ESMO Congress 2023 | OncologyPRO

Abstract 1043P

Background

TU2218 is a highly potent, oral dual inhibitor against TGFβ type I receptor (TGFβRI /ALK5) and VEGFR2. VEGF and TGF-β pathways play important roles in the function of TME, especially in immune tolerance inextricably related with poor outcomes of anti-PD-(L)1 therapy. This is a first-in-human study to investigate the safety and tolerability of TU2218 mono- and combination therapy with pembrolizumab.

Methods

This non-randomized, multinational, open-label study has been evaluating the safety, tolerability, PK, and preliminary efficacy of TU2218 mono- and combination therapy with pembrolizumab in advanced solid tumors. The eligible patients were aged ≥ 18 years, ECOG (0 or 1), and had measurable tumors per RECIST 1.1. TU2218 monotherapy was planned at 6 dose levels (30, 60, 105, 150, 195, 270 mg/day) with 2 weeks on and 1 week off in 3-week cycles according to the BOIN method. The starting dose of TU2218 given with pembrolizumab was determined after yielding TRAEs of at least Grade 2 in severity during monotherapy using the traditional 3+3 design.

Results

Seventeen patients with advanced solid tumors received 5 different dose levels of monotherapy. Major demographics, treatment-related adverse events (TRAEs) and PK parameters are summarized in the table.

Table: 1043P

Cohort	1	2	3	4	5
Total Daily Dose (mg)	30	60	105	150	195
N	3	4	4	3	3
Median age (Range)	54 (48-56)	61 (46-78)	70 (52-77)	72 (56-72)	65 (37-75)
Male/ Female	0/3	2/2	1/3	1/2	1/2
TRAE, n (Grade)	0	3 (G2)	2 (G2)	1 (G2)	6 (G2)
* G2 TRAEs were reported from 2 patients of Nausea, Dehydration, Fatigue in Cohort 2, 2 patients of Itching & Platelet Count Decreased in Cohort 3, 1 patient of Nausea in Cohort 4, and 3 patients of Itching, Skin Rash, Myalgia, Anorexia, Arthralgia & Mucositis oral in Cohort 5.
Mean PK Parameters
tmax (h)	1	0.7	1.6	1.2
Cmax (ng/mL)	95	162	374	781	1875
AUClast (ng·h/mL)	200	257	819	1854	3664
t1/2 (h)	2.1	1.7	1.7	2.6
* For cohort 5, simulated data

No TRAEs of Grade 3 or higher were reported while all Grade 2 TRAEs were tolerable in TU2218 monotherapy. Systemic exposure to TU2218 increased over-proportionally with the dose-escalation. The starting dose of TU2218 for the combination therapy with pembrolizumab was 105mg/day, with subsequent incremental doses of 150mg/day and 195mg/day. To date, clinical studies of TU2218 are ongoing.