Randomised phase 2 study comparing the efficacy and safety of the oral tyrosine kinase inhibitor nintedanib with single agent ifosfamide in patients with advanced, inoperable, metastatic soft tissue sarcoma after failure of first-line chemotherapy: EORTC-1506-STBSG "ANITA"

Abstract

Purpose: EORTC-1506-STBSG was a prospective, multicentric, randomised, open-label phase 2 trial to assess the efficacy and safety of second-line nintedanib versus ifosfamide in patients with advanced, inoperable metastatic soft tissue sarcoma (STS). The primary end-point was progression-free survival.

Patients/methods: Patients with a variety of STS subtypes were randomised 1:1 to nintedanib (200 mg b.i.d. p.o. until disease progression) or ifosfamide (3 g/m2 i.v. days 1-3, every 21 days for ≤6 cycles). A Korn design was applied aiming to detect an improvement in median progression-free survival (mPFS) from 3 to 4.5 months (HR = 0.667). An interim look was incorporated to stop the trial for futility if <19 of the first 36 patients treated with nintedanib were progression-free at week 12.

Results: At the interim analysis, among the first 36 eligible and evaluable patients randomised for nintedanib, only 13 (36%) were progression-free at week 12. The trial was closed for further accrual as per protocol. In total, 80 patients were randomised (40 per treatment group). The mPFS was 2.5 months (95% CI: 1.5-3.4) for nintedanib and 4.4 months (95% CI: 2.9-6.7) on ifosfamide (adjusted HR = 1.56 [80% CI: 1.14-2.13], p = 0.070). The median overall survival was 13.7 months (95% CI: 9.4-23.4) on nintedanib and 24.1 months (95% CI: 10.9-NE) on ifosfamide (adjusted HR = 1.65 [95%CI:0.89-3.06], p = 0.111). The clinical benefit rate for nintedanib and ifosfamide was 50% versus 62.5% (p = 0.368), respectively. Common treatment-related adverse events (all grades) were diarrhoea (35.9% of patients), fatigue (25.6%) and nausea (20.5%) for nintedanib; and fatigue (52.6%), nausea (44.7%) and vomiting, anorexia and alopecia (28.9% each) for ifosfamide.

Conclusion: The trial was stopped for futility. The activity of nintedanib did not warrant further exploration in non-selected, advanced STSs.

Trial registration: ClinicalTrials.gov NCT02808247.

Keywords: Chemotherapy; Fibroblast growth factor receptor; Ifosfamide; Nintedanib; Oral anticancer treatment; Soft tissue sarcoma; Tyrosine kinase inhibitor; Vascular endothelial growth factor receptor.

Conflict of interest statement

Conflict of interest statement PS has received travel support and institutional funding for participating in an advisory function for Boehringer Ingelheim outside of the scope of the nintedanib project; is an active investigator in multiple recent and ongoing Boehringer Ingelheim clinical trials. MT, VK, JDH, AW, SC, MB, JB, CC-B, SM, SL, LDM, and CO have no competing interests. AE received honoraria from Roche, MSD and AstraZeneca. Travel expenses and conferences from Pharmamar, Lilly and BMS. GM provided consultation or attended advisory boards for: GSK/Tesaro, Pharmamar, Lilly. Received honoraria from GSK/Tesaro, Roche, Clovis Oncology, Pharmamar, AstraZeneca, Lilly. Travel expenses from Roche, MSD, GSK/Tesaro, Pharmamar. MD-S has received speaker honoraria from Pierre-Fabre, Merck KGaA, Sanofi Aventis, Novartis, BMS; financial support for attending symposia from Novartis; consultation honoraria from Merck KGaA, Novartis. MB: No competing interests. NS provided consultation or attended advisory boards for AIMM Therapeutics, Boehringer Ingelheim (outside of the scope of the nintedanib project), Ellipses Pharma. N Steeghs received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim (outside of the scope of the nintedanib project), Bristol-Myers Squibb, Cantargia, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, InteRNA, Lilly, Merck Sharp & Dohme, Merus, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho, Takeda (outside the submitted work). VK: No competing interests. JDH: No competing interests. AW: No competing interests. SC: No competing interests. MD had no competing interests. Personal fees were received from Bristol-Myer Squibb, Roche, Astrazeneca, and MSD, outside the submitted work. JB: No conflict. CC-B: No competing interests. SM: No competing interests. SL: No competing interests. LDM: No competing interests. CO: No competing interests. HG has received institutional funding form Boehringer Ingelheim for another investigator-initiated study outside of the scope of the nintedanib project and is an active investigator in multiple recent and ongoing Boehringer Ingelheim clinical trials.

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