Efficacy and Safety of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Abstract

Introduction: Denileukin diftitox (Dd) is a recombinant fusion protein of diphtheria toxin and human interleukin-2. Dd was approved and marketed as ONTAK in the US from 1999-2014 for treatment of pts with relapsed/refractory CTCL. ONTAK was voluntarily taken off the market in 2014 due to manufacturing difficulties. E7777 was developed as a result of a refined manufacturing process and has an increased percentage of protein monomer species, with a concomitant decrease in levels of misfolded protein and protein aggregates. E7777 has ~1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK and is considered a new drug by the FDA. Methods: Objectives: Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial designed to assess efficacy and safety of E7777 in patients with relapsed/refractory CTCL. E7777 was given IV at 9 mcg/kg/day (established from Lead-in) over 60 min for 5 days every 21 days up to 8 cycles. Key inclusion/exclusion criteria included histopathologic diagnosis of CTCL (MF or SS); ECOG performance status 0 or 1; no prior exposure to ONTAK. The primary efficacy endpoint was objective response rate (ORR; CR+PR) per Independent Review Committee (IRC) assessment based on Global Response Score GRS (Olsen, et al., 2011). Secondary efficacy endpoints included duration of response (DOR), time-to-response (TTR), skin response (according to modified Severity Weighted Assessment Tool [mSWAT]), safety and tolerability of E7777, PK, and immunogenicity. Exploratory objectives included progression free survival (PFS), time to progression (TTP), pruritus improvement, and quality of life assessment. Results: A total of 112 patients with CTCL stage I-IV were enrolled in the study: 21 in the Lead-in and 91 in the Main Study. The primary efficacy population is comprised of 69 patients with stage I-III CTCL treated at 9 mcg/kg/day. Median number of prior anticancer therapies in Study 302 were 4.0 (range: 1 to 18). Forty-five patients (65.2%) received ≥4 prior anticancer therapies. Approximately half (34 of 69; 49.3%) of patients had prior exposure to 1 or more FDA-approved targeted therapeutics: romidepsin, brentuximab, or mogamulizumab. Demographic and baseline characteristics of patients included a median age of 64 (range 28-87); ECOG status 0 (56.5%) and 1 (43.5%); Race: 72.5% White, 18.8% Black; 9% Other. There disease stages were 43.5% IA/IB/IIA; 34.8% IIB; and 21.7% IIIA/IIIB. The median (range) number of cycles of E7777 received was 6.0 (1, 42). The primary efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR. ORR (95% CI) by Investigator was 42.3% (30.6%, 54.6%), with 8.5% achieving a CR (Table 1). DOR was at least 6 months for 13 (52.0%) responders and at least 12 months for 5 (20.0%) responders. TTR was rapid (median=1.41 months); the majority of responders (~70%) had a response after 1 to 2 cycles of treatment. Treatment with E7777 did not demonstrate any new or unexpected safety findings as compared to prior ONTAK experience. Most patients (98.6%) experienced at least 1 TEAE. Most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles, then decreased and remained low/stable over the remainder of therapy. Key adverse events of special interest (AESIs) associated with ONTAK in the past (i.e. capillary leak syndrome, hepatotoxicity, infusion reaction, and visual impairment) were primarily Grade 1/2 in our current study and will be discussed in detail in a separate abstract. Conclusions: In study 302, E7777 at a dose of 9 mcg/kg/day demonstrated clinical efficacy and clinically meaningful benefit in heavily pre-treated patients with relapsed/refractory CTCL. The ORR of 36.2% per IRC (42.3% by investigator assessment) showed that a substantial proportion of these heavily pretreated patients experienced clinical benefit after E7777 treatment similar to ONTAK. The observed tumor responses were rapid, durable, and deep. A BLA submission to the FDA is planned for the 2nd half of 2022. E7777 will provide a novel, efficacious, safe, and non-cross-resistant therapeutic option for CTCL patients who have failed other treatments and thus fulfill a serious unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal