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11 Immunotherapy inGenitourinary Malignancies
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Fig. 11.1 Kidney cancers are commonly divided by stage depending on size and involvement of
local and/or distant structures, which inform treatment options
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immunotherapy after surgery in some circumstances (see “Adjuvant Immunotherapy
in ccRCC”). Patients with unresectable and/or stage IV disease usually derive the
most benet from systemic therapy depending on tumor grading, risk factors, and
comorbidities.
Risk stratication beyond grade and stage plays a crucial role in predicting prognosis, selecting appropriate treatment strategies, and guiding clinical decisionmaking. Two commonly used risk stratication systems for RCC are the Motzer
Score (previously known as the Memorial Sloan Kettering Cancer Center or
MKSCC score) (Motzer etal., 2002) and the International Metastatic Renal Cell
Carcinoma Database Consortium (IMDC) Heng Risk score (Heng etal., 2009).
The Motzer Score takes into account clinical and laboratory parameters to classify patients into three risk categories: favorable, intermediate, and poor. Patients
with poor Karnofsky performance status (KPS), delayed treatment, low hemoglobin
(anemia), elevated corrected calcium levels, and increased LDH are expected to
experiencea worse prognosis. The IMDC Heng Risk score similarly includes KPS,
delayed treatment, hemoglobin, and corrected calcium but also neutrophil/platelet
levels (and does not include LDH). Both scores have demonstrated utility in risk
stratication and predicting outcomes in advanced or metastatic RCC and can be
used to guide treatment for metastatic disease.
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J. Orme
Immunotherapy inRenal Cell Carcinoma
History ofImmune Modulation inRCC
Renal cell carcinoma was one of the rst solid tumors to be treated with systemic
therapies targeting the immune system. Interleukin 2 (IL-2) is a cytokine that stimulates the growth and activation of T cells and natural killer (NK) cells. Recombinant
IL-2 was used clinically rst in the 1980s for its immunostimulatory properties and
as a treatment for RCC. IL-2 was thought to induce a greater immune response
against cancer cells. In 1992, the US Food and Drug Administration (FDA) approved
high-dose IL-2 (aldesleukin) as a treatment for metastatic RCC. This therapy
showed durable responses in a small subset of patients, with some achieving complete and long-lasting remissions. However, high-dose IL-2 is associated with signicant toxicities and was limited to patients with good performance status and
normal organ function.
Due to the limited efcacy and signicant toxicities of high-dose IL-2, researchers explored combination therapies to improve outcomes. IL-2 was combined with
other immunotherapies, such as interferon-alpha, to enhance response rates.
However, toxicity remained a challenge. In the 2000s, targeted therapies revolutionized the treatment of RCC, and alternative treatments like tyrosine kinase inhibitors
(TKIs) targeting vascular endothelial growth factor (VEGF) receptors and mammalian target of rapamycin (mTOR) inhibitors showed improved response rates and
progression-free survival compared to IL-2. These targeted therapies became the
standard of care for most patients with advanced RCC.
Immunotherapy inMetastatic ccRCC
The advent of immune checkpoint inhibitors, specically Programmed death-1
(PD-1) and Programmed death ligand-1 (PD-L1) inhibitors, ushered in a new era of
immune modulation in RCC. Pembrolizumab and nivolumab, PD-1 inhibitors, were
approved for advanced RCC patients who progressed on prior targeted therapies.
These inhibitors effectively reinvigorated the immune response against cancer cells.
Most of the evidence for immunotherapy in RCC has been for ccRCC.Papillary and
chromophobe subtypes are commonly treated with TKI alone or with an mTOR
inhibitor, as nccRCC experience demonstrably poorer responses to immunotherapy
(McDermott etal., 2021).
Clinical trials have gone on to evaluate the combination of immune checkpoint
inhibitors with targeted therapies in ccRCC.The combination of immune checkpoint inhibitors (e.g., avelumab, nivolumab, pembrolizumab) with VEGF inhibitors
(e.g., axitinib, cabozantinib, lenvatinib, also called tyrosine kinase inhibitors or
TKIs) has repeatedly shown improved overall survival and progression-free survival
compared to sunitinib, a standard VEGF-targeted therapy in clinical trials
(Table11.1).
