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| Penile cancer: Updates in systemic therapy |
Vidhu B. Joshia,Juskaran Chadhab,Jad Chahoudb,*( )
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aDepartment of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
bDepartment of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA |
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Abstract Penile cancer is a rare genitourinary malignancy with a greater incidence in parts of Asia, South America, and Africa. Outcomes are very poor in patients with advanced disease and in those who do not respond to first-line multimodal therapy. Among systemic therapy options, platinum-based chemotherapy is used in the first-line; however, approximately half of patients do not benefit. Response rates to systemic therapy as subsequent line treatment are historically dismal. There is also a paucity of prognostic and predictive tools within the context of penile cancer. As such, there remains an urgent need to expand systemic treatment options for patients with advanced penile cancer. The purpose of this review is to summarize the existing evidence for standard-of-care lines of systemic treatment, examine the potential of novel lines of systemic therapy, and provide an update as to the status of these new therapies within the context of penile cancer.
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Received: 19 January 2022
Available online: 20 October 2022
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Corresponding Authors:
Jad Chahoud
E-mail: jad.chahoud@moffitt.org
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| Study | Study type; total number of patients | Chemotherapy agent(s); number of patients | Responses and safety | Survival (median follow-up time, months) | | Bermejo et al., 2007 [125] | Retrospective; n=10 | ?
TIP; n=5
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BMP; n=3
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PC; n=2 | ?
4 CR (TIP [n=4]), 1 PR (PC [n=1]), and 5 SD (BMP [n=3], TIP [n=1], PC [n=1]) observed
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Grade 3 toxicities observed in 3/10 patients | 40% 5-year OS (62 months) | | Leijte et al., 2007 [16] | Retrospective; n=20 | ?
Bleomycin; n=3
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VBM; n=5
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5-FU + CIS; n=1
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PBM; n=10
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CIS + CPT-11; n=1 | ?
2 CR and 10 PR observed
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3 treatment-related deaths (Bleo-CIS-MTX [n=2], Bleo-VIN-MTX [n=1]) | 32% 5-year OS (23 months) | | Theodore et al., 2008 [126] | Prospective, phase II; n=7 | ?
CIS + CPT-11; n=7 | ?
1 CR, 1 PR, and 4 SD observed
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Safety data were unavailable for patients treated with NAC | NA | | Pizzocaro et al., 2009 [127] | Prospective; n=6 | ?
TPF; n=6 | ?
ORR of 83.3%
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Grade 3 toxicities observed in 1/6 patients | NA | | Pagliaro et al., 2010 [15] | Prospective, phase II; n=30 | ?
TIP; n=30 | ?
3 CR, 12 PR, and 9 SD observed
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Grade 3 infections were most common observed toxicities | Median OS of 17.1 months (34 months) | | Nicholson et al., 2013 [26] | Prospective, phase II; n=29 | ?
TPF; n=29 | ?
2 CR and 8 PR observed
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Grade 3 or 4 toxicities observed in 19/28 patients | Median OS of 7.1 months (14.5 months) | | Chiang et al., 2014 [128] | Retrospective; n=12 | ?
MTX + CIS + 5-FU + mitomycin C + bleomycin; n=12 | ?
4 CR, 6 PR, and 1 SD observed
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Grade 3 toxicities observed in 3/12 patients | NA | | Zou et al., 2014 [129] | Retrospective; n=24 | ?
Bleomycin + methopterin + CIS; n=24 | ?
ORR of 62.5%
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Safety data not available | 45.8% 5-year OS (NA) | | Djajadiningrat et al., 2015 [27] | Prospective; n=26 | ?
TPF; n=26 | ?
2 CR, 11 PR, and 15 SD observed
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All patients experienced toxicities and 6/26 patients discontinued TPF due to toxicity | Median OS of 10.1 months (30 months) | | Nicolai et al., 2016 [19] | Retrospective; n=28 | ?
TPF; n=28 | ?
1 CR and 11 PR observed
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1 treatment-related death
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Neutropenia was the most common Grade 3 or greater toxicity | 7.1% 2-year DFS (NA) |
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Summary of studies on NAC in penile cancer.
