Abstract PO1-01-09: Neoadjuvant endocrine therapy and avelumab with or without palbociclib in stage II/III endocrine receptor-positive breast cancer: the ImmunoADAPT trial
Authors: Zavras Phaedon , Chen Ruizhe , Qi Hanfei , Jones Mary Kate , Folmer Ann , Chae Hayden , Khodab Allen , Cimino-Mathews Ashley , Jacobs Lisa , Mullen Lisa , Hiton Christie , Elkhanany Ahmed , Khoury Katia , Cristofanilli Massimo , Jaffee Elizabeth , Stearns Vered , Santa-Maria Cesar 
Published: May 2024

Abstract
Background: Pre-clinical and clinical data suggest that CDK4/6 inhibitors can promote an immunogenic tumor microenvironment (TME) and when combined with programmed cell death ligand 1 (PD-L1) inhibitors synergistic anti-cancer effects are observed. To understand the differential effects of CDK4/6 inhibition in the context of immunotherapy we designed a study evaluating neoadjuvant endocrine therapy (ET) with a PD-L1 inhibitor (avelumab) with or without a CDK4/6 inhibitor (palbociclib, palbo) in patients (pts) with stage II/III endocrine receptor (ER)-positive breast cancer. Methods: In this randomized phase 2 pilot study, pts with stage II/III ER+, HER2-negative breast cancer were randomized 2:1 to ET (aromatase inhibitor, AI, for post-menopausal pts; tamoxifen+/-ovarian function suppression for pre-menopausal pts) with avelumab, with or without palbo (palbo vs. control arms). Avelumab was added after a 1-month lead-in of ET +/- palbo, and all drugs were continued for additional 3-month-long cycles prior to surgery. We obtained tumor tissue and breast MRIs on C1D1, C2D1, and at the end of treatment. Imaging assessment was done according to RECIST 1.1 criteria at each time point. The primary endpoint was clinical complete response (cCR) by MRI in the palbo arm (H0: cCR=10% vs. 40% at a two-sided alpha level of 0.1). Secondary endpoints included pathologic CR (pCR), overall response rates (ORR), percent sum diameter changes, and adverse effects (AE). We report descriptive statistics on patient characteristics, clinical response rates, and changes in the sum of the longest diameters of the target lesions (SLD). Translational correlatives including imaging mass cytometry, spatial transcriptomic assessments, and other pathologic biomarkers will be reported at the meeting. Results: From 2018-2023, 33 pts were enrolled, and 30 were eligible for the primary analysis, including 20 pts on the palbo arm (1 pt with bilateral breast cancer, response to each breast cancer evaluated separately) and 10 to the control arm (1 pt with missing data). Clinical and pathologic characteristics were well balanced between arms, however, there was a higher proportion of patients with node-positive disease on the palbo arm (80% vs 60%). The study did not meet its primary endpoint as only 1 pt achieved a cCR and pCR in the palbo arm (cCR/pCR rate 4.8%) vs. no pts in the control arm. ORR was numerically higher in the palbo arm, 42.9% vs. 11.1% (p=0.204). After 1-month of ET+palbo, the mean SLD decreased by 11.6% compared to 9.4% in the ET-only control group (p=0.704). After avelumab was added to both arms, the mean SLD decreased by a further 15.2% in the palbo arm in contrast to a 6.9% increase in the control arm (p=0.018). Subgroup analysis in the palbo arm did not identify clinical or pathologic variables significantly associated with responses. No new safety or toxicity signals were observed. Notably, however expected, grade 3 or higher immune-related adverse events were observed including autoimmune diabetes (n=1), hepatitis (n=1), and colitis (n=1). Conclusions: As shown in previous studies, the addition of palbo to ET did not improve responses in the neoadjuvant setting; however, increased responses to palbo+ET were seen after PD-L1 inhibition, whereas not to ET, suggesting synergy between ET/palbo and avelumab. Translational correlative analysis will aim to decipher TME changes that augment PD-L1 inhibitor responses. Future studies in high-risk pts, where the toxicity of immunotherapy is acceptable, are warranted.
Citation Format: Phaedon Zavras, Ruizhe Chen, Hanfei Qi, Mary Kate Jones, Ann Folmer, Hayden Chae, Allen Khodab, Ashley Cimino-Mathews, Lisa Jacobs, Lisa Mullen, Christie Hiton, Ahmed Elkhanany, Katia Khoury, Massimo Cristofanilli, Elizabeth Jaffee, Vered Stearns, Cesar Santa-Maria. Neoadjuvant endocrine therapy and avelumab with or without palbociclib in stage II/III endocrine receptor-positive breast cancer: the ImmunoADAPT trial [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 PO1-01-09.