Global Society of Rare GU Tumors 2020

GSRGT 2020: Evolution of Systemic Therapies and the Landscape of Clinical Trials Enrolling Patients

(UroToday.com) To discuss the evolution of systemic therapies and the landscape of clinical trials among patients with penile cancer, Dr. Philippe Spiess, the co-Course Director of the Global Society of Rare Genitourinary Tumors (GSRGT) 2020 Virtual Summit, invited Dr. Jad Chahoud, his colleague from the Moffitt Cancer Center.


Dr. Chahoud started by highlighting that penile cancer is a rare disease in the US, representing 0.7% of all cancer, with high-risk HPV responsible for ~50% of all penile squamous cell carcinoma. The majority of these patients will present with localized or locally advanced disease whereby platinum-based combination chemotherapy remains the front-line therapy. The InPACT trial is actively enrolling patients to determine the frontline therapy for locally advanced penile cancer, given there have been limited treatment advancements in the last decade. Survival for patients with lymph node-positive penile cancer is heterogeneous and the pathological nodal status remains the strongest predictor of survival.

For patients with locally advanced penile squamous cell carcinoma, a multimodal approach with neoadjuvant chemotherapy followed by consolidation surgery is recommended by the National Comprehensive Cancer Network (NCCN) and European guidelines, as it has been the most studied in Phase II trials. Single-agent cisplatin in the 1980s showed an objective response rate of 15%, and the doublet combinations with cisplatin with 5-FU or irinotecan reported objective response rates of 30%. However, few patients were successfully reported as having undergone consolidation surgery. As follows is a summary of reported studies on neoadjuvant chemotherapy for advanced penile squamous cell carcinoma:

reported studies on neoadjuvant chemotherapy for advanced penile squamous cell carcinoma

Dr. Chahoud notes that until the InPACT trial offers us the much-needed level 1 evidence, currently the standard of care is to use neoadjuvant chemotherapy followed by consolidation surgery based on the landmark Phase II study by Paglior et al (with only 30 patients).1 Among these patients, 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. For those that underwent surgery, 10% of these patients had no viable tumor on final pathology. Improved time to progression and overall survival were significantly associated with a response to chemotherapy (p < 0.001 and p = 0.001, respectively), absence of bilateral residual tumor (p = 0.002 and p = 0.017, respectively), and absence of extranodal extension (p = 0.001 and p = 0.004, respectively) or skin involvement (p = 0.009 and p = 0.012, respectively). But what happens if chemotherapy fails in these patients? Among the 19/30 patients that recurred in the neoadjuvant paclitaxel, ifosfamide, and cisplatin (TIP) trial, 12 patients received cisplatin based regimens and 7 received other treatment modalities, highlighting the dismal outcomes with an estimated survival of less than 6 months among these patients that recurred. Dr. Chahoud notes that this highlights two unmet needs, including (i) the need to improve on frontline treatment TIP to reduce the percentage of refractory/relapsed disease, and (ii) the need for salvage treatment options beyond chemotherapy.

According to Dr. Chahoud, the above unmet needs potentially open the door for immunotherapy combinations with chemotherapy in the neoadjuvant disease space, perhaps benefiting from the synergistic effect. Furthermore, the neoadjuvant setting is associated with a higher neoantigen expression and might lead to the improved clinical activity of immunotherapy.

Third, there is recent data from early-stage squamous cell carcinoma of the lung showing feasibility, safety, and clinical activity using a similar approach. There have been recent trials evaluating regimens in patients who may not tolerate TIP or have distant metastasis at presentation. Looking at data presented at the 2018 American Society of Clinical Oncology - Genitourinary Cancers Symposium (ASCO GU), Pickering and colleagues used vinflunine as first-line therapy with an objective response rate of 27%, with a median progression-free survival (PFS) of 2.9 months and overall survival (OS) of 8.4 months. Additionally, preliminary data from a Phase I trial assessing the combination of nivolumab and cabozantinib reported a 33% response rate. As follows is a summary of studies of systemic therapy in metastatic or relapsed penile squamous cell carcinoma:

summary of studies of systemic therapy in metastatic or relapsed penile squamous cell carcinoma

Dr. Chahoud also discussed first-line dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, specifically the {hase II trial lead by Dr. Andrea Necchi.2 Among 28 patients treated in this trial, 8 (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) had clinically involved bilateral lymph nodes. Over a median follow-up duration of 19.8 (IQR 6.3-25.7) months, there was 1 complete and 8 partial responses (objective response rate [ORR] 32.1%, 80% confidence interval [CI] 21.0-43.0%). The median progression-free survival was 4.1 months (95% CI 3.1 to not reached) with a 12-month progression-free survival rate of 26.2% (95% CI 13.2-51.9). The median overall survival was 13.7 months (95% CI 9.9 to not reached) with a 12-month overall survival rate of 54.9% (95% CI 36.4-82.8). As follows is the Kaplan-Meier overall survival curve with the corresponding 95% confidence intervals:

pan HER tyrosine confidence intervals

Dr. Chahoud also highlighted that another clinical trial opportunity is for novel systemic therapy with HPV directed options. Beyond the prognostic role of HPV status, HPV should be explored in the relapsed setting to open up potential trial opportunities for these patients with regards to (i) HPV specific T-cell therapy, (ii) vaccine therapy with or without immunotherapy, and (iii) novel anti-PD-L1 and TGF-beta trap fusion proteins. As follows is a list of trials assessing therapeutic cancer vaccines and potential implications for HPV-positive penile squamous cell carcinoma:

implications for HPV positive penile squamous cell carcinoma

Dr. Chahoud concluded his presentation of systemic therapies and the landscape of clinical trials with the following take-home messages:

  • Relapsed penile squamous cell carcinoma 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 penile squamous cell carcinoma to rationally develop clinical trials
  • Multi-institutional collaboration between academic centers of excellence is needed to develop well thought out clinical trials designed to advance outcomes

Presented by: Jad Chahoud, MD, PhD, Assistant Member, Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md during the 1st Global Society of Rare Genitourinary Tumors Virtual Summit, December 11-12, 2020

References:

1. Pagliaro, Lance C., Dallas L. Williams, Danai Daliani, Michael B. Williams, William Osai, Michael Kincaid, Sijin Wen, Peter F. Thall, and Curtis A. Pettaway. "Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study." Journal of Clinical Oncology 28, no. 24 (2010): 3851.

2. Necchi, Andrea, Salvatore Lo Vullo, Federica Perrone, Daniele Raggi, Patrizia Giannatempo, Giuseppina Calareso, Nicola Nicolai 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 International 121, no. 3 (2018): 348-356.
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