Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer

Wim van Boxtel; Maike J M Uijen; Stefanie D Krens; Tim Dijkema; Stefan M Willems; Marianne A Jonker; Sjoert A H Pegge; Adriana C H van Engen-van Grunsven; Carla M L van Herpen

doi:10.1016/j.ejca.2021.10.033

Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer

Wim van Boxtel, Maike J M Uijen, Stefanie D Krens, Tim Dijkema, Stefan M Willems, Marianne A Jonker, Sjoert A H Pegge, Adriana C H van Engen-van Grunsven, Carla M L van Herpen^*

^*Corresponding author for this work

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Abstract

AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC.

PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included.

RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively.

CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate.

TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

Original language	English
Pages (from-to)	128-137
Number of pages	10
Journal	European Journal of Cancer
Volume	161
DOIs	https://doi.org/10.1016/j.ejca.2021.10.033
Publication status	Published - Jan-2022

Keywords

Aged
Anilides/adverse effects
Female
Humans
Male
Middle Aged
Neoplasm Metastasis
Neoplasm Recurrence, Local
Pyridines/adverse effects
Receptor Protein-Tyrosine Kinases/pharmacology
Salivary Gland Neoplasms/drug therapy

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van Boxtel, W., Uijen, M. J. M., Krens, S. D., Dijkema, T., Willems, S. M., Jonker, M. A., Pegge, S. A. H., van Engen-van Grunsven, A. C. H., & van Herpen, C. M. L. (2022). Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer. European Journal of Cancer, 161, 128-137. https://doi.org/10.1016/j.ejca.2021.10.033

@article{aca21af01a774883bf4d0ff7503e61bc,

title = "Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer",

abstract = "AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC.PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included.RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively.CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate.TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.",

keywords = "Aged, Anilides/adverse effects, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local, Pyridines/adverse effects, Receptor Protein-Tyrosine Kinases/pharmacology, Salivary Gland Neoplasms/drug therapy",

author = "{van Boxtel}, Wim and Uijen, {Maike J M} and Krens, {Stefanie D} and Tim Dijkema and Willems, {Stefan M} and Jonker, {Marianne A} and Pegge, {Sjoert A H} and {van Engen-van Grunsven}, {Adriana C H} and {van Herpen}, {Carla M L}",

year = "2022",

month = jan,

doi = "10.1016/j.ejca.2021.10.033",

language = "English",

volume = "161",

pages = "128--137",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "ELSEVIER SCI LTD",

}

TY - JOUR

T1 - Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer

AU - van Boxtel, Wim

AU - Uijen, Maike J M

AU - Krens, Stefanie D

AU - Dijkema, Tim

AU - Willems, Stefan M

AU - Jonker, Marianne A

AU - Pegge, Sjoert A H

AU - van Engen-van Grunsven, Adriana C H

AU - van Herpen, Carla M L

PY - 2022/1

Y1 - 2022/1

N2 - AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC.PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included.RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively.CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate.TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

AB - AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC.PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included.RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively.CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate.TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

KW - Aged

KW - Anilides/adverse effects

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasm Metastasis

KW - Neoplasm Recurrence, Local

KW - Pyridines/adverse effects

KW - Receptor Protein-Tyrosine Kinases/pharmacology

KW - Salivary Gland Neoplasms/drug therapy

U2 - 10.1016/j.ejca.2021.10.033

DO - 10.1016/j.ejca.2021.10.033

M3 - Article

C2 - 34920917

SN - 0959-8049

VL - 161

SP - 128

EP - 137

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer

Abstract

Keywords

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