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Table 11.1 Current clinical trials of combination therapy in renal cell carcinoma
ORR
Regimen
Avelumab + axitinib 55% Any JAVELIN Renal- 101
Pembrolizumab + axitinib 60% Any KEYNOTE- 426
Nivolumab + cabozantinib 56% Any CheckMate- 9ER
Pembrolizumab + lenvatinib 71% Any CLEAR
Atezolizumab and
cabozantinib
Nivolumab/ipilimumab (no
TKI)
(%) Risk group Trial
(NCT02684006) Motzer etal. (2019)
(NCT02853331) Powles etal.
(2020a)
(NCT03141177) Choueiri etal.
(2021a)
(NCT02811861) Motzer etal. (2021)
58% Not yet
approved
42% Intermediate/
poor
COSMIC- 021 (NCT03170960) Pal
etal. (2021)
CheckMate- 214
(NCT02231749)
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In clinical practice, four combinations (in alphabetical order: avelumab/axitinib,
nivolumab/cabozantinib, pembrolizumab/axitinib, pembrolizumab/lenvatinib) are
commonly used for any risk metastatic ccRCC.None of these regimens have been
compared head-to-head and are thought to be similarly efcacious.
JAVELIN Renal-101 (NCT02684006) was a phase III clinical trial that evaluated
the efcacy and safety of avelumab in combination with axitinib as a rst-line treatment for advanced RCC (Motzer etal., 2019). The trial compared avelumab/axitinib
combination therapy to sunitinib and demonstrated improved progression-free survival (median 13.8months, HR 0.69 [95% CI 0.56–0.84]) and response rate (55.2%)
in patients receiving avelumab plus axitinib compared to sunitinib, leading to the
approval of this regimen for certain patients with advanced RCC.
Similarly, KEYNOTE-426 (NCT02853331) compared pembrolizumab/axitinib
in rst-line treatment to sunitinib (Powles etal., 2020a). The trial demonstrated
signicantly improved overall survival (median not reached, HR 0.53 [95% CI
0.38–0.74]), progression-free survival (median 15.1 months, HR 0.69 [95% CI
0.57–0.84]), and objective response rate (59.3%) in patients receiving pembrolizumab plus axitinib compared to sunitinib, leading to the approval of this regimen
for certain patients with advanced ccRCC.
Also similarly, CheckMate-9ER (NCT03141177) compared nivolumab/cabozantinib to sunitinib in ccRCC (Choueiri etal., 2021a). The trial demonstrated superior overall survival (median not reached, HR 0.60 [reported 98.89% CI 0.40–0.89]),
progression-free survival (median 16.6months, HR 0.51 [95% CI 0.41–0.6]), and
objective response rate (55.7%) in patients receiving nivolumab plus cabozantinib
compared to sunitinib, leading to the approval of this regimen for certain patients
with advanced ccRCC.
Lastly, CLEAR (NCT02811861) compared pembrolizumab/lenvatinib to both
lenvatinib/everolimus and sunitinib in ccRCC (Motzer etal., 2021). The trial demonstrated signicantly improved overall survival (median not reached, HR 0.66
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[95% CI 0.48–0.88]), progression-free survival (median 23.9 months, HR 0.47
[95% CI 0.38–0.58]), and objective response rate (71%) in patients receiving lenvatinib plus pembrolizumab compared to sunitinib, leading to the approval of this
regimen for certain patients with advanced ccRCC.
The above clinical trials have not been compared head-to-head, and we generally
advocate selecting treatment based on the clinician’s experience, drug availability/
affordability, and convenience of administration. Side effects from TKIs are generally similar and can include diarrhea, blood pressure elevation, hand/foot syndrome
(a red rash on the palms and soles), voice changes, and increased risk of bleeding.
The doses of each of these TKIs can be adjusted to minimize side effects.
An additional trial, CheckMate-214, has also shown ICI efcacy without a TKI
in intermediate- and poor-risk ccRCC (NCT02231749) (Motzer etal., 2018). In this
phase III clinical trial, nivolumab was combined with ipilimumab, a cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as a rst-line treatment for
advanced RCC.Notably, patients with good risk (by Heng/IMDC) disease were
excluded from this trial. The trial demonstrated improved overall survival and
objective response rates in patients receiving nivolumab plus ipilimumab compared
to sunitinib, leading to the approval of this combination. In clinical practice, some
clinicians advocate the use of this combination in young patients with good risk
disease not requiring a dramatic response.
