ESOU 2022: The Evolving Treatment Landscape and Clinical Trial Overview of Penile Squamous Cell Carcinoma

(UroToday.com) The 2022 EAU Section of Oncological Urology (ESOU) Annual Meeting included a session on the multidisciplinary management of high-risk node positive penile cancer and a presentation by Dr. Jad Chahoud discussing the evolving treatment landscape and clinical trial overview of penile squamous cell carcinoma. Dr. Chahoud notes that penile cancer is a rare disease, thus making it challenging to enroll and complete interventional trials. High-risk HPV infection is likely responsible for approximately 50% of cases of penile squamous cell carcinoma, making it a potential therapeutic target, with a different biology and immune landscape between HPV positive and negative cases. The majority of patients will present with localized or locally advanced disease, with heterogeneous survival rates for those with lymph node positive disease. Five-year disease-specific survival rates for pN0, pN1, pN2, and pN3 patients is estimated at 96%, 80%, 66%, and 37%, respectively.


For patients with advanced penile squamous cell carcinoma, platinum-based combination chemotherapy remains the front-line therapy for advanced disease. Penile cancer with bulky inguinal lymph nodes is best managed in a multimodal approach consisting of neoadjuvant, systemic chemotherapy followed by aggressive surgical resection in responders. Among 30 men with N2 or N3 disease without distant metastasis who underwent neoadjuvant paclitaxel 175 mg/m2 administered over 3 hours on day 1; ifosfamide 1,200 mg/m2 on days 1 to 3; and cisplatin 25 mg/m2 on days 1 to 3, Pagliaro et al.1 reported that 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. Three patients had no remaining tumor on histopathology. Nine patients (30.0%) remained alive and free of recurrence (median follow-up, 34 months; range, 14-59 months), and two patients died of other causes without recurrence.

Importantly, the InPACT trial is actively enrolling patients to determine the frontline therapy for locally advanced penile cancer. When the InPACT trial was designed in 2011, there were several important questions that were in at the forefront of penile cancer management:

  1. Neoadjuvant therapy – What is the role of neoadjuvant therapy? Does either chemotherapy or chemoradiation provide superior outcomes?
  2. Treatment of the pelvis – Among patients with prior inguinal lymphadenectomy and adverse features receiving chemoradiation, what is the role of prophylactic pelvic lymph node dissection? Particularly for patients with >=3 positive nodes and extranodal extension and those with bilateral metastases

The InPACT trial design is as follows:

image-0.jpg 

In patients that fail chemotherapy, median survival is ~4.3-5.6 months with limited treatment advances over the past decade, highlighting the importance of clinical trials. Immune checkpoint inhibitor trials have entered this disease space, with the following table highlighting ongoing trials:

 InPACT trial-1.jpg 

Dr. Chahoud notes that there is a rationale and benefit for immune checkpoint blockade combination with chemotherapy in the neoadjuvant setting, given there is increased neoantigen expression in the neoadjuvant setting. Furthermore, for lung cancer patients, those receiving immune checkpoint blockade combination with chemotherapy has shown promising results. However, the risk is potentially additional immune checkpoint blockade related toxicities. Ultimately, testing this approach requires a collaborative multi-site randomized clinical trial, with the addition of advocacy and industry support. As follows is a summary of studies of systemic therapy in metastatic or relapsed penile squamous cell carcinoma:

 InPACT trial-2.jpg 

Patients with penile squamous cell carcinoma have been enrolled as part of immune checkpoint blockade combination trials. Among 54 patients receiving nivolumab + cabozantinib +/- ipilimumab, 3 patients had penile squamous cell carcinoma, with one patient having a partial response and 2 having stable disease. Among 55 patients receiving nivolumab + ipilimumab, 5 patients had penile squamous cell carcinoma, with 2 patients having stable disease and 3 having progressive disease. In 2018, Necchi et al.2 reported results of a phase 2 study of first-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma. Among 28 patients, one complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0-43.0%). The median follow-up duration was 19.8 (IQR 6.3-25.7) months, whereby 12-month progression-free survival was 26.2% (95% CI 13.2-51.9), and 12-month overall survival was 54.9% (95% CI 36.4-82.8).

Dr. Chahoud also highlighted that there are novel potential targets that may be considered in basket trials. First, NOTCH1 loss of function mutation + Pi3K mutations are present in >50% of cases. Second, DDR genes are mutated in 20% of cases, which may lead to a role for PARP inhibitors in combination with immune checkpoint blockade trials. HPV positive disease may also lead to novel systemic therapy opportunities. As follows is a table summarizing therapeutic cancer vaccines and potential implications for HPV positive penile squamous cell carcinoma:

 InPACT trial-3.jpg 

Dr. Chahoud concluded his presentation of the evolving treatment landscape and clinical trial overview of penile squamous cell carcinoma with the following take-home messages:

  • Relapsed penile squamous cell carcinoma has dismal outcomes with chemotherapy, with the potential opportunity for testing novel combinations in the neoadjuvant and relapsed settings. As such, every patient should be considered for clinical trial enrollment
  • Funding support is needed to understand the biology and immune microenvironment of penile squamous cell carcinoma to rationally develop clinical trials
  • Multi-institutional, international collaboration between academic centers of excellence is needed to develop well thought out clinical trials designed to advance outcomes

Presented by: Jad Chahoud, MD, MPH, Moffitt Cancer Center, Tampa, FL

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 EAU Section of Oncological Urology (ESOU) Hybrid Annual Meeting, Madrid, Spain, Fri, Jan 21 – Sun, Jan 23, 2022.

References:

  1. Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: A phase II study. J Clin Oncol. 2010 Aug 20;28(24):3851-3857.
  2. Necchi A, Lo Vullo S, Perrone F, et al. 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. BJU Int 2018 Mar;121(3):348-356.