Abstract CT164: A phase II trial of cabozantinib with atezolizumab in refractory, metastatic pancreatic adenocarcinoma

Abstract Background: PDAC has a devastating prognosis and has been notoriously resistant to checkpoint inhibitors (CPI), primarily through mechanisms of immune suppression within the tumor microenvironment (TME). Our preclinical studies in patient PDAC tumor-derived organoid models and spatial biology analyses demonstrate that cabozantinib (C), a multitargeted tyrosine kinase inhibitor, depletes the TME of the myeloid derived suppressor cells (MDSCs) after which treatment with a checkpoint inhibitor leads to an influx of activated CD8+ T lymphocytes (CTLs) and tumor cell death. We investigated this approach in a phase II clinical trial in refractory metastatic PDAC pts. Methods: A single-arm, Simon two-stage, phase II study was conducted in PDAC pts with ≥ 1 prior line of treatment. C was given at 40 mg PO daily and A at 1500 mg IV every 3 wks. Restaging with CT or MRI was performed every 9wks until disease progression. Safety evaluable was defined as pts who received 1 dose of treatment. Efficacy evaluable included only pts who had imaging completed at 9wks. Primary endpoint was 9wk disease control rate (DCR) as per mRECIST. 10 pts enrolled in the first stage. If at least 1 pt demonstrated response (PR) or SD, an additional 19 patients were enrolled. Secondary endpoints included progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier methods. Exploratory objectives included longitudinal biospecimen collections from pts pre- and on-treatment and analysis by spatial omics. Results: Median follow-up was 4mths. A total of 29 pts enrolled (n=4 SD in first 10 pts), with 67% male, median age of 72. Median number of prior therapies was 3. 27 pts were evaluable for efficacy and 29 for safety. 15 pts response evaluable with a DCR of 47% at 9 wks (n=7 SD, 3 for ≥18 weeks, 1 PR as best response for 90 weeks). Median PFS was 2.4 mths (n=25, 95%CI 2-4 mths), median OS was 4 mths (n= 21, 95%CI 3-11 mths). 74% of pts had a grade 3 or greater adverse event (AE) with the most common AEs being hypertension, sepsis, thromboembolic event, and electrolyte disturbances. The TME of pts exhibiting SD or PR showed that C/A correlated with depletion of the MDSCs and a reprogrammed stroma leading to an infiltration of granzyme+ CTLs. Pts with PD exhibited a TME with persistent infiltration of CD11b+MDSCs, desmoplastic stroma and therapy resistant cancer stem cells. Conclusion: The combination of C/A in PDAC showed a higher DCR at 9 wks compared to historical controls in a highly refractory population. No new safety signals were seen. The combination demonstrated an increased influx of activated CTLs in ptswith PR or SD. Spatial biology and organoid technologies have revealed a multitargeted effect of C in reprogramming the TME and potential optimization of the efficacy of A in PDAC pts. (NCT04820179) Citation Format: Rachna T. Shroff, Junaid Arshad, Chiu-Hsieh Hsu, Gongzheng Yao, Prisca Zimmerman, Michele Chu-Pilli, Aaron J. Scott, Saptarshi Mallick, Jayati Chakrabarti, Yana Zavros. A phase II trial of cabozantinib with atezolizumab in refractory, metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT164.