Final analysis of nelipepimut-S plus GM-CSF with trastuzumab versus trastuzumab alone to prevent recurrences in high-risk, HER2 low-expressing breast cancer: A prospective, randomized, blinded, multicenter phase IIb trial.

Abstract

1 Background: Preclinical data shows synergism between trastuzumab (Tz) and HER2-targeted vaccines. We evaluated adjvuant nelipepimut-S (NPS) + GM-CSF with Tz compared to Tz with GM-CSF alone in HER2 low-expressing (LE) breast cancer (BC) patients (pts) to prevent recurrences. After a planned interim analysis showed benefit in triple negative BC (TNBC) pts, the decision was made to close the trial with guidance from the independent DSMB. Here, we report the final analysis of the trial with 7 months (mo) of added follow-up (f/u). Methods: The phase 2b trial enrolled clinically disease-free BC pts after standard therapy. Pts were HLA-A2, A3, A24, and/or A26+, had HER2-LE (IHC 1-2+, FISH non-amplified) BC and were node positive and/or TNBC. Pts were randomized to placebo with GM-CSF(control group, CG) or NPS with GM-CSF (vaccine group, VG), while all received Tz Q3wk for 1 year. GM-CSF or NPS + GM-CSF were given q3wks x 6 starting with the 3rd Tz dose, and boosters every 6 months x 4. Safety was assessed and pts were followed clinically for recurrences. The primary outcome was DFS at 24 mo. Results: 589 pts were screened at 26 sites. 275 pts were enrolled and randomized (VG:136, CG:139). There were no clinicopathologic differences between groups. Concurrent Tz and NPS was safe with no added overall or cardiac toxicity compared to CG and no grade 4/5 toxicities. In the ITT analysis (median f/u 25.7 mo), the estimated DFS was favorable but did not reach significance in the VG compared with the CG (HR 0.62, 95% CI: 0.31-1.25, p = 0.18). In the TNBC pts, the VG had statistically improved DFS compared to the CG (HR 0.26, 95% CI: 0.08-0.81, p = 0.013). Conclusions: The combination of NPS with Tz is safe with no added toxicity compared to Tz alone, even after prolonged exposure (25.7 mo). In this final analysis, there was a trend towards benefit in the ITT population that improved since the interim analysis with added f/u. The significant benefit seen at interim in the TNBC pts continued to strengthen in the VG group. These findings could position the NPS + Tz combination as an adjuvant therapy for early-stage TNBC and warrant further study. Clinical trial information: NCT01570036.