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Checkpoint Inhibition in Bladder Cancer: Comparison
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Please note this is a comparison between Version 3 by Vicky Zhou and Version 2 by Vicky Zhou.

In contrast with other strategies, immunotherapy is a treatment aimed at empowering the patient’s immune system in order to increase immunity and the response against cancer. A new class of drugs, immune checkpoint inhibitors, has shown potential in increasing treatment chances for patients with bladder cancers, improving their survival. However, predicting the response to immune checkpoint inhibition is important, since only a group of patients develop a good response. Biomarkers to predict the response to checkpoint inhibition must identify tumors’ and patients’ specific profiles. 

  • checkpoint inhibition
  • bladder cancer
  • immunotherapy biomarkers
  • cancer immunoprofiling
  • BCG failure

1. Background: Bladder Cancer and the Promises of Immunotherapy

Bladder cancer (BC) is the seventh most commonly diagnosed cancer in males worldwide, and the eleventh when considering both genders [1]. The worldwide age-standardized incidence rate (per 100,000 person/years) is 9.0 for men and 2.2 for women. In 2018, nearly 550,000 new cases were diagnosed worldwide, with 200,000 deaths [1].
The most common histological type of BC is urothelial carcinoma. Moreover, about 75% of patients with BC present with a non-muscle-invasive disease (non-muscle-invasive bladder cancer—NMIBC) confined to the mucosa (stage Ta; carcinoma in situ—CIS) or submucosa (stage T1). NMIBC is classified in different risk groups according to different prognostic factors [2], and it has different recurrence rates that require several endoscopic transurethral treatments. On the other hand, muscle-invasive and metastatic BC need multimodal strategies, including surgery and chemotherapy, in neoadjuvant, adjuvant, or palliative settings.
Ten to fifteen percent of patients with muscle-invasive BC are already metastatic at diagnosis [3]. Moreover, approximately 50% of patients with muscle-invasive non-metastatic BC will relapse after radical cystectomy, mostly with distant metastases (30% local recurrence, 70% distant metastases).
Several strategies have been tested to improve the disease-free survival (DFS) and overall survival (OS) of these patients, testing the role of chemotherapy and radiotherapy in neoadjuvant and adjuvant settings. At present, locally advanced disease is preferentially treated with neoadjuvant cisplatin-based chemotherapy, which is able to achieve an 8% 5-year absolute improvement in OS [4]. Adjuvant treatment, on the other hand, remains a valid option for high-risk diseases [5]. Despite several efforts to develop a more effective pre- and/or postoperative treatment, the OS for metastatic BC patients who received platinum-based chemotherapy is estimated to be 12–14 months, and it is reduced to <7 months in patients with a relapsing disease [6]. Moreover, up to 50% of patients with metastatic BC are ineligible for cisplatin-based chemotherapy [7] (patients with at least one of the following criteria: performance status >1; glomerular filtration rate ≤ 60 mL/min; grade ≥2 audiometric loss; peripheral neuropathy; and New York Heart Association class III heart failure).
In contrast with other strategies, immunotherapy is the only treatment aimed at empowering the immune system to increase the response against tumor growth. Recently, a new class of immunotherapeutic agents, immune checkpoint inhibitors (ICI), has shown potential in increasing treatment chances for patients with genitourinary cancers, improving their oncological outcomes [8].
Immune checkpoint inhibitors (ICI) are approved for use in metastatic BC by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Clinical efficacy of ICI has been shown in both the first-line treatment of cisplatin-ineligible patients, with programmed death ligand 1 (PD-L1)-positive tumors (atezolizumab, pembrolizumab), and in second-line settings, for progression after platinum-based chemotherapy (atezolizumab, pembrolizumab, and nivolumab for FDA and EMA; durvalumab and avelumab FDA alone) [9][10][11][12][13][14][15][16].

