Immunotherapy may benefit certain patients with penile cancer

ByMatthew Shinkle

Fact checked byMindy Valcarcel, MS

Immune checkpoint inhibitors may confer benefit to certain patients with advanced penile squamous cell carcinoma, according to retrospective study results.

Penile cancer is rare, with approximately 2,070 new cases diagnosed in the United States each year. Treatment options are limited, and most patients initially receive platinum chemotherapy.

Graphic showing response rate among patients with lymph node-only metastases — Data derived from El Zarif T, et al. *J Natl Cancer Inst*. 2023;doi:10.1093/jnci/djad155.

Talal El Zarif, MD, oncology research fellow at Dana Farber Cancer Institute and a member of Yale Cancer Center, and colleagues reviewed data from 92 patients with locally advanced or metastatic penile squamous cell carcinoma treated with immune checkpoint inhibitors between 2015 and 2022 at one of 24 centers in the United States, Europe and Asia.

The four most common regimens included pembrolizumab (Keytruda, Merck) monotherapy (28%); nivolumab (Opdivo, Bristol Myers Squibb) in combination with ipilimumab (Yervoy, Bristol Myers Squibb) with or without multitargeted tyrosine kinase inhibitors (25%); nivolumab monotherapy (17%) or cemiplimab (Libtayo, Regeneron Pharmaceuticals) monotherapy (16%).

Findings showed 13% of all patients — and 35% (n = 7 of 20) of those with lymph node-only metastases — responded to immune checkpoint inhibitor therapy.

Median OS was 9.8 months (95% CI, 7.7-12.8) and median PFS was 3.2 months (95% CI, 2.5-4.2). Twenty-seven patients (29%) experienced treatment-related adverse events (grade 3 or higher, 9.8%).

Healio spoke with El Zarif about the findings and their potential implications.

Healio: Can you offer insights into typical treatment approaches for penile cancer?

El Zarif: For penile cancer, the first question is whether the tumor is resectable. That answer depends on the stage of the cancer and where it has spread.

If it is localized, surgery would be performed. In cases of advanced or metastatic penile cancer, systemic treatment would be implemented with or without surgery. This usually consists of neoadjuvant chemotherapy followed by surgery. There are cases in the metastatic setting where surgery is not performed and treatment relies on systemic therapy alone, which may be chemotherapy or — most recently — immunotherapy.

Healio: What motivated you to conduct this study?

El Zarif: Immune checkpoint inhibitors have been used often in other genitourinary cancers like kidney or bladder cancer, and they also have been investigated in prostate cancer. The question remained as to the effectiveness of these agents for penile cancer. Prior to this work, there was no full publication of a clinical trial in this space and data were limited.

The other big motivation is that we’re interested in virus-driven tumors, and 50% of penile cancers are HPV-driven. Finally, we’ve had success in prior multi-institutional studies and thought we could leverage the same approach to answer this very important question.

Healio: Can you describe your reaction to the findings? Did anything surprise you?

El Zarif: I want to make sure we acknowledge the limitations of the study first. It is retrospective, it is multi-center and it includes many different treatment regimens, so it is difficult to make very strong conclusions. However, one striking conclusion is that there is a low response rate of penile cancer to immunotherapy — about 13% in the overall cohort. We went into this project with no expectations. We didn’t know if we’d see high or low response rates.

It did surprise me a bit because this is an HPV-driven tumor, and we have seen HPV-driven tumors in head and neck [cancer], for example, have better prognosis and better response to immunotherapy. If it’s a virus-driven process, we expect a higher load of neoantigens, and thus that would give us the expectation that immunotherapy is going to work better in this setting. But that was not the case, at least in our experience. I think the main surprise is that when you compare HPV-positive vs. HPV-negative tumors — an analysis that was limited because we didn’t have data for all patients — we didn’t see a lot of differences in terms of response or survival.

Healio: What do you consider the most important clinical implication of these findings?

El Zarif: Based on what we saw, the patients who had lymph node-only disease and less visceral metastases tended to do better. Seven of the 11 total responders had lymph node-only disease. That hinted toward where immunotherapy might fit in the context of penile cancer.

We hope this gives oncologists the ability to have shared decision-making with their patients, being able to show what they can expect based on the response and toxicity rates from our study to engage in a benefit-risk conversation.

Healio: What questions must be addressed in future research?

El Zarif: First, what can we do about the lymph node-only disease population? Is there a clinical trial that can focus on these patients? Second, a trial that has completely profiled the HPV-driven tumors would be important to answer the question of whether HPV status has any difference in the choice of optimal therapy because that will guide treatment selection.

Further, molecular profiling would tell us if there is a high tumor mutational burden (TMB). We know that immunotherapy is approved for any cancer type with a TMB greater than 10 [mutations/megabase]. A prior abstract showed penile cancer across the board has lower TMB, which would partly explain why we saw a low response rate overall. Investigating TMB and genomic alterations in penile cancer treated with immune checkpoint inhibitors would be helpful.

Healio: Is there anything else you feel is important to emphasize?

El Zarif: In this study, we aimed to describe our experience with a unique population where clinical trials are very challenging to be done. I would like to acknowledge that this was a huge effort by the investigators and that multi-institutional collaborations are the way to go in rare diseases and unique populations. I also would like to highlight that, although immunotherapy offered promise for patients with penile cancer, response was only limited to 13% of patients in our cohort. With that, it is important to take into context the toxicities that can occur from immunotherapy, which may be overwhelming to our patients. Oncologists and patients should make a shared decision before proceeding with this treatment, and we hope our study can provide more clarification and make this conversation easier.