Immunotherapy Trials Offer Hope in Advanced Penile Cancer

Guru Sonpavde, MD

Penile cancer is a historically poor-prognosis disease, with patients who progress following chemotherapy having little to no effective options. This needs to change, says Guru Sonpavde, MD, starting with replacing the standard of care with novel regimens being explored in clinical trials.

Some of the most exciting studies are with immunotherapy, says Sonpavde, as about 50% of patients with penile cancer overexpress PD-L1. There is an ongoing trial of pembrolizumab (Keytruda) in the post-platinum setting, and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) is being evaluated in a large study of rare tumors, including penile cancer.

In a phase II study of patients with advanced penile squamous cell carcinoma who have undergone prior chemotherapy, pembrolizumab is given intravenously at 200 mg on the first day of each 3-week cycle (NCT02837042). The primary outcome measure for this study is objective response rate, and secondary outcomes are duration of response, stable disease, progression-free survival, and overall survival.

Patients eligible for this study are those who are in the locally advanced unresectable or metastatic stage, have radiologic evidence for progressive disease after more than 1 prior chemotherapy regimen, have measurable disease, and demonstrate adequate organ function.

Another ongoing trial with immunotherapy for patients with penile cancer is the National Cancer Institute’s study of nivolumab and ipilimumab in patients with rare tumors (NCT02834013). The primary outcome measure for this trial is overall response rate.

There are also trials looking at targeted agents, such as dacomitinib and afatinib (Gilotrif), for this patient population.

OncLive: Can you discuss the treatment and management of this population?

In an interview with OncLive, Sonpavde, director of Bladder Cancer at Dana-Farber Cancer Institute, discussed the importance of clinical trial enrollment for patients with penile cancer and shared his insight on immunotherapy research in this setting.Sonpavde: Patients with metastatic or advanced penile squamous cell carcinoma have a very poor prognosis with current chemotherapy. This consists of cisplatin-based combinations, including cisplatin plus 5-fluorouracil and sometimes 3-drug combinations, such as ifosfamide, paclitaxel, and cisplatin. However, we know that the median survival with these cisplatin-based combination regimens is approximately in the 8- to 9-month range, so it’s quite dismal. Most patients will progress and fail; that is when we get into the salvage options, results of which are even more dismal.

Is anyone attempting to answer the question of what to do after chemotherapy fails?

We've historically used taxanes like paclitaxel, and sometimes docetaxel, but we know that the response rates with those drugs are approximately 20%. No one is curable with those regimens. We need to change our mindsets and think about enrolling patients on clinical trials, especially in the salvage setting, but also in the first-line setting.A number of exciting trials are going on. We know that EGFR protein is a target in this disease, as EGFR is overexpressed at the protein level and at the gene expression level. There is also gene amplification at the DNA level. One trial just got published looking at dacomitinib, which is a panHER EGFR and HER2 inhibitor in patients in the first-line setting. In the first-line setting, dacomitinib demonstrated a response rate of about 32%, so about one-third of patients had mostly partial responses. There is a trial ongoing looking at afatinib, a panHER oral tyrosine kinase inhibitor in the post-platinum salvage setting. Those are HER-family inhibitors.

There are also exciting trials going on looking at PD-1 inhibitors. There is a phase II trial with pembrolizumab in the post-platinum setting. There is another very exciting trial looking at the CTLA-4 inhibitor ipilimumab plus nivolumab. This combination is being looked at in all rare cancers; it is a kind of a basket study that includes any rare cancer.

Will immunotherapy show a similar benefit in penile cancer that it has shown in other genitourinary tumors?

In addition, chemotherapy is being looked at [in a trial based] in the United Kingdom with vinflunine. A trial with chemotherapy and pazopanib (Votrient) closed prematurely because it could not enroll rapidly enough. Angiogenesis [inhibitors were] looked at, but it is always challenging to accrue on these trials because penile cancer is so rare. We really need an international effort to accrue well on these trials.There is a clearly a lot of promise for PD-1 checkpoint inhibitors, and CTLA-4 plus PD-1 combination strategies. PD-L1 is overexpressed in approximately 50% of tumors, so there is a clearly the promise that PD-1 inhibitors will work.

What do you believe is the biggest unmet need in this disease?

What is your take-home message for urologists and community oncologists?

About half of these patients also have tumors driven by human papilloma virus (HPV). With HPV being a viral antigen, we expect some activity with PD-1 inhibitors. PD-L1 is high, and HPV drives tumors in half of these cases, so we fully expect some activity.There are unmet needs in all settings. In first- and second-line advanced disease, we cannot cure patients with currently available chemotherapy. We need to make advances in the neoadjuvant setting for locally advanced disease and the adjuvant setting, because we know that neoadjuvant or adjuvant chemotherapy with or without radiation improves outcomes modestly in data from retrospective studies. The message that I want to convey is that the standard of care for penile cancer should be clinical trials. Cisplatin-based chemotherapy in the first-line setting is modestly effective—around 35%—it is not a curative regimen. The second-line setting is even worse.

Before we give everybody taxanes, we ought to be thinking of clinical trials, and we should also be conducting molecular profiling of these tumors. I want to remind everyone out there that pembrolizumab is approved regardless of tumor type if the tumor is microsatellite instability-high (MSI-H), which is the DNA mismatch-repair defect. We don’t know how common that is in penile cancer, but most cancers have a population that has this defect. That is something that people need to remember, and to look for the genomic defects to guide patients toward pembrolizumab if the patient is MSI-H, or the appropriate clinical trial.