Abstract PO2-18-11: Short-term Pre-OPerative Durvalumab (MEDI 4736) in early small triple negative breast cancer patients (POP-Durva)
Authors: Ribeiro Joana Mourato , Pic Isabelle , Blampey Quentin , Rassy Elie , Ibrahimi Nusaibah , Salabert Laura , Trédan Olivier , Arnedos Monica , Dogan Semih , Serhal Kamar Serhal , Mahaut Clementine , Viansone Alessandro , Laghouati Salim , Pistilli Barbara , Dutertre Charles-Antoine , Lacroix-Triki Magali , Scoazec Jean-Yves , Derosa Lisa , Zitvogel Laurence , Balleyguier Corinne , Bercovici Nadege , Cournede Paul-Henry , Michiels Stefan , André Fabrice 
Published: May 2024

Background: Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advancements in cancer treatment. Anti-programmed cell death protein 1 (Anti-PD1)/PD-L1 ICIs have improved progression-free survival in patients with metastatic triple negative breast cancer (TNBC) and pathologic complete response (pCR) and event-free survival in patients with early TNBC. Nevertheless, some patients treated with anti-PD(L)1 ICIs experience recurrence or do not achieve sustained clinical benefit. In addition, very interesting data show the existence of a subgroup of patients with exceptional tumour responses to monotherapy with anti-PD(L)1 ICIs. These exceptional responses are observed in various tumour types, such as colorectal or breast cancer. Although in colorectal cancer, the determinants for this extreme sensitivity to immunotherapy treatment are identified (existence of MSI) in breast cancer, this is not the case. There is still a lack of knowledge about predictive biomarkers and mechanisms of action for ICIs. Trial Design: POP-Durva (NCT05215106) is a prospective, one-arm-only study aiming at determining the pCR rate after two administrations of Durvalumab monotherapy in patients with stage I TNBC. This window-of-opportunity study will recruit 195 consecutive cases of stage I TNBC (ER &lt; 1%, PR &lt; 1%, HER2 negative) and TILs≥5%, eligible for short-term treatment with durvalumab. Study treatment consists of two administrations of intravenous Durvalumab monotherapy, 10mg/kg, at two weeks intervals. After study treatment, patients will receive a standard treatment strategy (surgery or neoadjuvant systemic treatment) as per physician choice. The primary endpoint is the pCR rate after treatment with Durvalumab, defined as the absence of invasive disease in the breast and negative axillary nodes (ypT0/yTis ypN0). Assessment of the primary endpoint will be performed at the surgery or at the biopsy at the end of treatment) for patients undergoing neoadjuvant treatment. For patients in whom neo-adjuvant therapy is the first standard treatment strategy (i.e. after study treatment) a breast ultrasound-guided biopsy is mandatory at the end of the treatment visit. If the biopsy-proven residual disease is demonstrated, patients can receive standard neoadjuvant therapy at the discretion of the treating investigator. Patients with biopsy-proven residual disease will be considered as having no pCR. Those with a complete response may proceed directly to surgery. The expected pCR rate with Durvalumab monotherapy is 20%. The sample size of 195 patients will allow us to estimate this expected pCR rate with a 95% confidence interval of a precision of 6.2%. Secondary objectives are objective response rate and safety. Exploratory objectives are to: a. describe immune cell dynamics associated with exceptional responses to ICI (using spectral cytometry analysis), b. describe somatic genetic contributions to the determination of immune responsiveness (using whole exome sequencing (WES) and in a subset of patient's single-cell RNA-seq), c. characterize tumour cells – immune cells' interaction/spatial distribution(using imaging mass cytometry), d. explore the association between gut microbiome composition/signatures predictive of response to ICI (using 16s rRNA sequencing) and e. identify predictive tissue/blood-based biomarkers of response and to anti-PD(L)1 ICIs therapy. A total of two dedicated FFPE samples and two fresh biopsies will be collected at the time of inclusion and at the end of treatment biopsy or on the surgical specimen. In addition, we will collect stool samples pre and at the completion of all Durvalumab treatments and blood samples at the time of inclusion, during treatment (before each Durvalumab administration) and at the end of treatment for serum and plasma extraction and whole blood to serve as a control for WES.

Citation Format: Joana Mourato Ribeiro, Isabelle Pic, Quentin Blampey, Elie Rassy, Nusaibah Ibrahimi, Laura Salabert, Olivier Trédan, Monica Arnedos, Semih Dogan, Kamar Serhal Serhal, Clementine Mahaut, Alessandro Viansone, Salim Laghouati, Barbara Pistilli, Charles-Antoine Dutertre, Magali Lacroix-Triki, Jean-Yves Scoazec, Lisa Derosa, Laurence Zitvogel, Corinne Balleyguier, Nadege Bercovici, Paul-Henry Cournede, Stefan Michiels, Fabrice André. Short-term Pre-OPerative Durvalumab (MEDI 4736) in early small triple negative breast cancer patients (POP-Durva) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-11.