After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

P1, N=60, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression.

The Ang/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

P1, N=60, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Feb 2023 --> Feb 2024

P1, N=193, Completed, Mirati Therapeutics Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Apr 2022

Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination demonstrated antitumor activity and encouraging survival in CPI-experienced patients with non-squamous NSCLC.

Our study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.

P2, N=3, Terminated, C. Kent Osborne, MD | N=30 --> 3 | Trial completion date: Feb 2026 --> Jan 2023 | Recruiting --> Terminated | Trial primary completion date: Feb 2024 --> Jan 2023; Terminated by sponsor due to lack of interest

P3, N=420, Ongoing, BeiGene, Ltd.

P1, N=193, Active, not recruiting, Mirati Therapeutics Inc. | Unknown status --> Active, not recruiting | Trial completion date: Nov 2020 --> Dec 2022 | Trial primary completion date: Aug 2020 --> Apr 2022

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Oct 2022 --> Mar 2023 | Trial primary completion date: Oct 2022 --> Mar 2023

Sitravatinib plus tislelizumab demonstrated a manageable safety/tolerability profile and antitumor activity in systemic therapy-naïve patients with PD-L1+, locally advanced/metastatic nonsquamous NSCLC. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Tamsin Grewal, MSc, and Louise Oakes, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Sitravatinib plus tislelizumab demonstrated a manageable safety/tolerability profile and antitumor activity in systemic therapy-naïve patients with PD-L1+, locally advanced/metastatic squamous NSCLC. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Tamsin Grewal, MSc and Louise Oakes, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

P1/2, N=42, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Apr 2024 --> Sep 2022 | Trial primary completion date: Apr 2023 --> Sep 2022

P2, N=30, Recruiting, Haider Mahdi | Not yet recruiting --> Recruiting

Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

Furthermore, by using TIE-2 kinase-specific inhibitors such as regorafenib or rebastinib, we demonstrated that an active TIE-2 signaling was required for optimal suppressive activity of these cells after ANGPT2 exposition. Collectively, these results support that TIE-2 M-MDSC/ANGPT2 axis represents a potential immune escape mechanism in melanoma.

P2, N=96, Recruiting, Fudan University | N=61 --> 96 | Trial completion date: Jan 2023 --> Jun 2023

A total of 420 pts will be randomized (1:1) to take TIS 200 mg intravenously (IV) once every three weeks (Q3W) plus sitravatinib 100 mg orally once a day, or docetaxel monotherapy 75 mg/m 2 IV Q3W, until disease progression, intolerable toxicity, or death. Secondary endpoints include investigator-assessed (INV) PFS, IRC-assessed objective response rate (ORR), duration of response (DoR), disease control rate (DCR), quality of life, safety, and pharmacokinetics (PK) of sitravatinib. Exploratory endpoints include INV-assessed ORR, DoR, DCR, PK of the active metabolite of sitravatinib, predictive and prognostic value of PD-L1 expression, and biomarker analysis.

Initial screening (300 drugs, including 33 MET-TKIs) was performed using Ba/F3 cells carrying METex14 plus MET D1228A/Y because anecdotal case reports suggested that D1228X mutations were more refractory to second-line MET-TKIs than Y1230X mutations.This screening found four candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). We then performed further growth inhibitory assays using these four candidates plus other four MET-TKIs (type Ib; capmatinib and tepotinib, type II; cabozantinib and merestinib) in Ba/F3 cells carrying METex14 plus one of MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations... The type II MET-TKI foretinib may be an appropriate second-line MET-TKI for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at D1228 or Y1230 residues.212

Sitravatinib plus tislelizumab demonstrated a manageable safety and tolerability profile as well as antitumor activity in patients with PD-L1+, locally advanced or metastatic squamous NSCLC who had not received prior systemic treatment in the metastatic setting.

Sitravatinib plus tislelizumab showed a manageable safety and tolerability profile and demonstrated antitumor activity in patients with PD-L1+, locally advanced or metastatic non-squamous NSCLC who had not received prior systemic treatment in the metastatic setting.

