ethical reasons; this ended up happening for 148, or 73%, of the 203 placebo patients, according to an article in the Feb. 10 issue of the New England Journal of Medicine.

The result was to confound the detection of a treatment-related survival benefit, the authors note. An accompanying editorial also notes that any effect on overall survival is obscured by the crossover design, "an ethically sound design that compromises the assessment of overall survival." FDA officials have lamented the widespread use of crossover designs, which necessitate a separate study to assess overall survival, which may be difficult to conduct.

Nevertheless, the PFS results were very strong - a median 11 months in the 207 patients taking Afinitor, compared with 4.6 months for those on placebo - a 65% reduction in the risk of progression.

However, FDA's enthusiasm for PFS endpoints for oncology drugs has been waning, as the agency signaled in a letter to Genentech and a decision memo from Office of Oncology Drug Products Director Rick Pazdur about FDA's move to withdraw approval of Avastin (bevacizumab) for metastatic breast cancer (Also see "FDA's Avastin Decision Puts Pressure On Progression-Free Survival Endpoints" - Pink Sheet, 3 Jan, 2011.).

In the letter, FDA noted that PFS "is primarily determined by radiographic measurement of tumor(s) and may not correlate with symptomatic improvement or improved overall survival."

New Treatments Needed

But the setting matters, and "the five-year survival rate of patients with metastatic [pancreatic neuroendocrine tumors], which involves more than 50% of the cases reported in most studies, is 30% to 40% and has not changed for 20 years. ...Furthermore, studies of chemotherapy for these tumors report an objective response rate of 10% to 45%, responses are rarely complete and such treatment is associated with considerable adverse events," the editorial states.

Teva's Zanosar (streptozocin), approved in 1982, is the only therapy for pancreatic neuroendocrine tumors with FDA clearance, the study authors point out. The role of chemotherapy in late-stage disease is subject to debate, they add.

This lack of new treatments helps account for the enthusiasm for the results for Afinitor and Pfizer's Sutent, which is up for a similar indication and had similar results in more than doubling PFS ('Sunitinib Doubles Progression-Free Survival Of Advanced Pancreatic Neuroendocrine Tumors,' Health News Daily, Feb. 10, 2011).

"These studies provide optimism regarding the treatment of malignant pancreatic neuroendocrine tumors, because both drugs are effective at prolonging disease-free survival, even in patients in whom other treatments have failed, and thus offer effective therapies where there were none before," the NEJM editorial said.

One Study Drug-Related Death

Most adverse events in the Phase III trial were seen as manageable and consistent with previous experience with the drug, with similar rates as in the renal cell carcinoma trials despite a significantly longer exposure, the study authors comment.

There was a higher rate of death in the Afinitor arm: 12 deaths (6%) for the active arm vs. 4 (2%) in the placebo arm. The investigators thought five of the patient deaths in the active arm were due to the underlying disease, leaving another seven that were due to AEs, only one of which the investigators considered to be related directly to the drug - a patient who died of acute respiratory distress syndrome.

The most common drug-related adverse events were stomatitis (64% vs. 17%), rash (49% vs. 10%) and diarrhea (34% vs. 10%) - mostly grade 1 or 2. There was "a low rate of severe adverse events," the authors say. The safety profile is important for the NET therapy, which will likely be used long-term.

Infections and pneumonitis, which occurred in 23% and 12%, respectively, of the patients in the active arm, and interstitial lung disease, which occurred in 2% of these patients - versus no cases of these three conditions in the placebo arm - "represented some of the most important clinical concerns and were primarily grade 1 or 2," the study report says.

Novartis Oncology CEO and President David Epstein recently highlighted Afinitor as an example of the "sequential indication building" method that Novartis uses to grow many of its initially niche products into blockbusters (Also see "Novartis Sales Grow at Double Digits, Helped by Generics, Vaccines" - Pink Sheet, 27 Jan, 2011.). However, he noted that the trial results may lead to "a good debate" among ODAC members. Novartis is enrolling further trials in other tumor types including metastatic breast and gastric cancers.

Afinitor, an mTOR inhibitor, is already approved in the U.S. for renal cell cancer and for certain types of brain tumors.

Editor's note: An additional Phase III trial will be part of the advisory committee review as well. The RADIANT-2 trial, testing combination therapy with Novartis; Sandostatin LAR, failed to meet its primary endpoint, though the company argues there was some benefit.

-Martin Berman-Gorvine ( [email protected] )