Abstract RF02-06: AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658)

Abstract Background: Chemotherapy (chemo) + H is standard of care therapy for pts with refractory HER2+ MBC. It is unknown whether the addition of immune checkpoint inhibitor (ICI) or a 4-1BB agonist (U) improves efficacy of standard chemo + H for this population. Methods: Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1. Pts previously treated with N or ICI were excluded. 100 pts were randomized 1:2:2 to tx with NH, NHA, or NHAU. ER status and presence of liver metastases were stratification factors. The original co-primary objectives were to compare progression-free survival (PFS) of (1) NHA vs NH; and (2) NHAU vs NHA. In 2021, due to discontinuation of clinical development of U, an unplanned interim futility analysis reviewed by IDMC led to closure of NHAU and randomization of the final 13 pts to NH or NHA. For the comparison of NH vs NHA, with 60 pts randomized (20 vs 40) there was 88% power for a log-rank test to detect improvement in median PFS (mPFS) from 2 to 4 mos with one-sided alpha of 0.1. Corresponding 2-sided 80% confidence intervals (CI) were reported for the stratified Cox model hazard ratios (HR), along with stratified one-sided log-rank p-value. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety/tolerability. Results: 100 pts were randomized from 7/2018-3/2023, and 97 pts started tx on trial: 18 NH, 45 NHA, and 34 NHAU (prior to its closure). Pts were 99% female, with median age 54 yrs (range 26-78 yrs); 70% White, 14% Black, and 8% Asian; 7% were Hispanic. 66% of pts had hormone receptor-positive tumors, and 76% had visceral metastases. All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan. 63% of pts had received ≥3 lines of HER2 tx for MBC (range 1-13 lines), and median interval from MBC diagnosis to randomization was 32 mos (interquartile range 22-61 mos). mPFS and ORR results are shown in the Table. One patient remained progression-free on tx at analysis. NHA was associated with a statistically significant improvement in PFS compared to NH (HR=0.56 (80% CI 0.37-0.86, p=0.04)). No difference in PFS was observed between NHAU vs NHA (HR=1.20 (80% CI 0.84-1.73) as final estimate after closure of NHAU for futility). Of 9 pts with confirmed responses in NHA arm, 3 pts had DOR 12 mos. Grade 3-4 treatment-emergent adverse events (AEs) were similar by tx: 61% NH, 62% NHA, and 67% NHAU. There were no grade 5 treatment-related AEs. Immune-related all grade AEs in the A-containing arms (n=79 safety-evaluable pts treated with A) included: AST increase (n=15), ALT increase (n=9), hyper/hypothyroidism (n=8), adrenal insufficiency (n=2), and pneumonitis (n=1), of which two events were grade 3 (adrenal insufficiency and AST increase) and none were grade 4. Only 3 pts (1 in NHA; 2 in NHAU) stopped trial tx for unacceptable AEs. Required baseline and on-tx biopsies were performed; PD-L1 and TIL data will be presented. Conclusions: This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC. Further investigation of ICI with chemo/H for pts with refractory HER2+ MBC is warranted, and the potential predictive value of immune biomarkers should be explored. *one-sided stratified log rank test p-value Citation Format: Adrienne Waks, Ruichao Shi, Meredith Regan, Chau Dang, Cesar Santa-Maria, Kelly Westbrook, Vandana Abramson, Rashmi Murthy, Rita Nanda, Hope Rugo, Amy Clark, Candace Mainor, Claire Dees, Valentina Hoyos, Kathy Miller, Erica Stringer-Reasor, Natasha Hunter, Sun Young Oh, Michelle DeMeo, Amanda Okpoebo, Erin Elias, Busem Kurt, Nancy Lin, Mothaffar Rimawi, Antonio Wolff, Elizabeth Mittendorf, Shom Goel, Sara Tolaney, Sherene Loi, Ian Krop. AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658) 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 RF02-06.