SUO 2019: Novel Systemic Therapies in Penile Cancer
Dr. Chahoud then summarized the limited studies available on neoadjuvant chemotherapy (NAC) for advanced PSCC and highlighted the Phase II study by Drs. Pagliaro and Pettaway, which had shown that the neoadjuvant regimen of paclitaxel, ifosfamide, and cisplatin (TIP) followed by consolidative surgery induced clinically meaningful responses in patients with bulky regional lymph node metastases from penile cancer. Based on this study, the current standard of care for penile cancer with bulky inguinal lymph nodes is a multi-modal approach consisting of neoadjuvant, systemic chemotherapy followed by aggressive surgical resection in responders. Patients who do not respond to frontline chemotherapy undergo more cisplatin-based chemotherapy, radiotherapy, or combination chemoradiotherapy, but survival rates are abysmal. This is an unmet need in penile cancer, and areas of further research and trials could involve improving frontline and salvage therapy.
Dr. Chahoud mentioned that immune checkpoint blockade (ICB) therapy, which has resulted in several approved drugs recently for other solid organ malignancies could be explored as a treatment option. The rationale for the use of ICB is based on studies that looked at rates of PD-L1 positivity in penile cancer patients and found them to be high (40-60%). These data provide a basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapy in patients with advanced PSCC. Tumor mutational burden could be another potential biomarker that has again been looked at by Dr. Pettaway’s group at MD Anderson Cancer Center (MDACC). PSCC appears to be genomically similar to other SCCs and HPV-related cancers, and this provides the opportunity to include a rare tumor like PSCC in future ‘basket type’ trials using novel agents targeting multiple SCCs that may exhibit similar biology. Based on these findings, several new Phase I and II trials are available in penile and rare GU cancers evaluating ICB as single or in combination with another agent looking at overall response rate in the salvage setting.
Dr. Chahoud then presented arguments in favor of ICB therapy trials in the neoadjuvant setting. Patients that achieved complete response with TIP had significantly better long-term outcomes, and chemo plus ICB might increase overall response rate/complete response rates. There is also increased neoantigen expression in the neoadjuvant setting, which has shown promising results in lung cancer and could be translated to penile cancer. However, these need to be balanced with toxicity and logistic support for conducting such clinical trials.
Finally, Dr. Chahoud talked about targeted therapies in PSCC, such as EGFR targeted therapy with Cetuximab. He highlighted the retrospective study from MDACC, which showed that Cetuximab has antitumor activity in metastatic penile cancer and may enhance the effect of cisplatin-based chemotherapy. A 24% partial response rate was seen in their cohort. Prospective studies of EGFR-targeted therapies in men with these tumors are warranted. He also highlighted the results from first-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic PSCC. The overall response rate was 32.1%. Dacomitinib was active and well-tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. He then summarized the studies looking at genomic alterations in PSCC, which could identify novel potential targets. Top mutated genes in PSCC are similar to other squamous cell cancer. NOTCH1 loss of function mutation and Pi3K mutations are present in greater than 50% of cases. DDR genes are mutated in another 20%; thus, there could be a role for PARP inhibitor trials. There could also be a role for therapeutic cancer vaccines in HPV+ PSCC, with multiple trials investigating these options. Dr. Chahoud highlighted a Phase I/II study from lung cancer literature looking at T-cell receptor gene therapy, one patient had complete regression of her lung metastases and has no evidence of disease three years after treatment.
Dr. Chahoud concluded his excellent overview with a summary that relapsed PSCC has dismal outcomes with chemotherapies and every patient should be considered for clinical trial enrollment. Funding support is needed to understand the biology and immune microenvironment of PSCC to develop clinical trials rationally. Multi-institutional collaboration between academic centers of excellence is needed to develop well thought clinical trials to advance outcomes.
Presented by: Jad Chahoud, MD, MPH, GU Medical Oncologist, Moffitt Cancer Center, Tampa, Florida
Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA, @shekabhishek, at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC