Case Report: Two Cases of Chemotherapy Refractory Metastatic Penile Squamous Cell Carcinoma With Extreme Durable Response to Pembrolizumab

Abstract

BackgroundPenile squamous cell carcinoma (PSCC) is a rare malignancy, and those patients with metastatic disease have limited treatment options. Treatment is largely comprised of platinum-based chemotherapy; however, patients progressing after initial chemotherapy have a median overall survival (OS) of less than 6 months. Based on a high percentage of PD-L1 expression in patients with PSCC, and its biological similarities to other squamous cell carcinomas, we present two patient cases treated with pembrolizumab with extraordinary durable treatment response far beyond treatment with standard therapy.Main BodyThe first patient is a 64 year old male with PSCC who was treated with neoadjuvant chemotherapy, partial penectomy, and adjuvant radiation prior to developing metastatic disease. He had a high TMB (14 mutations/Mb) and was started on pembrolizumab with a complete response, which has been maintained for 38 months. The second patient is an 85 year old male with PSCC who was treated with partial penectomy and adjuvant chemotherapy and radiation prior to developing metastatic disease. He had positive PD-L1 expression CPS 130) and was started on pembrolizumab with a partial response, which has been maintained for 18 months after starting treatment.ConclusionsThese two cases of extreme durable response with pembrolizumab (with molecular data including TMB and PD-L1 status) represent a significant clinical benefit in this patient population. With limited treatment options that result in a median OS of less than 6 months, along with the toxicity profile of chemotherapy which may not be tolerated in elderly patients with comorbidities, this survival benefit with pembrolizumab, along with advances in tumor sequencing and clinical trials shows that there is a potentially significant benefit with novel therapies in this patient population.

Immune Checkpoint Inhibitors in Penile Cancer

“…As a result of the biological rationale and the compelling need for additional systemic options, a few ICIs have been explored in patients with advanced PCa, with promising results. Chahoud [ 13 ] and others originally reported on two cases who received anti-PD-1 agent pembrolizumab after chemotherapy, radiation and surgery: one man with a high tumor mutation burden achieved a complete response maintained for >38 months and another man achieved a partial response, maintained for >18 months. 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 ].…”

Multimodal Treatment Combining Salvage Surgery-Assisted Chemotherapy and Checkpoints Blockade Immunotherapy Achieves Complete Remission on a Recurrent Penile Cancer Patient: A Case Report

“… 27 Another stage IV patient with both high TMB and PD-L1 showing resistance to platinum-based chemotherapy and chemoradiation, got CR of lymph node metastasis after starting pembrolizumab. 25 These cases shows that pSCC patients could benefit from CPI therapy, and a composite of high TMB plus high PD-L1 would further enrich the benefit to CPI. 28 Meanwhile a recent study revealed that a relatively low TMB is commonly found in penile squamous cell carcinoma.…”

“…A case reported that a penile cancer patient with strongly positive PD-L1 status showed PR since starting pembrolizumab 18 months ago. 25 And another T2N2M0 penile cancer patient who used the PD-L1 inhibitor atezolizumab as second-line therapy reached near complete response after 2 years’ therapy. 26 But the expression level of PD-L1 and/or TMB was lacking in these cases.…”

Cemiplimab for Cisplatin Resistant Metastatic Penile Cancer

“…Combination of anti-CTLA4 and anti-PD-1, notably ipilimumab and nivolumab, has led to an impressive response in a patient with metastatic penile SCC whose cancer was refractory to the paclitaxel, ifosfamide, cisplatin regimen and showed a high PD-L1 expression, high TMB, high microsatellite instability, and alterations in DNA mismatch repair genes [12]. Although increased toxicity may be expected with dual inhibition this was not reported and the limited data from the literature are consistent with a favourable toxicity profile for penile cancer patients treated with single-agent CPI [10]. Consistent with this, our patient did not experience toxicity neither clinical nor biological.…”

“…The first report of a response, albeit partial, to the anti PD-1 nivolumab, in a multi-treated patient with a CDKN2A altered penile cancer brought hope in this poor-prognosis situation [9]. Other encouraging reports with pembrolizumab were later released including 1 patient with high tumour-mutational burden (TMB) but with unknown PD-L1 status who experienced a long-lasting 38-month CR [10].…”