Abstract PR005: Countering adenosine (ADO) in rectal cancer to improve RT responses to immune checkpoint blockade: a trial to test the safety and efficacy of PD1 (AB122) and ADO dual receptor (AB928) antagonists with chemotherapy after short-course RT

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Abstract Background: Rectal cancer (RC) is unresponsive to single agent immune checkpoint blockade (ICB), with the exception of microsatellite instability (MSI) high tumors. Neoadjuvant radiotherapy (RT), however, is a standard treatment for locally advanced RC. A recent analysis of RC showed that upregulation of genes reflecting an increased T cell-inflamed and IFN-I response in post-RT samples compared with pre-RT biopsies correlated with pathological responses. The efficacy of combining RT with ICB in RC remains a focus of several ongoing and recently reported clinical trials. Extracellular adenosine (eADO) signaling, an important immunosuppressive pathway in RC, may hinder immune activation as TCGA and our preclinical data, respectively, suggests that eADO generation and signaling is elevated at baseline and exacerbated by RT. In mouse models, inhibition of eADO generation improved systemic responses to ICB in otherwise refractory tumors. Hypothesis: We hypothesize that inhibition of ADO signaling in RC is safe and an effective method to enhance RT-induced anti-tumor T cell responses as a means to sensitize RC to RT and anti-PD1 therapy. Brief Methods: NCT05024097, PANTHER RC trial, is a prospective phase I-II neoadjuvant study in patients with locally-advanced RC. Patients receive upfront (wk 1) SC-RT (25 Gy in 5 fx) to the pelvis in combination with the dual A2aR/A2bR (adenosine receptors) antagonist etrumadenant (AB928). Chemotherapy (wks 3-15), mFOLFOX x 6 cycles, is given with etrumadenant and anti-PD1 antibody zimberelimab (AB122). All patients undergo clinical response assessment (weeks 17-20) followed by watch and wait (if cCR) or total mesorectal excision for pathologic response assessment. The primary endpoint is the proportion of patients who achieve a CR. Secondary endpoints include 3-year disease-related treatment failure and 5-year overall survival. Part I is a modified 3+3 safety run-in for etrumadenant plus SC-RT. Part II is an open label single arm Simon’s 2-stage optimal design. With a sample size of 27 patients (stage 1 = 15 patients and stage 2 =12 patients) the trial is powered to detect a CR rate of 25% or less versus the atlernative, at least 45%. Results: To date 21 patients have enrolled. One of six patients accrued to part I experienced a grade 3+ treatment related toxicity. A CR was observed in one of five (20%) evaluable patients. In part II, the first eleven of fifteen accrued patients to stage 1 completed treatment and were assessed for response. A CR rate of 82% (4 pCRs, 5 cCRs, 2 pPRs) was observed. The trial is anticipated to proceed to stage 2 and accrue an additional twelve patients (27 total). Conclusion: The preliminary responses are promising and patient enrollment is ongoing. Tumor biopsies, blood specimens, and stool samples before and after RT will be comprehensively analyzed to determine the immune contexture at baseline, during, and after therapy. Correlative studies will help determine whether RT with ADO signaling blockade produces anti-tumor T cells capable of achieving CRs in locally advanced RC. Citation Format: Encouse Golden, Sandra Demaria, Nir Ben Chetrit, Mehraneh Dorna Jafari, Manish Shah, Silvia Formenti. Countering adenosine (ADO) in rectal cancer to improve RT responses to immune checkpoint blockade: a trial to test the safety and efficacy of PD1 (AB122) and ADO dual receptor (AB928) antagonists with chemotherapy after short-course RT [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr PR005.

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