Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors

Talal El Zarif^{1

2}, Amin H Nassar², Gregory R Pond³, Tony Zibo Zhuang⁴, Viraj Master⁵, Bassel Nazha⁵, Scot Niglio⁶, Nicholas Simon⁷, Andrew W Hahn⁸, Curtis A Pettaway⁸, Shi-Ming Tu⁹, Noha Abdel-Wahab^{8

10}, Maud Velev¹¹, Ronan Flippot¹², Sebastiano Buti¹³, Marco Maruzzo¹⁴, Arjun Mittra¹⁵, Jinesh Gheeya¹⁶, Yuanquan Yang¹⁶, Pablo Alvarez Rodriguez¹⁷, Daniel Castellano¹⁷, Guillermo de Velasco¹⁷, Giandomenico Roviello¹⁸, Lorenzo Antonuzzo^{19

20}, Rana R McKay²¹, Bruno Vincenzi²², Alessio Cortellini^{22

23}, Gavin Hui²⁴, Alexandra Drakaki²⁴, Michael Glover²⁵, Ali Raza Khaki²⁵, Edward El-Am²⁶, Nabil Adra²⁷, Tarek H Mouhieddine²⁸, Vaibhav Patel²⁸, Aida Piedra²⁹, Angela Gernone³⁰, Nancy B Davis³¹, Harrison Matthews³², Michael R Harrison³², Ravindran Kanesvaran³³, Giulia Claire Giudice¹³, Pedro Barata³⁴, Alberto Farolfi³⁵, Jae Lyun Lee³⁶, Matthew I Milowsky³⁷, Charlotte Stahlfeld³⁸, Leonard Appleman³⁸, Joseph W Kim², Dory Freeman¹, Toni K Choueiri¹, Philippe E Spiess³⁹, Andrea Necchi⁴⁰, Andrea B Apolo⁷, Guru P Sonpavde⁴¹

Affiliations

¹ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
² Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
³ Department of Oncology, McMaster University, Hamilton, ON, Canada.
⁴ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.
⁶ New York University Grossman School of Medicine, New York, NY, USA.
⁷ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Winthrop P. Rockefeller Cancer Institute, Little Rock, AR, USA.
¹⁰ Assiut University Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt.
¹¹ Département d'Innovation Thérapeutique et Essais Précoces, Gustave Roussy-Paris-Saclay University, Villejuif, France.
¹² Medical Oncology Department, Institute Gustave Roussy, Villejuif, France.
¹³ Department of Medicine and Surgery, Oncology Unit, University Hospital of Parma, Parma, Italy.
¹⁴ Oncology 1 Unit, Istituto Oncologico Veneto IOV-Istituto Di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
¹⁵ Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹⁶ Genitourinary Oncology Section, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, Columbus, OH, USA.
¹⁷ Department of Medical Oncology, Hospital Universitario, 12 de Octubre, Madrid, Spain.
¹⁸ Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
¹⁹ Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.
²⁰ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
²¹ University of California San Diego, San Diego, CA, USA.
²² Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
²³ Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom.
²⁴ University of California Los Angeles, Los Angeles, CA, USA.
²⁵ Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
²⁶ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
²⁷ Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA.
²⁸ Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁹ Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
³⁰ Unit of Medical Oncology Policlinico, Bari, Italy.
³¹ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA.
³³ National Cancer Centre Singapore, Singapore.
³⁴ University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
³⁵ Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola, Italy.
³⁶ University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
³⁷ University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
³⁸ Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³⁹ Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
⁴⁰ Department of Genitourinary Oncology, Vita-Salute San Raffaele University, Milan, Italy.
⁴¹ Division of Medical Oncology, Advent Health Cancer Institute, Orlando, FL, USA.

PMID: 37563779
PMCID: PMC11032703
DOI: 10.1093/jnci/djad155

Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors

Talal El Zarif et al. J Natl Cancer Inst. 2023.

. 2023 Dec 6;115(12):1605-1615.

doi: 10.1093/jnci/djad155.

Authors

Affiliations

¹ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
² Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
³ Department of Oncology, McMaster University, Hamilton, ON, Canada.
⁴ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.
⁶ New York University Grossman School of Medicine, New York, NY, USA.
⁷ Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Winthrop P. Rockefeller Cancer Institute, Little Rock, AR, USA.
¹⁰ Assiut University Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt.
¹¹ Département d'Innovation Thérapeutique et Essais Précoces, Gustave Roussy-Paris-Saclay University, Villejuif, France.
¹² Medical Oncology Department, Institute Gustave Roussy, Villejuif, France.
¹³ Department of Medicine and Surgery, Oncology Unit, University Hospital of Parma, Parma, Italy.
¹⁴ Oncology 1 Unit, Istituto Oncologico Veneto IOV-Istituto Di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
¹⁵ Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹⁶ Genitourinary Oncology Section, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, Columbus, OH, USA.
¹⁷ Department of Medical Oncology, Hospital Universitario, 12 de Octubre, Madrid, Spain.
¹⁸ Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
¹⁹ Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.
²⁰ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
²¹ University of California San Diego, San Diego, CA, USA.
²² Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
²³ Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom.
²⁴ University of California Los Angeles, Los Angeles, CA, USA.
²⁵ Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
²⁶ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
²⁷ Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA.
²⁸ Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁹ Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
³⁰ Unit of Medical Oncology Policlinico, Bari, Italy.
³¹ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA.
³³ National Cancer Centre Singapore, Singapore.
³⁴ University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
³⁵ Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola, Italy.
³⁶ University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
³⁷ University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
³⁸ Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³⁹ Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
⁴⁰ Department of Genitourinary Oncology, Vita-Salute San Raffaele University, Milan, Italy.
⁴¹ Division of Medical Oncology, Advent Health Cancer Institute, Orlando, FL, USA.