2. Non-Muscle-Invasive Bladder Cancer Unresponsive to BCG

NMIBC has high recurrence rates, up to 60%, within the first year of diagnosis [2]. Standard treatment for high-risk NMIBC (CIS, T1G1, high-grade Ta) involves transurethral resection of the tumor followed by intravesical Bacillus Calmette–Guérin (BCG) induction and maintenance therapy for up to 3 years [2]. Adjuvant therapy with BCG is currently used to prevent recurrence in these high-grade NMIBCs. Although 70% of patients with NMIBC achieve pathologic complete response rate (pCRR), recurrence and/or progression to muscle-invasive bladder cancer (MIBC) occurs in up to 80% and 50% of patients, respectively (BCG-unresponsive patients), the majority of them (80%) having recurrence within 1 year [17]. Previous studies reported that BCG stimulates TH1 response and the recruitment of CTL/NK cells.
The immune checkpoint receptor PD-1 is commonly expressed on activated T lymphocytes that modulate immune response. In particular, tumor cells may use the interaction between PD-1 and its ligands PD-L1 to escape immune-mediated cytotoxicity [18]. An altered PD-1 pathway has been observed in NMIBC recurrence and progression and in BCG resistance.
Moreover, BCG raises PD-L1 expression, with 20-fold higher PD-L1 expression in BCG-unresponsive patients. Therefore, targeting the PD-1/PD-L1 pathway has emerged as a potential therapeutic option for NMIBCs. Recently, pembrolizumab obtained FDA approval for the treatment of BCG-unresponsive patients who refused or were ineligible for radical cystectomy, based on the preliminary results of the Keynote-057 phase II trial [19][20]. The trial enrolled BCG-unresponsive patients to receive pembrolizumab (200 mg) every three weeks, until life-threatening toxicity, persistent/recurrent high-risk NMIBC, progression to MIBC, or up to 24 months of treatment. Preliminary data showed a complete response after 3 months of treatment in 40.2% of patients; moreover, 72.5% of these patients maintained it at a median follow-up of 14 months (80.2% of them had a complete response that exceeded 6 months). However, it must be emphasized that the Keynote-057 trial is still enrolling patients without carcinoma in situ (CIS), while data on the efficacy of pembrolizumab are available only for a cohort with carcinoma in situ (CIS) with/without papillary disease.
Promising results of a phase I trial of intravesical BCG combined with pembrolizumab in high-grade NMIBCs have recently been published. All patients had failed at least two courses on intravesical therapy (one contains BCG), and the preliminary analysis showed that the combination therapy had an overall response rate of 67% and an acceptable safety [21].
Two other trials are still ongoing for BCG-unresponsive patients: the Keynote-676 and the CheckMate 9UT trials. The Keynote-676 RCT is an open-label phase III study randomizing patients to receive either pembrolizumab and BCG versus BCG alone in high-risk NMIBCs, persistent or recurrent after adequate BCG induction (ineligible patients: patients who received BCG maintenance or a second induction). The primary endpoint is the CCR rate in patients with CIS, defined as the absence of high-risk NMIBC as determined by urine cytology, biopsy, radiology assessments, and local cystoscopy evaluation.
The other ongoing RCT is the CheckMate 9UT trial, which analyzes nivolumab monotherapy versus nivolumab + BMS-986205 (target therapy, IDO-1 inhibitor) with or without BCG in patients with BCG-unresponsive CIS, with or without a papillary-associated tumor. The first results are not yet available. Finally, a recent phase II RCT studied the association between avelumab and radiotherapy (whole bladder, 60–66 Gy) for BCG-unresponsive NMIBC, in patients unfit for radical cystectomy. It is a promising trial, though it is not yet recruiting.

3. Non-Metastatic Muscle-Invasive Bladder Cancer

3.1. Neoadjuvant Single-Agent Immune Checkpoint Therapy

Radical cystectomy remains the standard of care for patients with non-metastatic MIBC, and ICI therapy is not currently approved for non-metastatic MIBC. However, in patients with MIBC unfit for cisplatin-based neoadjuvant chemotherapy, the use of ICIs in the neoadjuvant setting could be favorable (Table 1). The use of pembrolizumab and atezolizumab for neoadjuvant treatment of non-metastatic MIBC has recently been tested in two phase II nonrandomized clinical trials (PURE-01 for pembrolizumab [22], and ABACUS for atezolizumab [23]).
Table 1. Neoadjuvant clinical trials.
Agent Administration Conditions Trial Name/NCT Number Clinical Stage Patients Age (Median; IQR); Male% PD-L1 + Phase Toxicity Grade 3–4 *

(%)		 Results
Single-agent ICI    
]. For this reason, several ongoing clinical trials are assessing the feasibility of a combination therapy (cisplatin-based chemotherapy plus ICIs) to gain higher response rates and disease-free survival in tumors with or without PD-L1 expression. The majority of these trials consider the pathologic downstaging to non-muscle-invasive bladder cancer at the time of radical cystectomy (T1 N0 M0) as the primary endpoint. Furthermore, preliminary results are currently only available from two phase I/II trials (Table 1).

