Abstract P3-07-18: CCTG IND.239: A phase 2 study of combined CFI-400945 and durvalumab in patients with advanced triple negative breast cancer (aTNBC)
Authors: Hilton John , Cescon David W. , Robinson Andrew , Dhesy-Thind Sukhbinder , Taylor Sara , Awan Arif , Ng Terry L. , Rushton Moira , Savard Marie-France , Muyot Lindsay , Reeves Marie Claude , Hagerman Linda , Lui Hongbo , Bray Mark , Tu Dongsheng , Seymour Lesley , Gaudreau Pierre-Olivier 
Published: March 2023

CCTG IND.239: A phase 2 study of combined CFI-400945 and durvalumab in patients with advanced triple negative breast cancer (aTNBC) John Hilton, David W. Cescon, Andrew Robinson, Sukhbinder Dhesy-Thind, Sara Kristina Taylor, Arif Awan, Terry Ng, Moira Rushton, Marie-France Savard, Lindsay Muyot, Marie Claude Reeves, Linda Hagerman, Hongbo Lui, Mark Bray, Dongsheng Tu, Lesley Seymour, Pierre-Olivier Gaudreau Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), which controls centriole duplication and mitotic progression, and was identified as a drug target based on functional screening of genomically unstable breast cancers. CFI-400945 monotherapy has anti-proliferative activity and enhances antitumor activity when combined with anti-PD-1 immune checkpoint blockade in transplantable murine cancer models. Material and methods: In this multi-centre phase II trial of CFI-400945 and durvalumab combination therapy, the primary objective was overall response rate (ORR) per RECIST 1.1. Patients with aTNBC with adequate organ function, PS 0-1, previously treated with &gt;1 line of chemotherapy including anthracycline and/or taxane, were eligible. CFI-400945 32mg monotherapy was administered on a 7-day on, 7-day off schedule for cycle 1 (which reduced the likelihood of significant hematologic toxicity). From cycle 2 onwards, CFI-400945 32mg daily was administered in combination with durvalumab 1500mg IV every 28 days; responses were assessed every 8 weeks. Following trial activation, 3 patients received a CFI-400945 dose of 40mg (same schedule) for a total of 9 cycles before 32mg was declared as the new recommended phase 2 dose (based on other ongoing trials using CFI-400945). A Simon 2-stage design was used; ≥3/15 responses in stage 1 were required to expand to stage 2. Exploratory PD-L1 expression was measured on immune and tumor cells using the SP263 assay. Results: 15 patients received a total of 45 cycles (1-12 cycles per patient). Median age was 56 (31-76); 53% PS1; 20% 3 prior chemotherapy lines and; 27% 4 sites of metastatic disease. Immune vs tumor cell PD-L1 expression was 1% in 50% and 23% of patients, respectively (immune and tumor cell expression was mutually exclusive). Immune vs tumor cell PD-L1 expression was 10% in 17% and 15% of patients, respectively. Grade 3 hematological adverse events (AEs) were lymphopenia (40%), neutropenia (20%), anemia and thrombocytopenia (7% for both). One serious AE at least possibly related to treatment was seen: grade 3 febrile neutropenia. Frequent AEs (˃5%) considered at least possibly related to CFI-400945 were: nausea and anorexia (both 20%), fatigue and dysgeusia (both 13%), headache, dizziness, maculo-papular rash, back pain and gastroesophageal reflux disease (all 7%), Frequent AEs (˃5%) considered at least possibly related to durvalumab were: anorexia (13%), arthritis, fatigue, back pain, pain in extremity and hot flashes (all 7%). No responses were observed in 14 evaluable patients during stage 1, therefore the pre-specified threshold for anti-tumor activity to proceed to stage 2 was not met. Disease control rate (complete response, partial response or stable disease ˃16 weeks in duration) was 7% (1/14). Conclusions: CFI-400945 and durvalumab was well tolerated, with no unexpected toxicities of the combination. However, in this heavily pretreated and PD-L1 unselected TNBC population, no responses were observed and the pre-specified threshold for anti-tumor activity for stage 2 was not met. The trial was closed to accrual on April 26, 2022. Final analysis and correlative analyses are ongoing. Acknowledgements: Coordinated by the CCTG. Funding supported by Astra Zeneca. CFI-400945 provided by Treadwell Therapeutics and durvalumab provided by Astra Zeneca.

Citation Format: John Hilton, David W. Cescon, Andrew Robinson, Sukhbinder Dhesy-Thind, Sara Taylor, Arif Awan, Terry L. Ng, Moira Rushton, Marie-France Savard, Lindsay Muyot, Marie Claude Reeves, Linda Hagerman, Hongbo Lui, Mark Bray, Dongsheng Tu, Lesley Seymour, Pierre-Olivier Gaudreau. CCTG IND.239: A phase 2 study of combined CFI-400945 and durvalumab in patients with advanced triple negative breast cancer (aTNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-18.