Metastatic penile squamous cell carcinoma with dramatic response to combined checkpoint blockade with ipilimumab and nivolumab

Abstract

Introduction Prognosis for patients with lymph node positive or metastatic penile squamous cell carcinoma remains poor. Chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP regimen) is recommended as a first-line option in this cohort of patients. No standard preferred subsequent-line therapy exists for patients with relapsed or refractory penile carcinoma following TIP chemotherapy. Molecular pathogenesis of penile cancer can be subdivided into human papilloma virus-dependent and human papilloma virus-independent pathways. Recent studies have demonstrated increased expression of programmed death ligand-1 in some penile tumors, commonly those that are human papilloma virus-negative. Given the rarity of penile carcinoma in industrialized countries and lack of effective therapies, checkpoint inhibitors may be an attractive treatment option for this subset of patients. Case report We report a case of metastatic penile cancer refractory to TIP chemotherapy, with a dramatic treatment response to ipilimumab and nivolumab. Molecular profiling of this tumor showed a high programmed death ligand-1 expression, high tumor mutational burden, high microsatellite instability, and alterations in DNA mismatch repair genes. Discussion This case highlights another dimension of information that may be gained with molecular genomic profiling of penile tumors, providing insight into the biologic behavior of this neoplasm and assessing for predictive biomarkers of response to immune checkpoint inhibitors.

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

“…Unlike in our study, simultaneous blockade of CTLA-4/CD80 and PD-1/PD-L1 axes has been more efficient than a single therapy in several studies [48][49][50]. Paradoxically, anti-PD-L1 administered as a single therapy may enhance CTLA-4/CD80-mediated immunosuppression in some patients due to the disruption of the tumor-suppressive CD80 and PD-L1 in cis interaction [9].…”

An update on treatment of penile cancer

“…In addition to significant responses from PD-1 and PD-L1 blockade, the consideration for combination ICB using PD-(L)1 and CTLA-4 inhibition has shown promise despite limited data, including a case report in a patient with metastatic penile cancer refractory to TIP, who had near resolution of large inguinal mass after two treatment cycles of nivolumab and ipilimumab. 102 An important ICB approval from a genomic standpoint was KEYNOTE 158, a multicohort phase II study of Pembrolizumab for advanced non-colorectal unresectable or metastatic cancers, that are MSI-H or mismatch repair-deficient (dMMR) tumors, and that have progressed following prior treatment without satisfactory alternative. Among the 233 enrolled patients, 27 tumor types were represented.…”

Immune Checkpoint Inhibitors in Penile Cancer

“…Conversely, a report of a Phase II trial conducted in various rare malignancies showed that pembrolizumab was not capable of providing any benefits in two patients with microsatellite-stable PCa, while a durable response was obtained in a single man with a microsatellite instability high tumor [ 14 ]. Combination of anti-CTLA-4 agent ipilimumab and anti-PD-1 agent nivolumab administered at standard doses was associated with a prominent response in a patient refractory to paclitaxel, ifosfamide and cisplatin who was selected for treatment with ICIs on the grounds of the results of extensive molecular analysis showing high PDL-1 expression, microsatellite instability and tumor mutational burden, as well as alterations in DNA mismatch repair genes [ 15 ]. Conversely, in a single-arm, multicohort, Phase II trial, assessing nivolumab and ipilimumab in patients with advanced rare genitourinary cancers not selected on the grounds of any molecular biomarker, only two of five patients evaluable for radiological response showed stable disease [ 16 ].…”