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Pembrolizumab for Advanced Penile Cancer: A Case Series from a Phase II Basket Trial - Beyond the Abstract

Advanced penile SCC (PSCC) is a rare diagnosis and carries a grim prognosis as patients who experience distant metastases are unlikely to live more than two years. There is very limited evidence to guide systemic treatment of advanced PSCC. Standard first-line treatment of advanced PSCC is paclitaxel, ifosfamide, and cisplatin (TIP). Optimal second-line or later treatment is unknown, and an unmet need exists for novel second-line or later treatments. Studies of PSCC tumor tissue found that 40-62% of PSCC cases express ≥ 1% programmed death-ligand 1 (PD-L1) on tumor cells or infiltrating immune cells.1-4 Thus, there has been interest in the efficacy of programmed cell death protein 1 (PD-1) or PD-L1 immune checkpoint inhibitors for advanced PSCC.


In our manuscript, we reported the efficacy and tolerability of pembrolizumab, a PD-1 immune checkpoint inhibitor, in three patients with advanced PSCC who progressed on standard-of-care treatment and participated in a single-arm, phase II basket trial for rare tumors (NCT02721732).5 One patient, case 1, experienced a partial response after six cycles of pembrolizumab.6 Prior to beginning pembrolizumab, he had a large local recurrence involving his proximal corpora cavernosum and urethra that was surgically unresectable, yet after his partial response, he underwent surgical consolidation and remains disease-free 38.7 months after trial enrollment. In posthoc tissue analyses, his modified proportion score (MPS) was 10%, and his post-treatment surgical specimen was microsatellite instability-high (MSI-H) due to loss of MLH-1 function and secondary loss of PMS2 expression by immunohistochemistry. Pembrolizumab is approved for tumors that are MSI-H, irrespective of tissue histology, so this explains his excellent outcome. The two other patients who received pembrolizumab on trial, case 2 and 3, experienced radiographic disease progression within three months of beginning treatment. The MPS score for these tumors was 80% and 1%, respectively. No patients experienced a grade 3 or 4 adverse event on pembrolizumab.

In sum, pembrolizumab was well tolerated as second-line therapy in a small cohort of patients with unresectable, advanced PSCC and produced an objective response in an MSI-H tumor. Our experience suggests all men with PSCC should undergo microsatellite instability testing, yet for men whose tumors are microsatellite stable, we cannot recommend single agent pembrolizumab as second-line or later treatment of advanced PSCC. Moving forward, PD-1/PD-L1 checkpoint inhibitors should continue to be investigated for PSCC in novel settings and rationale combinations. First, PD-1/PD-L1 checkpoint inhibitors have synergistic efficacy with agents that deplete myeloid-derived suppressor cells (MDSC), such as cabozantinib, in pre-clinical models of PSCC.7 A basket trial evaluating the combination of nivolumab, ipilimumab, and cabozantinib demonstrated 2 partial responses in 4 patients with advanced PSCC, so these combinations warrant further investigation.8 Second, PSCC is characterized by a period of locoregional growth prior to distant spread, and surgery remains the mainstay of treatment. Thus, rationale combinations, including PD-1/PD-L1 checkpoint inhibitors, should be investigated as neoadjuvant therapy for selected men with PSCC.

Written by: Andrew W. Hahn1 & Aung Naing2

  1. Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
  2. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX

References:

  1. Udager AM, Liu TY, Skala SL, et al. Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. Annals of oncology : official journal of the European Society for Medical Oncology 2016;27:1706-12.
  2. Cocks M, Taheri D, Ball MW, et al. Immune-checkpoint status in penile squamous cell carcinoma: a North American cohort. Human pathology 2017;59:55-61.
  3. Deng C, Li Z, Guo S, et al. Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma. Oncoimmunology 2017;6:e1269047.
  4. Ottenhof SR, Djajadiningrat RS, de Jong J, Thygesen HH, Horenblas S, Jordanova ES. Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status. The Journal of urology 2017;197:690-7.
  5. Hahn AW, Chahoud J, Campbell MT, et al. Pembrolizumab for advanced penile cancer: a case series from a phase II basket trial. Investigational new drugs 2021.
  6. Naing A, Meric-Bernstam F, Stephen B, et al. Phase 2 study of pembrolizumab in patients with advanced rare cancers. J Immunother Cancer 2020;8.
  7. Huang T, Cheng X, Chahoud J, et al. Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nat Commun 2020;11:2124.
  8. Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. Journal of Clinical Oncology 2018;36:515-.

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