PROJECT SUMMARY
Lung cancer is the leading cause of cancer-related death in men and women in Western countries, with non-
small cell lung cancer (NSCLC) accounting for ~85% of all lung cancer cases. Response rates to chemotherapy,
newer targeted therapies, and immune checkpoint inhibitor (ICI) monotherapy remain unsatisfactory and new
treatments are needed for NSCLC. Elevated levels and activation of signal transducer and activator of
transcription (STAT) 3, a transcription factor that serves as a master regulator of cancer, occur in most NSCLC
tumors and are associated with worse survival and ICI resistance mediated, in part, through the actions of
myeloid derived suppressor cells (MDSC) in the tumor microenvironment (TME). STAT3 activation also may
contribute to ICI-mediated immune-related severe adverse events (irSAE). The Tweardy group, working with a
clinical-stage biotechnology company (Tvardi Therapeutics, Inc.), used computer-based docking and lead-
compound optimization strategies to identify TTI-101, a potent, non-toxic and orally bioavailable inhibitor of
STAT3. TTI-101 hit target and blocked tumor growth in preliminary studies using the CC-LR K-ras mutant mouse
model of NSCLC and in published studies in nude mice bearing xenografts of the LKB1-null human NSCLC cell
line, A549. A Phase 1, dose-escalation study of TTI-101 monotherapy in patients with advanced/refractory solid
tumors (NCT03195699) completed enrollment in Q3 2022 and revealed no dose limiting toxicities or fatal
treatment-related adverse events and identified a RP2D. TTI-101 administration reduced levels of activated
STAT3 within tumors by 57% and was beneficial in 21 of 39 (54%) evaluable patients, including 5 confirmed
partial responses. Based on these results, TTI-101 was granted FDA Fast Track designation and has emerged
as the most promising small-molecule STAT3 inhibitor in clinical development to treat cancer. Our long-term
translational goal is to improve outcomes in patients with recurrent or metastatic (RM) NSCLC. The main
objective here is to determine if STAT3 targeting with TTI-101 is beneficial in treatment of RM NSCLC. The
specific aims designed to achieve this objective are: 1) to determine if TTI-101 alone or in combination with anti-
PD-1 monoclonal antibody is effective in treatment of NSCLC in the K-ras mutant (CC-LR) mouse model, 2)
determine the anti-tumor efficacy and immune-modulatory effects of TTI-101 alone or in combination with anti-
PD-1 in immune-competent mouse models of K-ras and Stk11/Lkb1 (KL) co-mutated NSCLC, and 3) determine
the safety and anti-tumor efficacy of STAT3 inhibition with TTI-101 in combination with pembrolizumab (anti-PD-
1) in previously treated patients with KRAS and STK11/LKB1 (KL) co-mutated RM NSCLC in a Phase IB/II
clinical trial. We will obtain tumor biopsies pre- and post-treatment in the Phase II trial and perform correlative
studies that include determining the relationships between pharmacokinetics, pharmacodynamics, the TME, and
clinical responses in patients and mice with NSCLC treated with TTI-101 alone or in combination with anti-PD-1
therapy. If successful, our research will improve survival and decrease toxicity in patients with RM NSCLC.