A particularly important question in the eld of ccRCC is whether immunotherapy should be used in the second-line after the failure of a rst-line immunotherapy. For instance, after failure of combination pembrolizumab/axitinib, should
a patient start atezolizumab/cabozantinib or simply use single-agent cabozantinib?
This question was at least partially addressed in the phase III CONTACT-03 trial
(NCT04338269) in which an interim overall survival analysis showed no signicant
benet of combined atezolizumab/cabozantinib versus cabozantinib alone in the
second-line after prior immunotherapy (ORR 40.5% versus 40.9%, PFS 10.6 versus
10.8months, p=0.784 and OS 25.7months versus NE, p=0.690) (Albiges etal.,
2023). Many clinicians advise against reexposure to immunotherapy given these
data, although other ICI combinations have not been tested in this setting.
Adjuvant Immunotherapy inccRCC
The most common treatment for stage I through stage III kidney cancer is nephrectomy—surgical resection of all or part of the involved kidney. Surgical resection has
been extremely important. Most kidney cancers do not respond well to chemotherapy. For patients with certain characteristics, however, there is a very high risk of
disease recurrence. Thus, adjuvant (i.e., postsurgical) treatments to prevent recurrence may be useful in some circumstances. Pembrolizumab was tested in the adjuvant setting for patients with ccRCC in KEYNOTE 564 (NCT03142334) (Choueiri
etal., 2021b). Patients with high-risk features including stage II disease with highgrade (i.e., grade 4 of 4) or sarcomatoid features, any stage III disease, or M1 disease rendered NED (no evidence of disease) by surgery and were included in the
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study. They were randomized to receive up to 1year (or 17cycles) pembrolizumab
or placebo. Patients in the pembrolizumab group experienced an improved two-year
disease-free survival (77.3%) than those in the placebo group (68.1%) in the study
(DFS HR 0.68, [95% CI 0.53–0.87], p=0.002). In addition, there was a small overall survival benet (HR 0.54, 95% CI 0.3–0.96).
While KEYNOTE 564 was a positive study reaching its prespecied endpoint,
the disease-free survival at 3 years was nearly identical. Nineteen percent of patients
receiving pembrolizumab experienced grade 3 AEs. In clinical practice, each patient
is different and each has different preferences. Commonly, we see young patients
who wish to be as aggressive as possible take the added risk of immunotherapy
while older patients with competing comorbidities often defer systemic therapy in
hopes of never requiring it.
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Bladder/Urothelial Cancers
Introduction
Bladder cancer is the most common urinary system cancer with over 80,000 cases
and nearly 17,000 deaths each year (Siegel etal., 2023). Most bladder cancers are
urothelial (also known as transitional cell) carcinomas. Most of the available data on
immunotherapy in bladder cancers is based on urothelial cancers that arise directly
from the bladder. However, some bladder cancers comprise other histologies (e.g.,
squamous cell carcinoma, small cell carcinoma, adenocarcinoma, and mixed), and
some urothelial cancers also arise from outside the bladder, including from the ureters and renal pelvis (together termed uppertract urothelial cancers or UTUC).
Associated risk factors for bladder cancer include tobacco use, occupational
exposures to aniline dyes, and inammatory conditions of the bladder such as schistosomiasis. Any chronic bladder inammation can lead to bladder cancer, including
chronic urinary tract infections, consumption of aristolochic acid, and exposure to
arylamines, benzene, plastics, and petrochemicals. Some medical treatments,
including cyclophosphamide, thorium dioxide, and radiation therapy, can also elevate the risk of developing bladder and urothelial cancers. Similarly, genetic syndromes like Balkan nephropathy have been associated with increased bladder
cancer risk.
