Skip to main content

Advertisement

SpringerLink
Log in

Pembrolizumab for advanced penile cancer: a case series from a phase II basket trial

  • SHORT REPORT
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background: Treatment options for unresectable, locally advanced or metastatic penile squamous cell carcinoma (SCC) are limited. Previous studies have shown that 40–62% of patients with penile SCC express PD-L1. We report three cases of locally advanced or metastatic penile SCC treated with pembrolizumab. Case Presentations: Herein, we present three patients with recurrent, locally advanced or metastatic penile SCC who progressed on a platinum-based chemotherapy triplet and were treated with pembrolizumab, administered as part of a phase II clinical trial for rare tumors (NCT02721732). One patient with a microsatellite instability high (MSI-H) tumor experienced a durable partial response to pembrolizumab, underwent surgical consolidation, and remains disease-free 38.7 months later. Two patients experienced progressive disease within 3 months of beginning pembrolizumab. No one experienced a grade 3 or worse treatment-related adverse event. Conclusion: In sum, single-agent pembrolizumab was well tolerated as salvage therapy in a small cohort of patients with unresectable, locally advanced or metastatic penile SCC. Pembrolizumab produced an objective response in an MSI-H tumor, yet it did not control disease in two patients with MSS penile SCC. Rationale combination therapies, including pembrolizumab, warrant further investigation. Trial registration: ClinicalTrials.gov identifier: NCT02721732. Registered March 23, 2016.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from the study sponsor according to available guidelines at the time of the request.

Abbreviations

CGI:

Cisplatin, gemcitabine, ifosfamide

CPS:

Combined positive score

IHC:

Immunohistochemistry

MDACC:

MD Anderson Cancer Center

Mg:

Milligrams

MMR-d:

Mismatch repair deficient

MSI-H:

Microsatellite instability high

MPS:

Modified proportion score

NCCN:

National Comprehensive Cancer

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PD-L1/PD-L2:

Programmed death-ligand 1 or 2

PR:

Partial response

SCC:

Squamous cell carcinoma

SD:

Stable disease

TIP:

Paciltaxel, ifosfamide, cisplatin

TMB:

Tumor mutation burden

References

  1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70:7–30

    Article  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  3. Sánchez-Ortiz RF, Pettaway CA (2004) The role of lymphadenectomy in penile cancer. Urol Oncol 22:236–244 discussion 44-5

    Article  Google Scholar 

  4. Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S (2008) Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-Centre analysis of 700 patients. Eur Urol 54:161–168

    Article  Google Scholar 

  5. Spiess PE (2013) New treatment guidelines for penile cancer. J Natl Compr Cancer Netw 11:659–662

    Article  CAS  Google Scholar 

  6. Pagliaro LC, Williams DL, Daliani D, Williams MB, Osai W, Kincaid M, Wen S, Thall PF, Pettaway CA (2010) Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol 28:3851–3857

    Article  CAS  Google Scholar 

  7. Wang J, Pettaway CA, Pagliaro LC (2015) Treatment for metastatic penile Cancer after first-line chemotherapy failure: analysis of response and survival outcomes. Urology 85:1104–1110

    Article  CAS  Google Scholar 

  8. Azizi M, Aydin AM, Hajiran A, Lai A, Kumar A, Peyton CC, Minhas S, Sonpavde GP, Chahoud J, Pagliaro LC, Necchi A, Spiess PE (2020) Systematic review and meta-analysis-is there a benefit in using Neoadjuvant systemic chemotherapy for locally advanced penile squamous cell carcinoma? J Urol 203:1147–1155

    Article  Google Scholar 

  9. Mann SA, Lopez-Beltran A, Massari F, Pili R, Fiorentino M, Koch MO, Kaimakliotis HZ, Wang L, Scarpelli M, Ciccarese C, Moch H, Montironi R, Cheng L (2017) Targeting the programmed cell Death-1 pathway in genitourinary tumors: current Progress and future perspectives. Curr Drug Metab 18:700–711

    Article  CAS  Google Scholar 

  10. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, Lunceford J, Cheng J, Chow LQM, Seiwert TY, Handa M, Tomassini JE, McClanahan T (2017) PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in Cancer. Clin Cancer Res 23:3158–3167

    Article  CAS  Google Scholar 

  11. Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  Google Scholar 

  12. Marabelle A, Fakih MG, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller W, Italiano A, Kao S, Piha-Paul SA, Delord JP, McWilliams RR, Aurora-Garg D, Chen M, Jin F, Norwood K, Bang YJ (2019) Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann Oncol 30:v477–v4v8

    Article  Google Scholar 

  13. National Comprehensive Cancer Network. Penile cancer (Version 2.2019). https://www2.tri-kobe.org/nccn/guideline/urological/english/penile.pdf. Accessed 10 Jan 2021

