A phase II, open-label trial of bortezomib (VELCADE®) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Background Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin. Methods Chemotherap...

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Published in:	Cancer chemotherapy and pharmacology Vol. 77; no. 5; pp. 949 - 956
Main Authors:	Kontopodis, E., Kotsakis, A., Kentepozidis, N., Syrigos, K., Ziras, N., Moutsos, M., Filippa, G., Mala, A., Vamvakas, L., Mavroudis, D., Georgoulias, V., Agelaki, S.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2016 Springer Nature B.V
Subjects:	Aged Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Bortezomib - administration & dosage Bortezomib - adverse effects Bortezomib - therapeutic use Cancer Research Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - mortality Carcinoma, Non-Small-Cell Lung - pathology Cisplatin - administration & dosage Cisplatin - adverse effects Cisplatin - therapeutic use Deoxycytidine - administration & dosage Deoxycytidine - adverse effects Deoxycytidine - analogs & derivatives Deoxycytidine - therapeutic use Disease-Free Survival Dose-Response Relationship, Drug Drug Administration Schedule Female Humans Lung Neoplasms - drug therapy Lung Neoplasms - mortality Lung Neoplasms - pathology Male Medicine Medicine & Public Health Neoplasm Staging Oncology Original Article Pharmacology/Toxicology Bortezomib Gemcitabine Cisplatin Non-small cell lung cancer
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Summary:	Background Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin. Methods Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m 2 i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m 2 , (days 1 and 8), and cisplatin 70 mg/m 2 (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity. Results Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3–4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2–4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9–27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %. Conclusion The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.
ISSN:	0344-5704 1432-0843
DOI:	10.1007/s00280-016-2997-7