A randomized phase II trial evaluating the addition of low dose, short course sunitinib to docetaxel in advanced solid tumours

Yvonne L E Ang,Wan Qin Chong,Raghav Sundar,Wei Peng Yong,Sing Huang Tan,Lingzhi Wang,Soo-Chin Lee,Boon Cher Goh,Joline S J Lim,Samuel G W Ow,Ross A Soo,Phyu Pyar Soe,Gwo Fuang Ho,Bee Choo Tai

doi:10.1186/s12885-020-07616-4

Abstract

BackgroundWe previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC.MethodsPatients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS).ResultsWe enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers.There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38–3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14–1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15–3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51–1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups.Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792).ConclusionsThe addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial.Trial registrationThe study was registered (NCT01803503) prospectively on clinicaltrials.gov on 4th March 2013.

Highlights

We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicincyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients
Data from Phase III randomized trials evaluating the addition of small molecule anti-angiogenic tyrosine kinase inhibitors (TKIs) like sunitinib and sorafenib to chemotherapy in solid tumours have been largely negative [3,4,5]
The treatment groups were balanced with respect to baseline demographic and disease characteristics, except that the docetaxel-sunitinib group had a higher proportion of Chinese patients (84.8%) compared to the docetaxel alone group (48.6%) (Table 1)

Summary

Introduction

We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicincyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. Data from Phase III randomized trials evaluating the addition of small molecule anti-angiogenic tyrosine kinase inhibitors (TKIs) like sunitinib and sorafenib to chemotherapy in solid tumours have been largely negative [3,4,5]. Pre-clinical studies have suggested that anti-angiogenic agents could transiently normalize tumour vasculature, but further continuous administration at full dose of these agents results in destruction of tumour vasculature [6, 7]. This may paradoxically result in reduced delivery of chemotherapy to the tumour [8, 9]. Intermittent dosing of a small molecule TKI at a lower dose prior to chemotherapy to transiently ‘normalize’ tumour vasculature may improve drug and oxygen delivery and potentiate sensitivity to chemotherapy [10, 11]

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Results

Discussion

Conclusion