First‐line therapy with dacomitinib, an orally available pan‐HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open‐label, single‐arm, single‐centre, phase 2 study

Objective To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan‐epidermal growth factor receptor (HER) inhibitor. Patients and Methods In a phase 2 study (NCT01728233)...

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Published in:BJU international 2018-03, Vol.121 (3), p.348-356
Main Authors: Necchi, Andrea, Lo Vullo, Salvatore, Perrone, Federica, Raggi, Daniele, Giannatempo, Patrizia, Calareso, Giuseppina, Nicolai, Nicola, Piva, Luigi, Biasoni, Davide, Catanzaro, Mario, Torelli, Tullio, Stagni, Silvia, Togliardi, Elena, Colecchia, Maurizio, Busico, Adele, Gloghini, Annunziata, Testi, Adele, Mariani, Luigi, Salvioni, Roberto
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Administration, Oral
Aged
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - therapeutic use
Bayesian analysis
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - secondary
Chemotherapy
dacomitinib
Disease-Free Survival
Enzyme inhibitors
Epidermal growth factor
epidermal growth factor receptor
Epidermal growth factor receptors
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - genetics
Exanthema
Gene Amplification
Genital cancers
Human papillomavirus
Humans
Lymph nodes
Lymphatic Metastasis
Male
Metastases
Middle Aged
Mutation
Neoplasm Staging
penile cancer
Penile Neoplasms - drug therapy
Penile Neoplasms - genetics
Penile Neoplasms - pathology
Penis
Phosphatidylinositol 3-Kinase - metabolism
Quinazolinones - administration & dosage
Quinazolinones - therapeutic use
Rapamycin
Response Evaluation Criteria in Solid Tumors
RNA-directed DNA polymerase
Signal transduction
Signal Transduction - genetics
Skin
Solid tumors
Squamous cell carcinoma
Survival Rate
Telomerase
Telomerase - genetics
Telomerase reverse transcriptase
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tyrosine kinase inhibitors
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Summary:Objective To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan‐epidermal growth factor receptor (HER) inhibitor. Patients and Methods In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2–3 or M1 (Tumour‐Node‐Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. Results From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0–43.0%). The median (interquartile range [IQR]) follow‐up duration was 19.8 (6.3–25.7) months; 12‐month progression‐free survival was 26.2% (95% confidence interval [CI] 13.2–51.9); 12‐month overall survival (OS) was 54.9% (95% CI 36.4–82.8). The median (IQR) OS of locally advanced patients was 20 (11.1–not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high‐risk human papillomavirus‐positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non‐responders) and it was confirmed in all post‐dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non‐responders. Conclusion Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies.
ISSN:1464-4096
1464-410X
DOI:10.1111/bju.14013