There are limited treatment options for patients with PTCL and CTCL, especially when front line therapy has failed. Tolinapant (ASTX660) is a novel oral non-peptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which also induces necroptosis. Tolinapant is being evaluated in a first-in-human ongoing Phase I/II study in subjects with advanced solid tumors and lymphoma (NCT02503423). Phase I and the initial Phase II results were previously reported (Mita et al. Clin Cancer Res, 2020; Mehta et al., EHA 2019).
Here we report the preliminary efficacy and safety analysis for the Phase II PTCL and CTCL cohorts.
This is a single-arm open-label Phase II study. To be eligible, subjects must have documented progressive disease and received at least two prior systemic therapies. Subjects received tolinapant at the recommended Phase II dose of 180 mg/day on Days 1 to 7, and 15 to 22 in a 28-day cycle. The primary endpoint is investigator assessed best overall response rate (ORR) to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03. The efficacy data set is based on subjects who had tumor evaluation at baseline and at least 1 post-treatment evaluation, unless they died or stopped treatment due to progression or toxicity. The safety data set is based on all subjects that received at least one dose of tolinapant.
There were 98 PTCL subjects and CTCL 51 subjects that received drug with 98 and 50 evaluable, respectively. Enrollment is closed with a minimum of 6 months follow-up on all subjects at the time of the data cut (05JAN2022). Subject characteristics: median (range) age PTCL 62.5 (27, 82) and CTCL 62 (24,87), median number of previous therapies PTCL 3 (0-8) and CTCL 6 (1-10). Among all subjects, the most common related AEs of any grade (≥ 15%) were: lipase elevation (35%), amylase elevation (25%), rash (combined listings) (24%), ALT elevation (15%), and AST elevation (15%). Related AEs ≥ Grade 3 (≥ 5%) were: lipase elevation (15%), rash (9%), and amylase elevation (7%). Pancreatitis was identified in 2 subjects (1%) (both Grade 4). There were no related ≥ Grade 3 AEs for diarrhea, nausea or vomiting; for related Grade 2 AEs there was a 5% incidence of diarrhea and 1% incidence of nausea/vomiting.
The ORR for PTCL is 22%, including 9 complete responses (CRs) and 12 partial responses (PRs). The ORR in CTCL is 26% including 2 CRs and 11 PRs. The median durability of response for PTCL is 133 (Q1-Q3; 69 – 280) days and for CTCL is 148 (Q1-Q3; 103 – 294) days.
In this Phase II study, the novel oral agent tolinapant has shown meaningful single-agent clinical activity against PTCL and CTCL with a manageable safety profile. A new PTCL study combining tolinapant with oral decitabine/cedazuridine in relapsed/refractory PTCL is currently enrolling subjects.
This abstract has been presented at EHA 2022.