PMID: 37563779
PMCID: PMC11032703
DOI: 10.1093/jnci/djad155

Abstract

Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors.

Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons.

Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher.

Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

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Conflict of interest statement

Talal El Zarif reports honoraria from Art tempi. Amin H. Nassar acknowledges support from the Prime Center (SW-011); Consultant: The Oncology Research Information Exchange Network (ORIEN); Writing/Editor fees: editor of Elsevier Practice Update Bladder Cancer Center of Excellence. Bassel Nazha has served as an advisory board member for Exelixis, paid consultant for Cardinal Health, paid case discussant for AmerisourceBergen, and a speaker (education) from Medical Logix. Andrew W. Hahn is on the advisory board of Janssen and Intellisphere; travel support: Dava Oncology. Noha Abdel-Wahab received a K01 Mentored Research Scientist Development Award from the National Institute of Allergy and Infectious Diseases (K01AI163412) and received the University of Texas MD Anderson Cancer Center Institutional Research Grant, Division of Internal Medicine Development Award, and Survivorship Seed Money Award; received speaker fees and consulting fees from ChemoCentryx. Marco Maruzzo is on the advisory board of MSD, BMS, Merck Serono, Astellas, Janssen-Cilag, Pfizer, Eli Lilly, EISAI, Bayer, and IPSEN. Yuanquan Yang is on the advisory board of Exelixis; Consulting and Honoraria: The Whiteoak Group, AstraZeneca; Research support to institution: Incyte, Amgen, Novartis. Lorenzo Antonuzzo reports research funding (to institution) from Novartis, Merck Serono, Bristol-Myers Squibb, and AstraZeneca; personal honoraria as invited speaker from Roche, Bristol-Myers Squibb, Servier, AstraZeneca, Amgen, and MSD; participation in advisory board for Amgen, Merk Serono, Ely Lilly, AstraZeneca, Incite, Bristol-Myers Squibb, Servier, and MSD. Rana R. McKay is a consultant/advisory board Aveo, AstraZeneca, Bayer, BMS, Calithera, Caris, Dendreon, Exelixis, Janssen, Lilly, Merck, Myovant, Novartis, Pfizer, Sorrento Therapeutics, SeaGen, Sanofi, Telix, and Tempus; research funding from Bayer, AstraZeneca, Oncternal, and Tempus. Alessio Cortellini acknowledges consultant/Scientific Advisory Board roles at MSD, AstraZeneca, and IQVIA; speaker fees from AstraZeneca, Pierre-Fabre, and EISAI; and writing/editor fees from BMS. Ravindran Kanesvaran is a speaker, on the advisory board, and received honoraria from AstraZeneca, BMS, MSD, Merck, Pfizer, Novartis, Astellas, Eisai, Ipsen, Bayer, and Johnson &Johnson. Alberto Farolfi has received personal honoraria for lectures from AstraZeneca, GSK-Tesaro, and Clovis and institutional research grants from Astellas, MSD, and Bayer; was on the advisory board of Janssen, AstraZeneca, and GSK-Tesaro. Matthew I. Milowsky stock and other ownership interests in Pfizer, Merck, Gilead Sciences; consulting or advisory role with Loxo/Lilly; research funding (institution) from Merck, Roche/Genentech, Bristol-Myers Squibb, Seagen, G1 Therapeutics, Mirati Therapeutics, Incyte, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Clovis Oncology, Arvinas, ALX Oncology, Loxo, and Hoosier Cancer Research Network; and other relationships with Elsevier (co-editor, Clinical Genitourinary Cancer) and Medscape. Toni K. Choueiri reports institutional or personal paid or unpaid support for research, advisory boards, consultancy, and honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, IQVA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, and others), outside the submitted work; institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA; equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse; committees include NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan; medical writing and editorial assistance support may have been funded by Communications companies in part; no speaker’s bureau; mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or royalties potentially involved in research around the subject matter. T. K. Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. Guru P. Sonpavde is on the advisory board of EMD Serono, BMS, Merck, Seattle Genetics/Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Lucence Health, IMV, and Vial; a consultant/scientific advisory board of Suba Therapeutics, Syapse; research support to institution from Sanofi, AstraZeneca, Gilead, Helsinn, Lucence, EMD Serono, Jazz Therapeutics, Genecentric; is a speaker for BIO—INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltd, Seagen, Gilead, Natera, Exelixis; data safety monitoring committee (honorarium) from Mereo; Employment: Spouse employed by Myriad; Writing/Editor fees: Uptodate, editor of Elsevier Practice Update Bladder Cancer Center of Excellence

The remaining authors report that there are no potential competing interests pertaining to this work.

Figures

**Figure 1.**
Progression-free survival (A) and overall survival (B) of 92 patients with penile squamous cell carcinoma treated with immune checkpoint inhibitor (ICI)–based regimens.

**Figure 2.**
Overall survival by neutrophil/lymphocyte ratio (NLR) and status of visceral metastases. ICI = immune checkpoint inhibitor.

See this image and copyright information in PMC

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Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors

Affiliations

Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors

Authors

Affiliations

Abstract

Conflict of interest statement

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