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| Study | Study type; total number of patients | Chemotherapy agent(s); number of patients | Safety | Key finding | | Pizzocaro and Piva, 1988 [130] | Retrospective; n=12 | ?
VBM; n=12 | ?
Study reported mild toxicity (CTCAE grading not available) | ?
11/12 patients demonstrated no evidence of disease at a median follow-up of 42 months | | Hakenberg et al., 2006 [131] | Retrospective; n=8 | ?
PBM; n=8 | ?
Treatment-related death in one patient | ?
3/8 patients demonstrated no evidence of disease at a median follow-up of 54 months | | Noronha et al., 2012 [132] | Retrospective; n=19 | ?
Paclitaxel + cisplatin; n=15
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Paclitaxel + carboplatin; n=4 | ?
Treatment-related death in one patient
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Vomiting was the most common Grade 3 toxicity | ?
Significantly improved median DFS in patients who completed chemotherapy versus those that did not (23.1 months vs. 2.16 months, respectively; p=0.0001) | | Sharma et al., 2015 [18] | Retrospective; n=36 | ?
TPF; n=18
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Cisplatin + 5-FU; n=8
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VBM; n=8
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PBM; n=1
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TIP; n=1 | ?
NA | ?
Significant improvement in OS among responders versus non-responders (21.7 months vs. 10.1 months, respectively; p=0.048) | | Nicolai et al., 2016 [19] | Retrospective; n=19 | ?
TPF; n=19 | ?
Neutropenia was the most common Grade 3 or greater toxicity | ?
2-year DFS of 36.8% | | Necchi et al., 2019 [20] | Retrospective; n=171 | ?
Unspecific regimen; n=83
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VBM; n=34
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Cisplatin + 5-FU; n=27
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TPF; n=26
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TPG; n=1 | ?
NA | ?
Significant improvement in OS among patients with positive pelvic nodes |
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Summary of studies on adjuvant chemotherapy in penile cancer.
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| ClinicalTrials.gov identifier; study phase | Planned accrual; status | Setting | ICI agent(s) | Combination therapy (if applicable) | Primary endpoint | Basket trial (yes or no) | | NCT03391479; phase II | n=24; recruiting | Unresectable or metastatic disease in chemo-refractory or chemo-ineligible patients | Avelumab (anti-PD-L1) | None | ORR | No | | NCT03686332; phase II | n=32; recruiting | Advanced, unresectable disease | Atezolizumab (anti-PD-L1) | Radiotherapy | PFS | No | | NCT03774901; phase II | n=32; recruiting | Maintenance therapy following platinum-based chemotherapy | Avelumab (anti-PD-L1) | None | PFS | No | | NCT04224740; phase II | n=33; recruiting | First-line therapy for unresectable disease | Pembrolizumab (anti-PD-1) | Cisplatin or carboplatin plus 5-FU | ORR | No | | NCT04231981; phase II | n=18; not recruiting | Advanced unresectable or metastatic disease | INCMGA00012 (anti-PD-1) | None | ORR | No | | NCT02496208; phase I | n=152; not recruiting | Locally advanced or metastatic disease | Nivolumab (anti-PD-1) +/? ipilimumab (anti-CTLA-4) | Cabozantinib-s-malate | Phase II dose and AE incidence | Yes | | NCT02721732; phase II | n=225; not recruiting | Unresectable or metastatic disease | Pembrolizumab (anti-PD-1) | None | Non-progression rate | Yes | | NCT02834013; phase II | n=818; closed to accrual | Relapsed disease | Nivolumab (anti-PD-1) +/- ipilimumab (anti-CTLA-4) | None | ORR | Yes | | NCT03333616; phase II | n=100; recruiting | Unresectable advanced or metastatic disease | Nivolumab (anti-PD-1) + ipilimumab (anti-CTLA-4) | None | ORR | Yes | | NCT03427411; phase II | n=57; not recruiting | Locally advanced or metastatic HPV-associated disease | M7824 (also called bintrafusp alfa); M7824 is a bi-functional fusion protein targeting TGF-β trap and anti-PD-L1 | None | ORR | Yes | | NCT03517488; phase I | n=154; recruiting | Advanced disease | XmAb20717 (bi-specific anti-PD-1 and anti-CTLA-4 | None | Safety | Yes | | NCT03866382; phase II | n=224; recruiting | Metastatic disease | Nivolumab (anti-PD-1)+ipilimumab (anti-CTLA-4) | Cabozantinib | ORR | Yes | | NCT04357873; phase II | n=111; recruiting | Relapsed or metastatic disease | Pembrolizumab (anti-PD-1) | Vorinostat | ORR | Yes | | NCT04718584; phase II | n=127; recruiting | Advanced disease | LDP (anti-PD-L1 injection) | None | pCR and ORR | Yes |
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Ongoing clinical trials of ICI therapy in penile cancer.
