Dacomitinib as first-line treatment of locally-advanced (LA) or metastatic penile squamous cell carcinoma (PSCC): Interim analysis of an open-label, single-group, phase 2 trial

Abstract

Background: The survival results of neoadjuvant or 1st-line chemotherapy (CT) for LA or metastatic PSCC are poor. HER pathway alterations may be a driver and a suitable therapeutic target in PSCC. An open-label, single-arm, phase 2 trial of 1st-line/ neoadjuvant Dacomitinib, an irreversible pan-HER tyrosine kinase inhibitor, is currently recruiting patients ( pts, NCT01728233) The results of a planned interim analysis are presented. Methods: 37 pts with chemonaive cN2-3 or M1 disease will receive Dacomitinib 45 mg daily until surgery or disease progression (PD)/unacceptable toxicity. Computed tomography and PET scan are repeated q2 months. Simon's Optimal 2-stage design is applied. The primary endpoint (PE) is the objective response-rate (ORR = CR/PR according to RECIST v1.1: H0 ≤ 5%, H1 ≥ 20%, α and β = 10% resulting in ≥4 responses required). Univariable Cox analyses were done. Next generation sequencing (NGS) with on tumor tissue from all pts is planned (Ion Torrent, Life Technologies). Results: From 06/13 to 02/16, 20 pts were enrolled (18 evaluable for response). Median age was 59 yrs (IQR: 54-78). 5 (25%) pts had a metastatic and 15 a LA-PSCC. At clinical staging, 9 (45%) had clinical pelvic nodes and 11 (55%) bilateral nodal disease. There were 5 confirmed PR (ORR = 27.8%, 95% confidence interval [CI]: 9.7-53.5), 9 stable diseases and 4 PD. 11 pts (61.1%) had a PET PR. 10 pts underwent post-dacomitinib lymphadenectomy: >90% necrosis was seen in one patient. Median follow-up was 13.1 months, 6-month PFS was 37.9% (95%CI: 20.2-71.1), 6-months OS was 85.7% (95%CI: 69.2-100). No significant factor was found for PFS/OS. Skin toxicity was observed in 9 pts (2 Grade 1, 7 Grade 2-3 [CTCAE v4.03 3]), Grade 2 diarrhea in 2. Tissue from one PR pt harbored missense mutations in FBXW7 (R505S), PTEN (A3T), and TP53 (R273H, loss of function mutation) genes. Conclusions: Dacomitinib is endowed with promising single-agent activity in PSCC. Pending the final results, the PE was already met. Translational results may provide insights into the targeting of HER pathway in PSCC. Preliminary data on molecular alterations linked to clinical benefit are being observed.