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.
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.
OncLive: Can you discuss the treatment and management of this population?
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.
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.
Is anyone attempting to answer the question of what to do after chemotherapy fails?
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.
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.
Will immunotherapy show a similar benefit in penile cancer that it has shown in other genitourinary tumors?
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.