Patrick Schöffski1, Olivier Mir2, Bernd Kasper3, Zsuzsanna Papai4, Jean-Yves Blay5, Antoine Italiano6, Charlotte Benson7, Katerina Kopeckova8, Nasim Ali9, Palma Dileo10, Axel LeCesne2, Franka Menge3, Sophie Cousin6, Eva Wardelmann11, Agnieszka Wozniak12, Sandrine Marreaud13, Saskia Litiere13, Facundo Zaffaroni13, Axelle Nzokirantevye13, Isabelle Vanden Bempt14, Hans Gelderblom15. 1. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium. Electronic address: patrick.schoffski@uzleuven.be. 2. Department of Medical Oncology, Gustave Roussy, Villejuif, France. 3. Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Mannheim, Germany. 4. State Health Center, Oncology Department, Budapest, Hungary. 5. Department of Medical Oncology, Centre Léon Bérard, NETSARC+, LYRICAN, and Université Claude Bernard Lyon I, Lyon, France. 6. Sarcoma Unit, Institut Bergonié, Bordeaux, France. 7. Royal Marsden Hospital, London, United Kingdom. 8. Department of Oncology, Motol University Hospital, Czech Republic. 9. Clatterbridge Cancer Centre, Wirral, United Kingdom. 10. Sarcoma Unit, University College London, United Kingdom. 11. University Hospital, Münster, Germany. 12. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium. 13. European Organization for Research and Treatment of Cancer, Brussels, Belgium. 14. Department of Human Genetics, KU Leuven, University Hospitals Leuven, Leuven, Belgium. 15. Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands.
Abstract
BACKGROUND: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION: EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS: EORTC 1317, NCT02216578, EudraCT 2014-000501-13.
BACKGROUND:Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION: EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS: EORTC 1317, NCT02216578, EudraCT 2014-000501-13.
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