Abstract P4-01-02: Results from a dose escalation phase 1b study of palbociclib and avelumab in advanced breast cancer in the PAveMenT Trial
Authors: Okines Alicia F. , Moghadam Houman , Sparks Laura , Mohammed Kabir , Dunne Kathryn , Nerurkar Ashutosh , Osin Peter , Swift Claire , Sardinha Ruth , Turner Nicholas 
Published: March 2023

Abstract
Background CDK4/6 inhibitors may trigger anti-tumour immunity, both through tumour cell intrinsic and extrinsic mechanisms, which can be enhanced by immune checkpoint blockade in pre-clinical studies. Although most triple negative breast cancers (TNBC) are resistant to CDK4/6 inhibition, palbociclib (palbo) has activity in pre-clinical models of the luminal androgen receptor (LAR) subtype. Here we report the dose finding phase Ib cohort A of the PAveMenT trial combining avelumab and palbociclib Methods The PAveMenT phase 1b trial consists of a dose finding phase (cohort A), to be followed by an expansion in androgen receptor positive (AR+) TNBC (Cohort B). The phase 1B phase investigated palbo dosing schedules (75mg intermittent dosing (ID), 100mg continuous dosing (CD) and 125mg ID) in combination with the anti-PD-L1 antibody, avelumab 10mg/kg 2-weekly (cohort A) to determine the optimal schedule for cohort B. The CD dose-level was pre-specified as the preferred schedule if tolerated, due to the proliferative nature of TNBC and potential for tumour re-growth with ID. Patients with previously treated advanced breast cancer (ABC) of any histology with measurable disease and adequate organ function, who had not received prior immunotherapy or CDK4/6 inhibitors or more than 2 lines of chemotherapy for ABC, were eligible for cohort A. Dose-limiting toxicities (DLTs) were defined as Grade(G) 4 neutropenia, complicated G3 neutropenia or G4 thrombocytopenia, or ≥G3 immune toxicity during cycle 1. AR staining of ≥10% using the SP107 antibody (Ventana) was considered AR+. PD-L1 was evaluated using CC23 Pharma Dx antibody (DAKO) and PD-L1 positive defined as CPS score of ≥10%. Results Fourteen patients were recruited to Part A, all female, 12 with TNBC, two with ER positive/HER2 negative ABC, median age 53.5 years. Three evaluable patients received palbo 75mg/day ID without DLTs, therefore two further dose levels were opened in parallel. Three evaluable patients received palbo 125mg/day ID without DLTs. Due to a DLT of fever with G3 neutropenia in one of 3 patients receiving palbo 100mg CD, 3 further evaluable patients received 100mg CD without DLTs. Two patients were not evaluable for DLTs having not received a full cycle of treatment so were replaced. One case of grade 3 colitis and one case of grade 2 hypothyroidism (both 100mg CD) occurred outside the DLT period. Amongst 12 patients with TNBC, metastatic tissue was available for 11, archival breast tissue for one. Four of 12 patients were AR+. Five of 10 TNBC patients with sufficient tissue were PD-L1 positive, all of whom had previously tested negative with the SP142 antibody (Ventana). One of the 5 PD-L1+ and 2/5 PD-L1 negative TNBC cases were also AR+. TNBC patients received a median of 2 cycles of treatment (range 1-17). Both ER+ patients were AR+ and PD-L1 negative; one progressed after 4 cycles, the other remains on treatment at 12 cycles. The 100mg CD schedule was selected for cohort B. Conclusions All schedules were tolerable, with activity observed in patients with both ER positive and TNBC cancers. Cohort B of the study is open to recruitment for patients with AR+ TNBC. NCT04360941.
Citation Format: Alicia F. Okines, Houman Moghadam, Laura Sparks, Kabir Mohammed, Kathryn Dunne, Ashutosh Nerurkar, Peter Osin, Claire Swift, Ruth Sardinha, Nicholas Turner. Results from a dose escalation phase 1b study of palbociclib and avelumab in advanced breast cancer in the PAveMenT Trial [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 P4-01-02.