Staging
Bladder cancer staging—that is, determination of the extent of the cancer—is critical for selecting appropriate treatment (Flaig etal., 2022). Staging is most commonly performed with the TNM system comprising size and extent of the primary
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tumor (T), involvement of lymph nodes (N), and distant metastatic spread (M). A
numerical stage from I to IV is assigned based on TNM results. Two critical thresholds are reached when urothelial carcinoma becomes muscle-invasive (T2a), termed
muscle-invasive bladder cancer (MIBC) as distinct from non-muscle-invasive bladder cancer (NMIBC), and when urothelial carcinoma either invades adjacent organs
like the prostate, vagina, uterus, or bowel (T4b) or becomes distantly metastatic
(M1), which is termed unresectable (Abu-Rustum et al., 2023). Notably, not all
lymph node or metastatic involvement is truly unresectable and will depend on surgical consultation. For treatment decisions, it is useful to think of bladder cancers as
either NMIBC, MIBC, or unresectable (Fig.11.2). However, there are nuances that
a qualied medical oncologist will consider for any given treatment.
Broadly speaking, NMIBC and MIBC may be curable with a combination of
systemic and localized (i.e., surgical or radiotherapeutic) modalities. However,
patients with unresectable disease are rarely rendered “no evidence of disease”
(NED) and thus have much poorer outcomes. For this reason, most clinicians
aggressively treat NMIBC and MIBC with a goal of denitive surgical resection. In
most cases, immunotherapy is used alongside other treatment types—commonly
platinum-containing chemotherapy regimens—in order to provide the greatest
opportunity to achieve NED. This is particularly important in bladder cancer,
because unresectable disease is associated with poor overall survival.
Urothelial carcinoma can exhibit variant histologies, which are characterized by
distinct morphological patterns and behavior. These variants include squamous cell
Fig. 11.2 Bladder and urothelial cancers are divided into non-muscle invasive, muscle-invasive,
and unresectable for treatment selection
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carcinoma, adenocarcinoma, small cell carcinoma, micropapillary carcinoma, and
plasmacytoid carcinoma. The location along the urinary tract (e.g., in the bladder
itself versus UTUC arising from the upper tracts or from the urethra) is also important to consider, as biologically different tumors may arise from a different embryonic source in each location. These variants have unique clinical characteristics and
treatment approaches compared to typical urothelial carcinoma arising from the
bladder.
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Immunotherapy inBladder Cancer
Immunotherapy inNon-muscle-Invasive Bladder Cancer (NMIBC)
Bacillus Calmette-Guérin (BCG) is a weakened strain of mycobacterium that is
commonly instilled in the bladder for patients with localized NMIBC.This intravesicular BCG treatment incites an immune response in the bladder environment that
helps clear remaining tumor cells. Most commonly, BCG is given in weekly instillations in an induction phase of approximately 6 weeks followed by 3-week maintenance courses thereafter. Risks include local reactions like bladder irritability,
dysuria, and hematuria as well as systemic u-like symptoms, fever, and malaise. In
very rare instances, systemic infection with BCG has been observed. BCG is not
recommended in cases of traumatic catheterization, bacteriuria, persistent gross
hematuria, persistent severe local symptoms, or systemic symptoms. Alternatively,
some localized bladder cancers are treated with instilled chemotherapy rather
than BCG.
Approximately 30% of localized NMIBC do not respond to BCG immunotherapy, while others experience disease recurrence or progression despite initial
response. In cases where cancers are unresponsive or recur without muscle invasion,
immunotherapy with immune checkpoint inhibitor (ICI) pembrolizumab has been
studied in the KEYNOTE-057 trial (NCT02625961) (Balar etal., 2021). In this
study, patients with carcinoma in situ with Eastern Cooperative Oncology Group
(ECOG) performance status 0–2 received 200 mg intravenous pembrolizumab
every 3 weeks for up to 2 years or until disease persistence, recurrence, or progression or until discontinuation for any reason. The primary endpoint was complete
response rate (dened as no persistence or progression of disease) assessed by cystoscopy after 3 months. Of 96 patients with BCG-unresponsive bladder cancer who
received pembrolizumab on the study, 39 (41%) had a complete response at 3
months. Of those, approximately 50% of patients enjoyed disease-free survival for
at least 1 year and 98% were alive after 1 year. Thirteen percent of patients experienced grade 3 or 4 treatment-related adverse events. The median duration of treatment on study was 4.2months. Notably, there are other non-immunotherapy options
available in this setting that should also be considered.
