Several therapeutic targets for penile cancer are currently being explored. Immune checkpoint inhibitors (ICIs) and ICI combination regimens have demonstrated promising results. Most recently, a phase I evaluation of cabozantinib and nivolumab with or without ipilimumab demonstrated an objective response rate (ORR) of 44% in 9 patients treated, prompting the ongoing phase II ICONIC study. The phase II HERCULES study also demonstrated an ORR of 39% with combination chemoimmunotherapy in the first-line setting for patients with metastatic penile cancer.
HPV-targeted therapies are another area of interest as approximately 50% of penile cancers are HPV-positive. Ongoing trials are exploring HPV-targeted therapeutic vaccines, often in combination with other immune-related agents. HPV-targeted T-cell receptor (TCR) therapies have also shown promise for patients with HPV-positive cancers. A phase I trial achieved partial responses in 6 of 12 patients and stable disease in an additional 4 patients treated with E7 TCR T cells.
Antibody-drug conjugates (ADCs) also hold promise. They consist of an antibody targeted to a cell-surface marker attached via a link to a cytotoxic payload. Nearly a quarter of penile cancers demonstrate HER2 2+/3+ staining, and trastuzumab deruxtecan (T-DXd) has demonstrated an ORR of 37% in HER2-positive solid tumors. High-risk HPV has also been associated with higher expression of nectin-4 and TROP-2, making enfortumab vedotin and sacituzumab govitecan other possible options. The SMART trial (NCT06161532) explores the use of TROP-2-directed ADC sacituzumab govitecan with or without atezolizumab in penile cancer and other rare GU malignancies.
While options are currently limited after first-line platinum-based chemotherapy, ongoing trials employing various therapeutic mechanisms and targets offer a promising outlook for patients with penile cancer. Multidisciplinary, collaborative care is imperative to moving the field forward and providing the best possible care to patients with penile cancer.
Written by:
- Saad Atiq, MD, Department of Oncology, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Magnuson Clinical Center, Bethesda, MD
- Nicholas Simon, MD MSc, Department of Oncology, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Andrea Apolo, MD, Department of Oncology, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Magnuson Clinical Center, Bethesda, MD