Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial

Barbara Adamo, Meritxell Bellet, Laia Paré, Tomás Pascual, Maria Vidal, José A Pérez Fidalgo, Salvador Blanch, Noelia Martinez, Laura Murillo, Patricia Gómez-Pardo, Ana López-González, Kepa Amillano, Jordi Canes, Patricia Galván, Blanca González-Farré, Xavier González, Patricia Villagrasa, Eva Ciruelos, Aleix Prat, Barbara Adamo, Meritxell Bellet, Laia Paré, Tomás Pascual, Maria Vidal, José A Pérez Fidalgo, Salvador Blanch, Noelia Martinez, Laura Murillo, Patricia Gómez-Pardo, Ana López-González, Kepa Amillano, Jordi Canes, Patricia Galván, Blanca González-Farré, Xavier González, Patricia Villagrasa, Eva Ciruelos, Aleix Prat

Abstract

Background: The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed.

Methods: Postmenopausal women with untreated stage I-III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures.

Results: Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1-2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (- 73.2%) was superior to both monotherapy arms combined (- 49.9%; p = 0.001) and mVNB (- 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (- 73.2%) was numerically higher compared to LTZ (- 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases.

Conclusions: Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted.

Trial registration: NCT02802748 , registered 16 June 2016.

Keywords: Breast cancer; Gene expression; Letrozole; Metronomic; Vinorelbine; Window of opportunity.

Conflict of interest statement

Advisory role of A.P. for Nanostring Technologies, Pierre Fabre, Roche, Pfizer, Novartis, BMS, and Roche. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of the SOLTI-1501 VENTANA study
Fig. 2
Fig. 2
Distribution of the intrinsic subtypes before (a, c, e) and after treatment (b, d, f) in LTZ (a, b), mVNB-only (c, d), and combination (e and f) arms
Fig. 3
Fig. 3
Relative reduction of PAM50 proliferation score in Luminal A/B disease. a The 11-gene proliferative score at baseline vs. surgery. b Changes in the proliferation score in each arm. c Primary results of the study: On the left, the anti-proliferative effect of the combination of mVNB and LTZ vs. both monotherapy arms combined. On the right, comparison of the anti-proliferative effect between each treatment arm. Error bars indicate 95% confidence interval
Fig. 4
Fig. 4
Biological changes induced by each treatment at week 3 compared to baseline of selected genes and gene signatures
Fig. 5
Fig. 5
Global gene expression changes induced by each arm from baseline to surgery. a Heatmaps showing differential expression of 49 selected genes and gene signatures at 3 weeks in each arm. b 360° view summarizing the gene/signatures for the breast tumor microenvironment and immune response in LTZ+mVNB arm between baseline and surgery. c Venn diagram showing the overlap in the list of differentially expressed genes obtained in the before and after treatment across the comparisons of the three arms

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