Though they made known their reservations about the patient sample size and queried front-line vs. second-line use of tazemetostat, members of the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11-0 to recommend approval of the oral, first-in-class EZH2 inhibitor from Cambridge, Mass.-based Epizyme Inc.

Designed to treat metastatic or locally advanced epithelioid sarcoma (ES) not eligible for curative surgery, tazemetostat yielded data for the application from the 62-patient ES cohort of an ongoing phase II study. Ahead of the meeting, Jefferies analyst Michael Yee characterized the package of briefing documents as “pretty cautious, but this was expected as that is the whole point of the review and an adcom meeting.” About 120 patients are diagnosed with ES in the U.S. per year, and the soft-tissue cancer is “extraordinarily aggressive” with a dismal prognosis, panel member Richard Riedel of the Duke Cancer Institute in Durham, N.C., pointed out. It also strikes younger people more than many other cancers; the median age of patients in Epizyme’s trial is 37.

Specifically, the balloting question was, “Does the demonstrated benefit of tazemetostat outweigh the risks of the drug in the proposed indication?” Panelists discussed the observed overall response rate (ORR) of 15% in cohort 5 of study EZH-202 and 11% in cohort 6, with pooled ORR of 13% observed across cohorts, and duration of response ranging from 3.5 months to ≥24 months.

ODAC liked the duration of response for a small indication with high unmet need in a fatal cancer that has a limited number of treatment options, along with tazemetostat’s favorable safety/tolerability profile and impressive efficacy in the second-line setting.

Randy Hawkins, consumer rep from the department of internal medicine/pulmonary and critical care at Charles R. Drew University of Medicine and Science in Los Angeles, said he balanced the small patient numbers with the need in a rare disease. “I was impressed enough to say we should have this added to the toolkit of the oncologist,” he said. Anthony Sung, from Duke’s adult blood and bone marrow transplant clinic, said he “remain[s] unconvinced by the data in the first-line setting” and doubted tazemetostat is superior to existing therapies such as doxorubicin, at least according to findings available so far. He suggested approval of the drug for second-line use, a move that would “leave room for the proposed randomized clinical trial to occur in the front-line setting, because I think that question is still undecided.” He also urged Epizyme to build quality of life (QoL) measures into experiments, as sponsors in the past have come before ODAC to suggest QoL benefits with their drugs “but they do not have the data to back that up.”

Philip Hoffman, professor of medicine at the University of Chicago’s section of hematology and oncology, said he liked the duration of responses and safety. “While the concern for [patients developing] second malignancies is out there, it seems quite rare,” and is likely a concern “really not very important to that group of patients,” given the disease’s prognosis. Yet another Duke panelist, Susan Halabi, professor of biostatistics and bioinformatics, voiced concern about second malignancies, “but the data [are] missing. Definitely there needs to be a longer duration of follow-up” of cohorts 5 and 6, so that questions can be answered. She proposed that Epizyme “pick a clinically meaningful endpoint in your phase III trial, because I’m not convinced that progression-free survival [PFS] is your best endpoint.”

Up next, NDA in bigger-market follicular lymphoma

At administrative pre-NDA meetings, the FDA and Epizyme reached accord on the format and content for the proposed submission, though regulators said the ORR of 13% observed to date may be insufficient to serve as evidence of a treatment effect reasonably likely to predict clinical benefit in patients with locally advanced or metastatic ES. In 2017, the FDA designated tazemetostat an orphan drug for the treatment of soft tissue sarcoma. Also granted were fast track and priority review statuses for metastatic or locally advanced ES who have progressed on or following an anthracycline-based regimen.

In April 2018, the FDA placed IND trials relating to tazemetostat on clinical hold to allow time for analysis of the risk of secondary malignancies, including T-cell lymphoblastic lymphoma (T-LBL) potentially associated with the drug. The move followed a report of a case of T-LBL in a tazemetostat pediatric study. Gatekeepers lifted the hold in September 2018.

SVB Leerink analyst Andrew Berens said the panel vote caught him off guard. “While we had anticipated a favorable outcome, we were surprised by the universal endorsement by the ODAC panel,” since many members also were also present Tuesday to examine prospects for London-based Astrazeneca plc’s Lynparza (olaparib), “which received a more modest, favorable endorsement.” The committee voted 7-5 that the benefits for Lynparza as a frontline maintenance agent in susceptibility gene BRCA-mutated pancreatic cancer outweigh the risks. Talk focused mainly on the FDA's concerns raised in the briefing documents, including clinical relevance of a PFS benefit in the absence of overall survival upside or definitive improvement in patient quality of life vs. the placebo comparator. Poly ADP-ribose polymerase inhibitor Lynparza was first approved in late 2014 for advanced ovarian cancer.

Jefferies’ Yee didn’t see the unanimous vote for tazemetostat coming, either. Ahead of the ODAC meeting, he guessed “a 20-25% probability of a positive vote,” while saying a turndown would “not really change our thesis of significant upside potential from a potential approval in follicular lymphoma [FL],” which makes up an estimated $500 million-plus market vs. less than about $50 million for ES. The latter is “merely the lead indication to get the drug out in the market early, but the bigger and more important population of FL is pretty close behind,” he wrote, and Epizyme disclosed submission of the NDA late Wednesday. Approval in FL could happen by the summer or fall of next year. Yee cited a 75% to 80% probability of success in the indication, noting in a report after the adcom ES vote that the drug in FL has been “partially de-risked.”

Epizyme shares (NASDAQ:EPZM), trading of which was halted while ODAC was in session, closed at $20.09, up $1.90, or 10.5%.

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