  14. Udager AM, Liu TY, Skala SL, Magers MJ, McDaniel AS, Spratt DE, Feng FY, Siddiqui J, Cao X, Fields KL, Morgan TM, Palapattu GS, Weizer AZ, Chinnaiyan AM, Alva A, Montgomery JS, Tomlins SA, Jiang H, Mehra R (2016) Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. Ann Oncol 27:1706–1712

    Article  CAS  Google Scholar 

  15. Cocks M, Taheri D, Ball MW, Bezerra SM, del Carmen Rodriguez M, Ricardo BFP, Bivalacqua TJ, Sharma RB, Meeker A, Chaux A, Burnett AL, Netto GJ (2017) Immune-checkpoint status in penile squamous cell carcinoma: a north American cohort. Hum Pathol 59:55–61

    Article  CAS  Google Scholar 

  16. Deng C, Li Z, Guo S, Chen P, Chen X, Zhou Q, Chen J, Yu X, Wu X, Ma W, Xie Q, Ye Y, Li Y, Qin Z, Liu Z, Liu R, Zhang Z, Yao K, Han H, Zhou F (2017) Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma. Oncoimmunology 6:e1269047

    Article  Google Scholar 

  17. Ottenhof SR, Djajadiningrat RS, de Jong J, Thygesen HH, Horenblas S, Jordanova ES (2017) Expression of programmed death ligand 1 in penile Cancer is of prognostic value and associated with HPV status. J Urol 197:690–697

    Article  Google Scholar 

  18. Davidsson S, Carlsson J, Giunchi F, Harlow A, Kirrander P, Rider J, Fiorentino M, Andrén O (2019) PD-L1 expression in men with penile Cancer and its association with clinical outcomes. Eur Urol Oncol 2:214–221

    Article  Google Scholar 

  19. Naing A, Meric-Bernstam F, Stephen B, Karp DD, Hajjar J, Rodon Ahnert J, Piha-Paul SA, Colen RR, Jimenez C, Raghav KP, Ferrarotto R, Tu SM, Campbell M, Wang L, Sabir SH, Tapia C, Bernatchez C, Frumovitz M, Tannir N, Ravi V, Khan S, Painter JM, Abonofal A, Gong J, Alshawa A, McQuinn LM, Xu M, Ahmed S, Subbiah V, Hong DS, Pant S, Yap TA, Tsimberidou AM, Dumbrava EEI, Janku F, Fu S, Simon RM, Hess KR, Varadhachary GR, Amir Habra M (2020) Phase 2 study of pembrolizumab in patients with advanced rare cancers. J Immunother Cancer 8:e000347

    Article  Google Scholar 

  20. Canter DJ, Nicholson S, Watkin N, Hall E, Pettaway C (2019) The international penile advanced Cancer trial (InPACT): rationale and current status. Eur Urol Focus 5:706–709

    Article  Google Scholar 

  21. Jilaveanu LB, Shuch B, Zito CR, Parisi F, Barr M, Kluger Y, Chen L, Kluger HM (2014) PD-L1 expression in clear cell renal cell carcinoma: an analysis of nephrectomy and sites of metastases. J Cancer 5:166–172

    Article  CAS  Google Scholar 

  22. Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348:56–61

    Article  CAS  Google Scholar 

  23. Jacob JM, Ferry EK, Gay LM, Elvin JA, Vergilio JA, Ramkissoon S, Severson E, Necchi A, Killian JK, Ali SM, Schrock AB, Liu NW, Chung J, Miller VA, Stephens PJ, Welsh A, Corona RJ, Ross JS, Bratslavsky G (2019) Comparative genomic profiling of refractory and metastatic penile and nonpenile cutaneous squamous cell carcinoma: implications for selection of systemic therapy. J Urol 201:541–548

    Article  Google Scholar 

  24. Chahoud J, McCormick BZ, Netto F, Rao P, Pickering CR, Pettaway CA (2019) Penile squamous cell carcinoma is genomically similar to other HPV-driven tumors. J Clin Oncol 37:505

    Article  Google Scholar 

  25. Hui G, Ghafouri SN, Shen J, Liu S, Drakaki A (2019) Treating penile Cancer in the immunotherapy and targeted therapy era. Case Rep Oncol Med 2019:8349793

    PubMed  PubMed Central  Google Scholar 

  26. Trafalis DT, Alifieris CE, Kalantzis A, Verigos KE, Vergadis C, Sauvage S (2018) Evidence for efficacy of treatment with the anti-PD-1 Mab Nivolumab in radiation and Multichemorefractory advanced penile squamous cell carcinoma. J Immunother 41:300–305