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Immunotherapy inLocalized Muscle-Invasive Bladder Cancer (MIBC)
Muscle invasion signicantly elevates the risk of death from bladder cancer and,
consequently, increases the importance of curative-intent therapy where possible.
The most common treatment approach for MIBC is neoadjuvant (i.e., before surgery) chemotherapy including cisplatin where possible with the goals of (A) simplifying and improving surgical efcacy as measured by improved disease-free
survival, (B) determining the risk of recurrence based on post-chemotherapy pathology characteristics, and (C) ensuring that the disease is truly resectable before
undergoing an intensive surgery.
It is known that residual disease—particularly postchemotherapy T2-T4 or
node- positive (N1)—in the surgical specimen after chemotherapy portends a
higher risk of recurrence. For patients with these characteristics, the CheckMate-274
study sought to determine whether adjuvant (i.e., post-surgery) nivolumab could
improve a 6-month disease-free survival (DFS) (NCT02632409) (Bajorin etal.,
2021). In brief, this study enrolled 709 patients who either (A) had received neo-
adjuvant platinum- containing chemotherapy and had residual T2–T4 or nodepositive (N1) disease or (B) had not received neoadjuvant chemotherapy and had
T3, T4, or N1 disease. Patients were randomized to receive nivolumab or placebo.
The median disease-free survival in patients treated with nivolumab was
20.8 months (95% CI 16.5–27.6 months) versus 10.8 months (95% CI
8.3–13.9 months) with placebo (p < 0.001). Interestingly, this was not signicantly different for patients with PD-L1-positive (dened as PD-L1 expression of
1% or more) versus those with PD-L1-negative disease. Overall survival results
are not yet mature for this study.
It is uncertain how broadly these observations apply to other circumstances. For
instance, relatively few patients with upper tract urothelial cancers (UTUC, that is,
urothelial cancers above the bladder in the ureters or close to the kidneys) were
included in CheckMate-274 (21% of patients). It is thought that these tumors may
be less responsive to immunotherapy than regular bladder cancers, and clinical trials
addressing appropriate immunotherapies in UTUC are ongoing. Many patients with
UTUC have Lynch syndrome with alterations in DNA mismatch repair genes such
as MLH1 and MSH2, which may increase the likelihood of response. Genetic testing in advanced bladder cancer is advised to help direct targeted therapies, including
immunotherapy.
Notably, some immunotherapies have also been ineffective in this adjuvant
setting. In the IMvigor010 trial, which enrolled patients very similar to the
CheckMate-274 trial, patients with bladder cancers were randomized to receive
atezolizumab versus observation (Bellmunt etal., 2021). Median disease-free
survival was not signicantly improved (19.4 versus 16.6 months, HR 0.89
[95% CI 0.74–1.08]). Atezolizumab is not approved for adjuvant use in bladder cancer.
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Immunotherapy inUnresectable Bladder Cancer
Bladder cancer that is unresectable—whether due to wide metastatic spread or contraindications to localized therapies—presents a signicant and dangerous disease.
Until recently, cisplatin-based chemotherapy remains the most commonly used
rst-line therapy (Flaig etal., 2022). However, immunotherapy-based approaches
are gaining traction in three broad groups: (A) as co-therapies with targetedchemotherapy, (B) as maintenance therapies after response to chemotherapy, and (C) as
later-line monotherapies for patients with contraindications to chemotherapy (e.g.,
in patients with kidney disease that makes cisplatin and/or carboplatin chemotherapy untenable).
The combination of pembrolizumab with enfortumab vedotin in EV103/
KEYNOTE-869 (NCT03288545) has recently led to approval from the FDA as a
rst-line therapy in unresectable bladder cancer (Hoimes etal., 2023). Enfortumab
vedotin is a chemotherapy-conjugated anti-Nectin-4 therapeutic antibody (also
termed anantibody-drug conjugate or ADC). In this early-phase trial, 45 patients
who were not eligible for or refused platinum-based chemotherapy received enfortumab vedotin (1.25mg/kg) on days 1 and 8 and pembrolizumab (200mg) intravenously once every 3 weeks. The conrmed objective response rate after a median of
nine cycles was 73.3%, with a complete response rate of 15.6%. The median duration of response and overall survival were 25.6months and 26.1months, respectively. As a result, many oncologists use combination enfortumab vedotin and
pembrolizumab as a rst- or second-line treatment in cisplatin-ineligible or refractory settings, respectively. However, in clinical practice, the rates of peripheral neuropathy, rash, and fatigue can limit the added value of enfortumab vedotin.
