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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)348-356
Number of pages9
JournalBJU International
Volume121
Issue number3
DOIs
Publication statusPublished - Mar 2018

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Protein-Tyrosine Kinases
Squamous Cell Carcinoma
Epidermal Growth Factor Receptor
Therapeutics
Drug Therapy
Mutation
Phosphatidylinositol 3-Kinase
Confidence Intervals
Neoplasm Metastasis
Survival
PF 00299804
Telomerase
Sirolimus
Exanthema
Disease-Free Survival
Neoplasms
Histology
Lymph Nodes
Genes

Keywords

  • Administration, Oral
  • Aged
  • Antineoplastic Agents/administration & dosage
  • Carcinoma, Squamous Cell/drug therapy
  • Disease-Free Survival
  • ErbB Receptors/antagonists & inhibitors
  • Gene Amplification
  • Humans
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Staging
  • Penile Neoplasms/drug therapy
  • Phosphatidylinositol 3-Kinase/metabolism
  • Quinazolinones/administration & dosage
  • Response Evaluation Criteria in Solid Tumors
  • Signal Transduction/genetics
  • Survival Rate
  • TOR Serine-Threonine Kinases/metabolism
  • Telomerase/genetics

Cite this

@article{a18d363aa5644add8f30eb29155e306c,
title = "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",
abstract = "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.",
keywords = "Administration, Oral, Aged, Antineoplastic Agents/administration & dosage, Carcinoma, Squamous Cell/drug therapy, Disease-Free Survival, ErbB Receptors/antagonists & inhibitors, Gene Amplification, Humans, Lymphatic Metastasis, Male, Middle Aged, Mutation, Neoplasm Staging, Penile Neoplasms/drug therapy, Phosphatidylinositol 3-Kinase/metabolism, Quinazolinones/administration & dosage, Response Evaluation Criteria in Solid Tumors, Signal Transduction/genetics, Survival Rate, TOR Serine-Threonine Kinases/metabolism, Telomerase/genetics",
author = "Andrea Necchi and {Lo Vullo}, Salvatore and Federica Perrone and Daniele Raggi and Patrizia Giannatempo and Giuseppina Calareso and Nicola Nicolai and Luigi Piva and Davide Biasoni and Mario Catanzaro and Tullio Torelli and Silvia Stagni and Elena Togliardi and Maurizio Colecchia and Adele Busico and Annunziata Gloghini and Adele Testi and Luigi Mariani and Roberto Salvioni",
note = "{\circledC} 2017 The Authors BJU International {\circledC} 2017 BJU International Published by John Wiley & Sons Ltd.",
year = "2018",
month = "3",
doi = "10.1111/bju.14013",
language = "English",
volume = "121",
pages = "348--356",
journal = "BJU International",
issn = "1464-4096",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "3",

}

TY - JOUR

T1 - First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma

T2 - results of an open-label, single-arm, single-centre, phase 2 study

AU - Necchi, Andrea

AU - Lo Vullo, Salvatore

AU - Perrone, Federica

AU - Raggi, Daniele

AU - Giannatempo, Patrizia

AU - Calareso, Giuseppina

AU - Nicolai, Nicola

AU - Piva, Luigi

AU - Biasoni, Davide

AU - Catanzaro, Mario

AU - Torelli, Tullio

AU - Stagni, Silvia

AU - Togliardi, Elena

AU - Colecchia, Maurizio

AU - Busico, Adele

AU - Gloghini, Annunziata

AU - Testi, Adele

AU - Mariani, Luigi

AU - Salvioni, Roberto

N1 - © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - Administration, Oral

KW - Aged

KW - Antineoplastic Agents/administration & dosage

KW - Carcinoma, Squamous Cell/drug therapy

KW - Disease-Free Survival

KW - ErbB Receptors/antagonists & inhibitors

KW - Gene Amplification

KW - Humans

KW - Lymphatic Metastasis

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neoplasm Staging

KW - Penile Neoplasms/drug therapy

KW - Phosphatidylinositol 3-Kinase/metabolism

KW - Quinazolinones/administration & dosage

KW - Response Evaluation Criteria in Solid Tumors

KW - Signal Transduction/genetics

KW - Survival Rate

KW - TOR Serine-Threonine Kinases/metabolism

KW - Telomerase/genetics

U2 - 10.1111/bju.14013

DO - 10.1111/bju.14013

M3 - Article

C2 - 28921872

VL - 121

SP - 348

EP - 356

JO - BJU International

JF - BJU International

SN - 1464-4096

IS - 3

ER -