    Article  CAS  Google Scholar 

  27. Baweja A, Mar N (2021) Metastatic penile squamous cell carcinoma with dramatic response to combined checkpoint blockade with ipilimumab and nivolumab. J Oncol Pharm Pract 27(1):212–215

  28. Su X, Zhang J, Fu C, Xiao M, Wang C (2020) Recurrent metastatic penile Cancer patient with positive PD-L1 expression obtained significant benefit from immunotherapy: a case report and literature review. Onco Targets Ther 13:3319–3324

    Article  Google Scholar 

  29. Stoehr R, Wendler O, Giedl J, Gaisa NT, Richter G, Campean V, Burger M, Wullich B, Bertz S, Hartmann A (2019) No evidence of microsatellite instability and loss of mismatch-repair-protein expression in squamous cell carcinoma of the penis. Pathobiology 86:145–151

    Article  CAS  Google Scholar 

  30. Huang T, Cheng X, Chahoud J, Sarhan A, Tamboli P, Rao P, Guo M, Manyam G, Zhang L, Xiang Y, Han L, Shang X, Deng P, Luo Y, Lu X, Feng S, Ferrer MM, Alan Wang Y, DePinho RA, Pettaway CA, Lu X (2020) Effective combinatorial immunotherapy for penile squamous cell carcinoma. Nat Commun 11:2124

    Article  CAS  Google Scholar 

  31. Nadal RM, Mortazavi A, Stein M et al (2018) Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. J Clin Oncol 36:515

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank the patients and their families for participating in this clinical trial.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. provided the study drug and funded the study. Support was also provided by the National Institutes of Health/National Cancer Institute under award number P30CA016672.

Author information

Author notes

  1. Andrew W. Hahn and Jad Chahoud contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Andrew W. Hahn & Jennifer Wang

  2. Divsion of Genitourinary Oncology, Department of Hematology/Oncology, Moffitt Cancer Center, Tampa, FL, USA

    Jad Chahoud

  3. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Matthew T. Campbell & Shi-Ming Tu

  4. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX, 77030-4009, USA

    Daniel D. Karp, Bettzy Stephen & Aung Naing

  5. Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Curtis A. Pettaway

Authors
  1. Andrew W. Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jad Chahoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew T. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel D. Karp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bettzy Stephen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shi-Ming Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Curtis A. Pettaway
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Aung Naing
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Andrew W Hahn, Jad Chahoud, and Aung Naing wrote the initial draft of the manuscript. All authors meaningfully contributed to revisions and approved the final draft of the manuscript. Matthew T Campbell, Curtis A Pettaway, Jennifer Wang, Daniel D Karp, and Shu-Ming Tu participated in the care of the patients included in this case series. Aung Naing and Bettzy A. Stephen were responsible for the design and monitoring of the clinical trial.

Corresponding author

Correspondence to Aung Naing.

Ethics declarations

Ethics approval and consent to participate

The patients reported here participated in a clinical trial that was registered on ClinicalTrials.gov (NCT02721732). The trial protocol was approved by the US Food and Drug Administration and the institutional review board at MDACC. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All study participants provided written informed consent before enrollment.

Research involving human participants

The patients reported here participated in a clinical trial that was registered on ClinicalTrials.gov (NCT02721732). The trial protocol was approved by the US Food and Drug Administration and the institutional review board at MDACC. All procedures performed in studies of human subjects were in accordance with the ethical standards of the institutional review board and with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Informed consent

All study participants provided written informed consent before enrollment.

Consent for publication

Individual patient consent for publication is not necessary because this case series does not include identifying data.

Competing interests

Andrew W. Hahn, Jad Chahoud, Jennifer Wang, and Bettzy A. Stephen have no conflicts to disclose.

Matthew T. Campbell reports consulting/honorarium: Eisai, Exelixis, EMD Serono, Pfizer, AstraZeneca, Seattle Genetics, research grant funding: Exelixis, Pfizer, EMD Serono, ApricityHealth, Janssen.

Curtis A. Pettaway reports consulting to Wolters Kluwer for “UpToDate series.”

Aung Naing reports consulting to CytomX Therapeutics, Novartis, Kymab, Genome, OncoSec KEYNOTE-695, and STCube Pharmaceuticals. He reports travel and accommodation expenses from ARMO BioSciences. He reports research funding to his institution from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology. Spouse reports research funding to her institution from Immune Deficiency Foundation Jeffery Modell Foundation and chao physician-scientist, and Baxalta; and is on the advisory board of Takeda, CSL, Behring, Horizon, and Pharming.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hahn, A.W., Chahoud, J., Campbell, M.T. et al. Pembrolizumab for advanced penile cancer: a case series from a phase II basket trial. Invest New Drugs 39, 1405–1410 (2021). https://doi.org/10.1007/s10637-021-01100-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-021-01100-x

Keywords

Search

Navigation