ESMO18: With tazemetostat update, Epizyme on track for first FDA filing

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Epizyme plans to file an NDA for tazemetostat in the first half of 2019. (Nadine Doerlé)

Epizyme presented updated data from a phase 2 trial of its lead asset, tazemetostat, in epithelioid sarcoma. The data, current as of Aug. 21, showed an objective response rate (ORR) of 13% across 62 patients, with treatment-naïve patients faring better than relapsed or refractory patients, having an ORR of 21% versus 8% respectively. 

“We believe these data will be sufficient for submission of our NDA,” said Epizyme CEO Robert Bazemore. The 13% ORR is “consistent with that shown in the 31 patients enrolled in the first half of the cohort,” he said. The FDA filing is on track for the first half of 2019, Bazemore said. 

While 13% might seem low, Bazemore and Epizyme Chief Medical Officer Shefali Agarwal emphasized that response rate isn’t the be all end all—survival and durability of response are also important in an aggressive cancer that has no specific treatments and is often fatal. Epithelioid sarcoma can be difficult to diagnose and therefore may not be discovered until it is advanced. 

Of the 62 patients, 24 had not been treated for the disease, while 38 had undergone prior treatment and relapsed. This might include multiple courses of chemotherapy or multiple surgeries, Agarwal said. The median survival of a treatment-naïve patient is about one year. This figure is less than six months in refractory patients, she said. 

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The median survival in relapsed and/or refractory patients was 47.4 weeks, nearly twice as long is typical in such patients. The median survival for all patients is currently at 82.4 weeks and it has not been reached in the treatment-naïve group. 

The disease control rate—a measure of patients with confirmed objective responses and those with stable disease for 32 weeks or longer—was 38% in treatment-naïve patients and 16% in refractory patients. 

“We are pleased with the clinically meaningful and durable objective responses observed in this study, with a number of stable disease patients who are still on treatment and have the potential to achieve an objective response in the future,” Agarwal said in a statement. 

“Some of those patients could respond, but even if they don’t, prolonged stable disease is important for them,” Bazemore said. 

Distal epithelioid sarcoma (the kind that starts in the soft tissue of a finger or limb) most commonly affects teenagers, while the proximal form (which starts in the torso) tends to affect adults, according to the Mayo Clinic. Either way, based on current survival rates, achieving stable disease in these patients could be just as good an outcome as an objective response, Bazemore said. 

In April, the FDA placed a partial clinical hold on EZH2 inhibitor tazemetostat, an enzyme that is overexpressed in multiple cancers. Despite not being able to enroll new patients with genetically defined solid tumors and hematologic malignancies, the company reported positive interim data for the drug in follicular lymphoma two months later. The FDA lifted the hold in September.

Analysts at Jefferies liked what they saw, saying in a note to clients today: “New Phase II pivotal epithelioid sarcoma (ES) data at ESMO shows positive efficacy profile for tazemetostat, with response rates, durability, OS, and good safety/tolerability vs chemo - thus looking very good in an unmet need w/ no FDA approved drugs.

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“PFS moved from 5.7 to 4.0 mos, but this is probably in part attributable to more pts and also inclusion criteria change for second set of 30 patients required to have "active disease progression"). (3) duration of response looks good and improved from >7.0 to >12.0 mos and (4) new overall survival (OS) is now at ~21 months and has not hit median in 1L pts so could continue to go higher.

“We think this ES dataset looks comparable to standard of care (chemo) and is approvable. FDA has suggested maintaining ~13% ORR rate on 60 pts with strong durability of response and PFS/OS could be approvable. As a broad comparison, oral pazopanib (Votrient) shows 4% ORR and 4.6-month PFS (vs 13% ORR and ~4-5 mo PFS for Tazemetostat in ES), while chemo shows 5-7% ORR and 2-4 mo PFS in other sarcomas.

“Tazemetostat's duration of response (DoR) of 12+ months looks better than 6.9 mo for JNJ's chemo Yondelis in liposarcoma. We also think the efficacy looks comparable to chemo combos (Lartruvo + Doxirubicin), which have shown 4.6 mo PFS, 11.9 mo OS and 9.0 mo DoR.”

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