Similar emerging data may suggest a further role for combining chemotherapy
and immunotherapy in unresectable bladder cancer. CheckMate-901 (NCT03036098)
tested multiple immunotherapy combinations to standard of care cisplatin/gemcitabine. In previously reported results, nivolumab/ipilimumab failed to improve
overall or progression-free survival. However, although the ofcial results have not
been reported formally, it has been conrmed that nivolumab/cisplatin/gemcitabine
met its combined overall and progression-free survival endpoint and is superior to
cisplatin/gemcitabine alone. Additional data are pending and the combination has
not yet been evaluated for approval by the FDA.
Maintenance therapies are treatments with favorable toxicity that are used to
maintain therapeutic gains after harsher treatments such as cisplatin-based chemotherapy. Avelumab is an approved immunotherapy for patients with partial response
(PR), complete response (CR), or stable disease (SD) after platinum-based chemotherapy as studied in the JAVELIN BLADDER 100 trial (NCT02603432) (Powles
etal., 2020b). In this clinical trial, 700 patients were randomized to receive avelumab maintenance therapy versus observation after 4–6cycles of gemcitabine/cisplatin or gemcitabine/carboplatin. Only patients who experienced SD or better were
included in the study. A striking improvement in a 1-year overall survival (71.3% in
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the avelumab group and 58.4% in the control group) was observed. Median overall
survival was 21.4 months versus 14.3 months (HR 0.69 [95% CI 0.56–0.86],
p = 0.001). While these gains are meaningful and we recommend maintenance
immunotherapy in patients who t these criteria, most patients in both arms experienced eventual disease progression.
Many patients cannot receive platinum-containing chemotherapies, and these
chemotherapies eventually fail for most patients with advanced bladder cancers. In
the absence or failure of prior chemotherapy regimens, ICI therapies offer important
additional approaches. Pembrolizumab, studied in the KEYNOTE-045 trial
(NCT02256436), showed promising results in patients with advanced urothelial
carcinoma who experienced progression after cisplatin-based chemotherapy
(Bellmunt etal., 2017). It was further studied in the KEYNOTE-052in patients who
were not eligible to receive cisplatin-based chemotherapy (Vuky etal., 2020). Both
studies demonstrated a favorable objective response rate, indicating that pembrolizumab has the potential to induce tumor shrinkage and improve disease control in
these patient populations. Atezolizumab, evaluated in the IMvigor 210 trial, demonstrated efcacy in patients with metastatic bladder cancer who expressed high levels
of PD-L1 (greater than 5%) who were not eligible for cisplatin (NCT02108652)
(Balar etal., 2017). Nivolumab, studied in the CheckMate-275 trial (NCT02387996)
(Sharma etal., 2017), showed modest but clinically meaningful responses in patients
with metastatic bladder cancer who had progressed after platinum-based chemotherapy. These ndings offer ICI as an important alternative treatment option for
patients whose tumors do not respond, who cannot tolerate, or who are ineligible for
cisplatin-based chemotherapy. It is yet unknown whether rechallenge with a second
ICI after prior failure of ICI has utility in bladder cancer.
J. Orme
Prostate, Testicular, andPenile Cancers
Immunotherapy inProstate Cancer
Prostate cancer is the most common cancer in men, affecting one in eight, and poses
a signicant health concern worldwide. Over the years, signicant advancements
have been made in the understanding, diagnosis, and treatment of this disease, leading to improved outcomes and enhanced quality of life for patients. Surgical or
radiotherapeutic interventions are most important in localized prostate cancer,
whereas treatments targeting the androgen receptor (AR) are essential components
of treatment in metastatic disease. Prostate cancers are often subdivided into
castration- sensitive (meaning they respond to androgen deprivation therapy or ADT,
which has been a mainstay of systemic treatment for over 80years) and castrationresistant (meaning they no longer respond to ADT) and are designated CSPC and
CRPC, respectively.
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