4. Metastatic Muscle-Invasive Bladder Cancer

4.1. First-Line Immunotherapy

Up to 50% of patients with metastatic BC are ineligible for cisplatin-based chemotherapy, due to renal insufficiency, older age, or comorbidities [7]. ICIs have recently been introduced as first-line therapy for these platinum-unfit patients, with pembrolizumab (PD-1 inhibitor) and atezolizumab (PD-L1 inhibitor) being the first agents to be approved by the FDA and EMA in 2017 for patients with a positive PD-L1 status.
Several randomized phase III trials are currently investigating the role of ICIs in the first-line setting of these patients; at the moment, published data are available only from two of them, which are both single-arm phase II trials (Table 2).
Table 2. Immune checkpoint inhibitors for the treatment of metastatic cisplatin-unfit bladder cancer.
Agent Administration Condition Trial Name/NCT Number Clinical Stage Patients Age (Median; IQR); Male% PD-L1+ Phase Toxicity Grade 3–4 * (%) Results
     
First-line therapy                 
        Pembrolizumab [22] 200 mg; 3 cycles, 3 weekly PURE-01/NCT02736266 T2-3aN0M0
Pembrolizumab [27] 200 mg on day 1 of each 3-week cycle, for up to 24 months KEYNOTE-052/NCT02335424114 66 (60–71); 82% 59% II 2.6% N+: 14%; visceral M+: 85%;

(liver: 21%)		Overall pCRR: 37%

(39.8% of the PD-L1 +)
370 74 (34–94); 77% 65% II Grade 3: 14%

Grade 4: 1% Overall ORR: 24%

(CR: 5%; PR: 19%) Atezolizumab [23] 75 pts: full treatment (2 cycles, 3 weekly);

20 pts: only 1 cycle		 ABACUS/NCT02662309 T2-4aN0M0
Atezolizumab [11] 1200 mg every 3 weeks until unacceptable toxicity or radiographic progression IMvigor120/NCT0210865295 74 (68–77); 85% 41% II 14.7% N+: 26%; visceral M+: 66%

(liver: 21%)		Overall pCRR: 31%

(37% of the PD-L1 +)
119 73 (51–92); 81% 67% II 7% Overall ORR: 23%

(CR: 9%);

median OS: 15.9 months Combination therapy        
Second-line therapy                     
    Pembrolizumab plus Gem ± Cis [24] Pembro: 200 mg (day 8) for 5 doses; Cis: 70 mg/m2 (day 1); Gem: 1000 mg/m2 (days 1 + 8), every 3 weeks for 4 cycles GU14-188/NCT02365766
Pembrolizumab versus Pacli/Doce/Vinflu [8T2-4N0M0

(T2: 50%) 40 ]65 (−); 75% 52% Pembro: 200 mg every 3 weeks; Pacli: 75 mg/m2 every 3 weeks; VinfluIb/II : 320 mg/m2 every 3 weeks, until unacceptable toxicity/radiographic progression/up to 24 months of Pembro KEYNOTE-045/NCT0225643632.5% - 542 Pembro: 67 (29–88); 74.1%

Chemo: 65 (26–84);

74.3%		 -

Grade 3–4 cytopenia: 57%		 IIIT1N0M0 at RC: 60%; 1-year OS: 94%
Pembro: 15%;

Chemo: 49.4% OS: 10.3 months (pembro) versus 7.4 months (chemo; p = 0.002); CR: 7%; PR: 22% Nivolumab plus Gem ± Cis [25] Cis: 70 mg/m2 (day 1), Gem: 1000 mg/m2 (day 1 + 8), Nivo: 360 mg (day 8) every 3 weeks for 4 cycles BLASST-1/NCT03294304 T2-4aN0-1M0 (T2N0: 90%) 43
Atezolizumab - [15]- II 20% Overall pCRR: 65.8%; downstaging: 83%
1200 mg on day 1 of 21-day cycles, until radiographic progression/loss of clinical benefit or unmanageable toxicity NCT02108652 N+: 14%; visceral M+: 78%

(liver: 31%)		 310 66 (32–91); 78% 67% II 16% Overall ORR: 15%

(CR: 5%; PR: 10%)		 Nivolumab plus Ipilimumab [26] Ipi: 3 mg/kg (day 1), Ipi + Nivo: 1 mg/kg (day 22), Nivo: 3 mg/kg (day 43) Vinflu: 320 mg/m2; Pacli: 175 mg/m2; Doce: 75 mg/m2 on day 1 of each 21-day cycle, until disease progression/unacceptable toxicityNABUCCO/NCT03387761 T3-4aN0M0

or N+		 24 - 60% Ib 42% Overall pCRR: 46%
PCRR: pathologic complete response rate; Gem: gemcitabine; Cis: cisplatin; RC: radical cystectomy; OS: overall survival; IQR: interquartile rate. * Adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Event classification, version 5.0.

