Anti-proliferative effect of oral metronomic vinorelbine in PAM50 Luminal/HER2-negative early breast cancer (SOLTI-1501 VENTANA): An open-label, randomized, three-arm, multicenter, window-of-opportunity study

Abstract

Background: The anti‐proliferative effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor (HR)‐positive/HER2‐ breast cancer has been scarcely addressed. Methods: Postmenopausal women with untreated stage I‐III breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5mg/day, oral mVNB 50mg 3 days/week or the combination. The 1ary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti‐proliferative effect of mVNB+LTZ was superior to monotherapy. An anti‐proliferative effect was defined as the mean relative decrease of the PAM50 11‐gene Proliferation Score in each arm. 2ary objectives included safety and the comparison of the anti‐proliferative effect between arms. An unplanned analysis of stromal tumor infiltrating lymphocytes (TILs) was performed. PAM50 analyses were performed using the nCounterVR ‐based Breast Cancer 360â„¢ panel. Results: A total of 61 patients were randomized and 54 paired samples (89%) were analyzed. Main patient characteristics were mean age 67, mean tumor size 1.7 cm, stage I (55.7%) and grade 1‐2 (90%). Grade 3 toxicities occurred in 3.3% of cases. Most baseline samples were Luminal A (74.1%) or B (22.2%). The anti‐proliferative effect of mVNB+LTZ (‐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 mVNB+LTZ (‐73.2%) was higher compared to LTZ (‐65.7%) but did not reach statistical significance (p=0.328). Stromal TILs (≥10% at week 3) were observed across arms in 6.6% (mVNB), 15% (LTZ) and 26% (mVNB+LTZ) of the cases. In tumors with ≤10% TILs at baseline, a significant increase in TILs was observed following VNB+LTZ (paired analysis p=0.012). Conclusions: mVNB is well‐tolerated and presents antiproliferative activity alone and in combination with LTZ. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. Of note, the increase of TILs observed with the combination opens the possibility of studying this combination with immunotherapy.