KEY TAKEAWAYS
- The AVIATOR phase II trial aimed to evaluate the impact of incorporating avelumab, on the efficacy of standard chemo + H in refractory HER2+ MBC patients.
- The primary endpoint was to compare PFS.
- Adding avelumab demonstrated significant PFS improvement, warranting further investigation of ICI with chemo/H for this population.
Standard therapy for refractory HER2+ MBC involves chemotherapy (chemo) + HER2-targeted therapy (H). The impact of adding immune checkpoint inhibitor (ICI) or 4-1BB agonist (U) to this regimen remains uncertain.
Adrienne G. Waks and her research team conducted the study that aimed to assess the potential efficacy enhancement of standard chemo + H by investigating the addition of ICI or U in refractory HER2+ metastatic breast cancer (MBC) patients.
Eligible participants, previously treated with H, pertuzumab (P), and T-DM1 for HER2+ MBC, excluding those with prior treatment with N or ICI, underwent randomization (1:2:2) into NH, NHA, or NHAU arms. Stratification factors included ER status and liver metastases. Originally comparing progression free survival (PFS) for NHA vs NH and NHAU vs NHA, an unplanned interim futility analysis in 2021, due to U discontinuation, led to NHAU closure.
The final 13 patients were randomized into NH or NHA. With 60 participants (20 vs. 40) for NH vs NHA, the study aimed for 88% power to detect a PFS improvement from 2 to 4 months. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety/tolerability.
About 100 patients underwent randomization between July 2018 and March 2023, with 97 of them initiating treatment on the trial. Among those starting treatment, 18 patients were on the NH arm, 45 on the NHA arm, and 34 on the NHAU arm (before its closure).The patient population was predominantly female (99%), with a median age of 54 years (range 26-78 years). The racial distribution was 70% White, 14% Black, and 8% Asian, with 7% being Hispanic. Hormone receptor-positive tumors were present in 66% of patients, and 76% had visceral metastases.
All patients had prior exposure to H, P, and T-DM1, and 17% had received trastuzumab deruxtecan previously. A majority (63%) had undergone three or more lines of HER2 treatment for MBC, with the range being 1-13 lines. The median interval from MBC diagnosis to randomization was 32 months, with an interquartile range of 22-61 months.
The main findings of the study, presented in the table, include the median PFS (mPFS) and ORR. Notably, one patient in the study remained progression-free at the time of analysis.
Significant differences were observed in PFS between the NHA and NH arms, with NHA associated with a statistically significant improvement (HR = 0.56, 80% CI 0.37-0.86, P=0.04). However, no significant difference in PFS was noted between NHAU and NHA (HR=1.20, 80% CI 0.84-1.73) as the final estimate after the closure of NHAU due to futility.
Among the patients in the NHA arm with confirmed responses, 3 of them exhibited a DOR exceeding 12 months.
The incidence of grade 3-4 treatment-emergent adverse events (AEs) was comparable across the different treatment arms, with rates of 61% in the NH arm, 62% in the NHA arm, and 67% in the NHAU arm. Notably, there were no occurrences of grade 5 treatment-related AEs in any of the treatment groups.
Among patients treated with the A-containing arms (n=79 safety-evaluable patients treated with A), immune-related AEs of any grade included AST increase (n=15), ALT increase (n=9), hyper/hypothyroidism (n=8), adrenal insufficiency (n=2), and pneumonitis (n=1). Of these events, two were grade 3 (adrenal insufficiency and AST increase), with none reaching grade 4 severity. Importantly, only 3 patients (1 in NHA, 2 in NHAU) discontinued trial treatment due to unacceptable AEs. Baseline and on-treatment biopsies were conducted, and data on PD-L1 and TIL will be presented at a later time.
The study demonstrated improved PFS with avelumab added to standard treatment for heavily pre-treated HER2+ MBC. The 4-1BB agonist did not show a PFS benefit. This is the first trial exploring chemotherapy/HER2-targeted therapy with or without ICI in HER2+ MBC. Further research on ICI with chemotherapy/HER2-targeted therapy is warranted for refractory HER2+ MBC, with a focus on exploring predictive immune biomarkers. Research is sponsored by Adrienne G. Waks.
Source: https://atgproductions.net/atgclients/sabcs/2023_SABCS_Abstract_Report-12-1-23_Compressed.pdf
Clinical Trial: https://clinicaltrials.gov/study/NCT03414658
Waks A, Shi R, Regan M, et al. (2023) ‘’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 (RF02-06).