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| Study | Study type; total number of patients | Targeted therapy agent(s) + other therapies; number of patients | Safety | Key finding(s) | | Carthon et al., 2014 [111] | Retrospective; n=24 | ?
Cetuximab (anti-EGFR) + cisplatin; n=12
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Cetuximab + carboplatin; n=1
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Cetuximab + TIP; n=3
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Cetuximab alone; n=5
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Erlotinib (anti-EGFR); n=2
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Gefitinib (anti-EGFR); n=1 | ?
Grade 1 or 2 rash was the most common AE (17/24 patients) | ?
Partial radiographic response observed only in patients who received cetuximab alone (1/5 patients), cetuximab + cisplatin (3/12 patients), or cetuximab + TIP (2/3 patients) | | Necchi et al., 2016 [112] | Prospective; n=11 | ?
Panitumumab (anti-EGFR); n=11 | ?
Grade 2 skin toxicity was the most common AE (5/11 patients) and one patient discontinued treatment due to Grade 3 skin toxicity | ?
Improvement in OS among responders versus non-responders (9.5 months vs. 7.6 months, respectively) | | Necchi et al., 2018 [113] | Prospective, phase II; n=28 | ?
Dacomitinib (pan-HER-TKI); n=28 | ?
Grade 3 skin toxicity occurred in 3/28 patients
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No serious AEs or discontinuation of treatment | ?
ORR of 32.1%
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Median OS of 20 months among chemo-na?ve patients |
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Summary of studies on targeted therapies in penile cancer.
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| ClinicalTrials.gov identifier; study phase | Planned accrual; status | Setting | HPV-targeting agent(s) | Combination therapy (if applicable) | Primary endpoint | | NCT02379520; phase I | n=32; not recruiting | Recurrent HPV+ disease or HPV+ disease ineligible for SOC treatment | HPV-16/18 E6/E7-specific T lymphocytes | Cytoxan, fludarabine, and nivolumab (anti-PD-1) | Incidence of DLT | | NCT02858310; phase I/II | n=180; recruiting | Recurrent or metastatic HPV+ disease | HPV-16 E7-targeting TCR T-cells (E7 TCR) | Aldesleukin, fludarabine, and cyclophosphamide | Phase II dosage | | NCT03418480; phase I/II | n=44; not recruiting | Recurrent HPV+ disease or disease-free patients | HPV anti-CD40 RNA vaccine | None | Incidence of DLT | | NCT03439085; phase II | n=77; recruiting | Recurrent or metastatic HPV+ disease | INO-3112 (HPV vaccine) | Durvalumab (anti-PD-L1) | ORR | | NCT04180215; phase I/II | n=200; recruiting | Relapsed or treatment-refractory HPV+ disease | HB-201 ± HB-202 (both express antigenic HPV-16 E6/E7 fusion protein) | None | Incidence of DLT and phase II dose | | NCT04287868; phase I/II | n=56; recruiting | Recurrent or metastatic HPV+ disease | PDS0101 (HPV vaccine) | M7824 (bintrafusp alfa and bi-functional fusion protein; TGF-β trap and anti-PD-L1) and NHS-IL12 | ORR | | NCT04432597; phase I/II | n=76; recruiting | Recurrent or metastatic HPV+ disease | PRGN-2009 (HPV vaccine) | M7824 (also called bintrafusp alfa); M7824 is a bi-functional fusion protein targeting TGF-β trap and anti-PD-L1 | Phase II dose and safety |
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Ongoing basket clinical trials of HPV-directed therapies in penile cancer.
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