Dacomitinib (Daco) induction therapy for locally advanced (LA) or metastatic penile squamous cell carcinoma (PSCC): An open label, single-arm, phase II study

399 Background: The prognosis of patients (pts) with PSCC is primarily depending on the involvement of regional lymph nodes (LN). Owing to the limited efficacy of chemotherapy (ChT), new drugs are warranted. Daco is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: In a phase 2 study (NCT01728233), pts received Daco 45 mg/d orally continuously. Inclusion criteria were SCC histology, and clinical stage N2-3 or M1; no prior ChT was allowed. Computed tomography (CT) and PET/CT scans were repeated q8 wks. Responding pts with LA-PSCC were offered radical surgery. The primary endpoint was the objective response-rate (ORR = CR+PR according to RECIST v1.1). The study was conducted according to a Bayesian design, based on predictive probability; the target was to demonstrate that the ORR exceeded 20%. Translational analyses on pre-Daco tumor samples included: EGFR and HER2 amplification (ampl), in-situ hybridization for HPV, and next generation sequencing. Results: From 06/13 to 09/16, 26 pts were treated. 7 (26.9%) had visceral metastases. 50% had pelvic and 57.7% clinically-involved bilateral LN. 1 CR + 7 PR were obtained (ORR = 30.4%, 95% credibility interval 14.9-48.6%). Median follow up = 16.6 months; 12-m PFS = 24.1% (95%CI: 11.1-52.3); 12-m OS = 50.7% (95%CI: 31.7-80.9). The current Bayesian posterior probability of exceeding the 20% ORR target is 89%. Tissue samples from 23 pts were analyzed. Only 2 pts were HPV+ (1SD, 1PD). EGFR ampl was found in 4 pts (1 CR, 1 PR, 2 SD) and it was confirmed in all post-Daco samples. TERT mutations (60%) were found in responders (R) only. Mutations in genes potentially associated with resistance to EGFR inhibitors ( HRAS, BRAF, PIK3CA, PTEN, STK11) were found in 47% non responders (NR) vs 25% R. HRAS and BRAF mutations segregated with NR (20%). Additional unfrequent mutations of druggable targets were found: RAC1, TSC1 and mTOR in R, FGFR2, RAD50, PDGFRB and FLT4 in NR, IGF2R in both. Conclusions: Dacomitinib was active in HPV-negative, advanced PSCC. Among multiple altered pathways, we were able to delineate the possible molecular profile of responders. An expansion cohort to confirm the translational findings is planned. Clinical trial information: NCT01728233.