Adding avelumab to vinorelbine plus trastuzumab improves the progression-free survival in heavily pre-treated patients with HER2+ metastatic breast cancer

Results of the AVIATOR trial show that the addition of avelumab to vinorelbine and trastuzumab (NHA) improves the progression-free survival (PFS) in patients with HER2+ metastatic breast cancer. However, a further addition of the agent blocking, 4-1BB did not lead to a better PFS than the NHA regimen.

Part of the clinical activity of trastuzumab is mediated through immunologic mechanisms, including antibody-dependent cell-mediated cytotoxicity and by generating adaptive immunity (CD8 T cell activation). The trial at hand aimed to enhance the treatment efficacy for patients with HER2+ metastatic breast cancer (mBC) by combining trastuzumab with an immune checkpoint inhibitor, and an inhibitor of 4-1BB immune pathway. 4-1BB is expressed on activated T cells and NK cells and increasing their cytotoxic function. Additionally, blocking 4-1BB was shown to have synergistic effects with trastuzumab in preclinical models. Based on these findings, this randomised phase II trial examined the safety and efficacy of trastuzumab plus chemotherapy combined with anti-PD-L1 immunotherapy and 4-1BB agonist utomilumab in HER2+ mBC.

Methods

The AVIATOR trial enrolled patients with HER2+ mBC previously treated with trastuzumab, pertuzumab, and T-DM1 who did not receive prior immunotherapy or vinorelbine. The initial design of the trial randomly assigned patients (1:2:2) to vinorelbine plus trastuzumab (NH), vinorelbine plus trastuzumab and avelumab (NHA) or vinorelbine plus trastuzumab, avelumab and utomilumab (NHAU). However, due to the discontinuation of clinical development of utomilumab in 2021, an unplanned interim futility analysis led to the closure of the NHAU arm. As such, the revised treatment scheme only included patients randomised (1:2) to NH or NHA. The primary objective was to determine whether NHA leads to an improved PFS compared to NH.

Results

In total, 100 patients were randomly assigned to NH (N= 18), NHA (N= 45), or NHAU (N= 34, prior to its closure). At this point, an interim futility analysis was performed, with the NHAU crossing the futility PFS boundary (HR for PFS: 1.14; p= 0.32). Of note, no increased toxicity was observed when adding utomilumab to NHA.

After a median follow-up of 27.9 months, the addition of avelumab to NH reduced the risk of death or progression by 47% (HR[95%CI]: 0.53[0.31-0.91]; p=0.025), with a median PFS of 3.8 vs. 2.0 months in the NHA and NHA arms, respectively. In addition, also the overall response rate (ORR) was numerically higher with NHA than with NH (20.0% vs. 11.1%), with a median duration of response (DoR) of 15.8 months (vs. not evaluable in the NH group). Baseline tissue evaluations revealed a trend for a longer PFS in patients with higher TIL values (≥10%; HR[90%CI]: 0.55[0.29-1.04]). However, no significant association was found between baseline PD-L1 score (CPS≥1 or <1) and PFS (HR[90%CI]: 0.77[0.43-1.36])

The rate of grade 3-4 adverse events (AEs) was similar between the treatment arms (62.2% vs. 61.1% in the NHA and NH arms, respectively). Common grade 3-4 AEs included anaemia (2.2 vs. 11.1% in the NHA and NH arms), a decreased absolute neutrophil count (55.6% vs. 38.9%) and a decreased white blood cells (17.8% vs. 5.6%). There were two grade 3 immune-related AEs occurred in the avelumab arm and no grade 4-5 immune-related AEs were observed. There were no unexpected treatment-emergent AEs.

Conclusions

This trial demonstrated a significant improvement in PFS with the addition of avelumab to NH in heavily pre-treated patients with HER2+ mBC. Conversely, adding the 4-1BB agonist utomilumab to the chemotherapy, trastuzumab, and avelumab regimen, did not improve the PFS further. Importantly, no unexpected toxicities were observed. These findings underscore the need for further exploration of ICI combined with chemotherapy and HER2-targeted therapy in patients with refractory HER2+ mBC.

Reference

Waks A, Shi R, Regan M, et al. 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). Presented at SABCS 2023; Abstract RF02-06.