The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.

Sitravatinib plus tislelizumab demonstrated a manageable safety and tolerability profile as well as antitumor activity in patients with PD-L1+, locally advanced or metastatic squamous NSCLC who had not received prior systemic treatment in the metastatic setting.

P2 | "The I-SPY2 platform trial tests novel agents given neoadjuvantly with a backbone of taxol (T) and trastuzumab (H) followed by doxorubicin and cyclophosphamide. Agents investigated in HER2+ bc were TH (control), MK2206, AMG386, pertuzumab (P), neratinib (N (given in place of H), and TDM1+P (given in place of TH)... pCR rates for patients with HER2+ bc treated with investigational agents, particularly dual HER2-blockade, were promising. Molecular response predictive subtype classification provides insight on how to better target therapy. The HER2+/Luminal group had low pCR rates with dual HER2-blockade but may have higher pCR rate with the addition of an AKT inhibitor and identifies a subgroup of HER2+ tumors in need of novel approaches."

To determine the pharmacodynamics of immune cells in ascites, syngeneic ID8 mice were pre-treated with 10 mg/kg/day rebastinib/control for a week, followed by rebastinib with or without 20 mg/kg carboplatin + 12 mg/kg paclitaxel (chemo) for two weeks. Rebastinib exerts differential effects on tumor cells and macrophages that could contribute to its mechanism of action. Rebastinib alters immune cells and increases cytotoxic T cells in ascites. Rebastinib combined with chemotherapy extends survival in PDX and syngeneic ID8 murine models of ovarian cancer.

Legal entity responsible for the study BeiGene Ltd. Funding BeiGene Ltd.

Median PFS was 4.1 months (95% CI, 4.0-5.1; preliminary median OS was 12.9 months (95% CI, 6.3-17.2. Conclusions : Sitravatinib plus tislelizumab was manageable with preliminary antitumour activity in patients with advanced PROC; further investigation is warranted.

P2; Trial completion date: Dec 2026 --> Dec 2031 | Trial primary completion date: Dec 2025 --> Dec 2030

P1, N=60, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2020 --> Feb 2023

Sitravatinib + tislelizumab was tolerable and showed preliminary antitumor activity in pts with advanced PROC. Further investigation of sitravatinib + tislelizumab in PROC is warranted.

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P1 --> P2

Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of melanoma patients.

Conclusions Our findings suggest that the activity of anti-PD-1 and ang-2 peptibody (trebananib) combination is hindered by an increase in immunosuppressive myeloid cells leading to decrease in memory and effector T cell populations. The association between baseline activated NK cell and the expansion of cytolytic NK cells with favorable outcomes should be further explored.

Conclusions Our findings suggest that the activity of anti-PD-1 and ang-2 peptibody (trebananib) combination is hindered by an increase in immunosuppressive myeloid cells leading to decrease in memory and effector T cell populations. The association between baseline activated NK cell and the expansion of cytolytic NK cells with favorable outcomes should be further explored.

Our results provide moderate quality evidence that bevacizumab-taxanes-capecitabine maybe the most effective bevacizumab plus chemotherapy on PFS and ORR in HER2-negative metastatic breast cancer, however it should be also considered that bevacizumab may add toxicity to chemotherapy and whether improve overall survival (OS) or not.

P1, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P2 --> P1

In vitro, ANGPT2443 was susceptible to proteolytical cleavage, resulting in a monomeric ligand (ANGPT2DAP) that inhibited ANGPT1- or ANGPT4-induced TIE2 activation but did not bind to alternative ANGPT2 receptor alpha5beta1 integrin. Collectively, these data reveal novel roles for the ANGPT2 N-terminal domain in blood vessel remodeling, tumor growth, metastasis, integrin binding, and proteolytic regulation.

All received ≥ 1 prior regimen with paclitaxel/carboplatin; the median number of prior therapies was 5 (2, 7). Funding: Deciphera Pharmaceuticals, LLC. Clinical trial identification: NCT03601897.

P1, N=60, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting