EUROPEAN UROLOGY FOCUS XXX (2019 ) XXX-XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
EUROPEAN UROLOGY FOCUS KIDNEY TRANSPLANTATION
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Mini Review
Rare Genitourinary Malignancies: Current Status and Future Directions of Immunotherapy
Bradley A. McGregor, Guru P. Sonpavde *
Genitourinary Oncology Division, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Article info
Article history: Accepted March 12, 2019
Associate Editor: Peter Black
Keywords:
Adrenal cancer Penile carcinoma Variant histologies Rare genitourinary Immunotherapy Chemorefractory germ cell tumors
Abstract
Treatment options for rare genitourinary malignancies, including adrenocortical carci- noma, bladder/upper tract cancers of variant histology, penile squamous cell carcinoma, and chemotherapy-refractory germ cell tumors, are limited, often with a poor response to systemic therapy. Given preclinical data and efficacy across multiple malignancies, immunotherapy has been and continues to be explored in this challenging setting. In this report, we explore the data for immunotherapy in these tumors and highlight ongoing clinical trials. International collaborations and innovative trials will be critical to advancing treatment for these rare tumors.
Patient summary: In this report, we explore the data for immunotherapy in rare genitourinary malignancies and highlight ongoing clinical trials. International collabora- tions and innovative trials will be critical to advancing treatment for these rare tumors.
@ 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Dana Farber Cancer Institute, 450 Brookline Avenue, D1230F, Boston, MA 02215, USA. Tel .: +1 617 632 2429; Fax: +1 617 632 2165. E-mail address: gurup_sonpavde@dfci.harvard.edu (G.P. Sonpavde).
The role of immunotherapy continues to evolve in the treatment of genitourinary (GU) malignancies with multi- ple immune checkpoint inhibitors approved for the treat- ment of platinum-refractory urothelial carcinoma and renal cell carcinoma. However, its role in rare GU malig- nancies-adrenocortical carcinoma (ACC), bladder/upper tract cancers of variant histology (BCVH), penile squamous cell carcinoma (PSCC), and chemotherapy-refractory germ cell tumor (GCT)-continues to evolve. While patients with BCVH could receive immunotherapy under current approval for urothelial histology, in the USA, only a small
fraction of patients with the other malignancies could receive immunotherapy with pembrolizumab for solid tumors with microsatellite instability (MSI). The frequency of MSI is 4.3% in ACC, and in a recent clinical trial, two of 22 patients with treatment-refractory GCT were found to have MSI [1,2]. A common surrogate for MSI, tumor muta- tion burden >20 mutations/Mb, was reported in 6% of specimens of penile carcinoma. However, this is likely due to POLE mutations and not mismatch repair deficien- cies [3]. As such, clinical trials to address this unmet need are imperative.
1. Adrenocortical carcinoma
Therapeutic options for metastatic ACC are limited and include surgery if oligometastatic, with platinum-based com- bination chemotherapy, mitotane, and streptozocin as the mainstay of systemic therapy. Fay and colleagues [4] demon- strated that programmed death ligand 1 (PD-L1) protein expression exists in ACC on both the tumor cell membrane (10.7%) and the tumor infiltrating mononuclear cells (70.4%), providing a rationale for programmed death 1 (PD-1)/PD-L1 inhibitor immunotherapy. While small studies have explored nivolumab and pembrolizumab monotherapy, the largest data set for immunotherapy for ACC involves the PD-L1 inhibitor avelumab. In a phase 1b trial, 50 patients with metastatic ACC unselected for PD-L1 expression progressing through platinum therapy were treated with avelumab at 10 mg/kg intravenously every 2 wk while continuing mito- tane. The overall response rate (ORR) was 6% (95% confidence interval [CI] 1.3-16.5), with three partial responses though stable disease observed in 21 patients for a disease control rate of 48%. Stratifying by PD-L1 expression, the ORR was 16.7 versus 3.3 (p= 0.192) for tumors with PD-L1 >5% on tumor cells. However, median progression-free survival was only 2.6 mo (95% CI 1.4-4.). Similar to other trials, it was well tolerated with immune-related toxicities occurring in 12 out of 50 patients [5]. While these response rates are low in unselected patients, it is an intriguing option particularly for those with increased PD-L1 expression [6]. Building on these data, trials are further exploring single-agent PD-1/ PD-L1 inhibition alone or in combination with CTLA-4 inde- pendent of PD-L1 expression (Table 1).
2. Chemotherapy-refractory GCTs
In contrast to other malignancies discussed in this review, the rarity is not defined by pathologic examination but rather by
the clinical course. GCTs are a model of curable cancer with cure rates among the highest in solid tumors with advanced stage disease [7]. However, 10-40% of patients fail cisplatin- based first-line treatment as a function of risk group, and require salvage treatment with conventional or high dose chemotherapy (with stem cell transplant) that may achieve sustained complete remission in 40-50% of relapsed patients. Subsequent relapses are clinically challenging, as they confer a substantially poorer prognosis with minimally proven effec- tive therapy. Given preclinical data exploring PD-L1 expres- sion on tumor cells, it has been studied in this population despite the low tumor mutation burden. Pembrolizumab monotherapy displayed no activity in a single phase 2 trial of 12 patients [8]. Similarly, durvalumab monotherapy induced no responses in 11 patients; 73% demonstrated fea- tures of hyperprogression. When used in combination with the CTLA-4 inhibitor tremelimumab, however, one of 11 patients achieved a partial response and another exhibited brief stable disease. The response was independent of PD-L1 expression, tumor mutation burden, or MSI [2]. While PD-1/ PD-L1 blockade alone does not have a role in this setting, these data support ongoing studies exploring combinations with CTLA-4 inhibitors (Table 1).
3. Penile squamous cell carcinoma
Systemic therapeutic options for penile carcinoma after failure of platinum therapy are limited. In the salvage setting, median overall survival is dismal (5-6 mo), and prognostic factors such as anemia and visceral metastases are associated with poor survival [9]. Preclinical data for checkpoint inhibition are intriguing; multiple studies have shown that up to 60% of PSCCs are positive for PD-L1 expression on infiltrating immune cells, although only anecdotal evidence exists for the activity of checkpoint inhibition in PSCC [10]. Given the dismal prognosis with traditional therapy and the activity of immunotherapy in
| Trial | Phase | Agents | Number of patients | Prior therapy allowed | ACC | BCVH | PSCC | Chemotherapy- refractory GCT |
|---|---|---|---|---|---|---|---|---|
| NCT02834013 | 2 | Nivolumab Ipilimumab | 707 | Yes | × | x | × | × |
| NCT02721732 | 2 | Pembrolizumab | 275 | Required | × | × | × | × |
| NCT03333616 | 2 | Nivolumab plus ipilimumab | 60 | No | × | x | × | × |
| NCT02496208 | 1 | Nivolumab Ipilimumab Cabozantinib | 135 | Yes | × | × | × | |
| NCT03430895 | 2 | Durvalumab Tremelimumab | 27 | Yes | x | |||
| NCT02673333 | 2 | Pembrolizumab | 39 | Yes | × | |||
| NCT03081923 | 2 | Durvalumab Tremelimumab | 120 | Yes | × | |||
| NCT03391479 | 2 | Avelumab | 24 | Yes | × ☒ | |||
| NCT02837042 | 2 | Pembrolizumab | 35 | Yes | × | |||
| NCT02379520 | 1 | HPV-specific T cells ± lymphodepletion, nivolumab | 32 | Yes | x (HPV-positive cancer) | |||
| NCT03357757 | 2 | Avelumab Valproic acid | 39 | No | x (Viral-related cancer) |
ACC = adrenocortical carcinoma; BCVH = bladder/upper tract cancer with variant histology; GCT = germ cell tumor; HPV = human papillomavirus; NCT = national clinical trials; PSCC = penile squamous cell carcinoma.
other squamous malignancies, multiple clinical studies are ongoing to explore its role in the treatment of PSCC. Two small phase 2 trials are evaluating the role of PD-L1 and PD-1 inhibition with avelumab and pembrolizumab, respectively. However, most trials accruing patients with penile carcinoma are basket trials including rare solid or GU malignancies. These include combinations of PD-1 and CTLA-4 inhibitors, with one trial exploring the addition of cabozantinib. Given the associa- tion of human papillomavirus (HPV) with PSCC, ongoing trials encompassing HPV targeted therapies include PSCC. A phase 1 trial is exploring the role of HPV-specific T cells administered concurrently with nivolumab, while another trial is pursuing vaccines with synthetic plasmids targeting HPV-12 and HPV-18 E6 and E7 proteins (Table 1).
4. Bladder/upper tract cancers of variant histology
BCVH account for up to 10-25% of all urothelial carcinomas (UCs). The recent World Health Organization classification of urothelial cancers lists 13 different histologic variants of UC [11]. In an analysis of 120 patients who received single-agent PD-1/PD-L1 inhibition, 28 of whom had mixed histology, pure versus mixed urothelial histology was not associated with a response (hazard ratio 1.52 [95% CI 0.59-3.98, p = 0.39]) [12]. However, those with pure BCVH-for example, sarco- matoid carcinoma, squamous cell carcinoma, plasmacytoid variants, small cell carcinoma, and adenocarcinoma-have been excluded from prior pivotal trials evaluating immuno- therapy. As such, ongoing trials are exploring the role of immunotherapy in this setting again including dual immune checkpoint inhibition (Table 1).
5. Conclusions
The role of immunotherapy in GU malignancies continues to evolve. Given the rarity of these tumor types, innovative nonrandomized basket trials encompassing all these malig- nancies are being employed to make therapeutic advances. Large and international collaborations will be critical to advancing care and developing precision medicine. Trans- lational studies to understand tumor biology are critical to discover major drivers of these poorly understood diseases that may be targeted in combination with immunotherapy.
Author contributions: Guru P. Sonpavde had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: McGregor, Sonpavde.
Acquisition of data: McGregor, Sonpavde.
Analysis and interpretation of data: McGregor, Sonpavde.
Drafting of the manuscript: McGregor.
Critical revision of the manuscript for important intellectual content: McGregor, Sonpavde.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Sonpavde.
Other: None.
Financial disclosures: Guru P. Sonpavde certifies that all conflicts of interest, including specific financial interests and relationships and affilia- tions relevant to the subject matter or materials discussed in the manu- script (eg, employment/affiliation, grants or funding, consultancies, hono- raria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Bradley McGregor-consul- tant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, and Genentech; research support to institution from Bristol Myers Squibb, Calithera, Exelixis, EMD Serono and Seattle Genetics; and speaker fees from Clinical Care Options and OncLive. Guru Sonpavde- consultant for Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, Astra- Zeneca, Merck, Genentech, Argos, EMD Serono, and Agensys/Astellas; research support to institution from Bayer, Boehringer-Ingelheim, Merck, Pfizer, Sanofi, Janssen, AstraZeneca, and BMS; author for Uptodate; speaker fees from Clinical Care Options, Physicians Education Resource (PER), Research to Practice (RTP), and Onclive.
Funding/Support and role of the sponsor: None.
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