 

3.2. Neoadjuvant Combination Therapy: Immune Checkpoint Inhibitors + Cisplatin-Based Chemotherapy; Immune Checkpoint Inhibitor + Immune Checkpoint Inhibitor

At present, for non-metastatic MIBCs, the pathologic complete response rate (T0 at radical cystectomy) of neoadjuvant pembrolizumab/atezolizumab remains inferior to that of cisplatin-based chemotherapy, which ranges between 30% and 40% [4
Atezolizumab versus Pacli/Doce/Vinflu
[
14
]
Atezo: 1200 mg on day 1 of 21-day cycles; IMvigor211/NCT02302807 N+: 13%; visceral M+: 77%

(liver: 29%)		 931 Atezo: 66 (33–88); 76%

Chemo: 67 (31–84); 78%		 25% III Atezo: 6.1%

Chemo: 46.5%		 PD-L1+ patients:

OS: 11.1 months (atezo) versus 10.6 months (chemo; p = 0.41);

ORR: 23% (atezo) versus 22% (chemo)
Nivolumab [28] 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity CheckMate275/NCT02387996 N+: 16%; visceral M+: 84%

(liver: 28%)		 270 66 (38–90); 78% 30% II 18% Overall ORR: 19.6% (28.4% in PD-L1+); CR: 2%; PR: 17%; OS: 8.7 months
Avelumab [29] 10 mg/kg every 2 weeks until disease progression/unacceptable toxicity JAVELIN/NCT01772004 visceral M+: 84% 249 68 (63–76); 72% 33% Ib 8% Overall ORR: 17%; overall CR: 6% (10% in PD-L1+); overall PS: 11% (14% in PD-L1+)
Durvalumab [30] 10 mg/kg every 2 weeks for up to 12 months or until disease progression/unacceptable toxicity NCT01693562 N+: 7.3%; visceral M+: 93%

(liver: 43%)		 191 67 (34–88); 71.2% 51% I/II 6.8% Overall ORR: 17.8%

(CR: 3.7%; PR: 14.1%);

OS: 18.2 months
ORR: objective response rate; CR: complete response; PR: partial response; OS: overall survival; Pacli: paclitaxel; Doce: docetaxel; Vinflu: vinflunine: Atezo: atezolizumab; Nivo: nivolumab; Chemo: chemotherapy. * Adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Event classification, version 5.0.
 

4.2. Second-Line Immunotherapy for Platinum Pre-Treated Patients

ICIs approved by the FDA for second-line treatment of metastatic BC progressing during or after platinum-based chemotherapy are pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab. All have demonstrated similar clinical efficacy and safety in phase I, II, and III trials (Table 2).
The randomized, open-label, phase III KEYNOTE-045 trial [8] tested pembrolizumab (either as monotherapy or in combination with paclitaxel, docetaxel, or vinflunine) on 542 patients as second-line treatment. The trial showed a significant median overall survival benefit in the pembrolizumab arm (10.3 months versus 7.4 months in the chemotherapy arm, independently of PD-L1 expression levels), a 7% complete response rate, and a 22% partial response rate.
Both 1-year and 2-year overall survival rates were higher with pembrolizumab (44% and 27%, respectively), compared to chemotherapy (30% and 14%, respectively), and pembrolizumab showed a higher rate of duration of response lasting more than 12 months (68% versus 35%).

5. Conclusions

Immunotherapy has a role in the treatment of BC due to these tumors’ high TMB and mostly prominent immune infiltrate. However, checkpoint inhibition is not successful in all patients. The disappointing clinical results reflect the complexity of the immune landscape of BC. The therapy or combination has to be adjusted to the tumor’s immunobiology. To assess a tumor’s immunophenotype, a marker panel to identify the T cells, macrophages, and Treg cells, together with PD-L1, is suggested. Applied by immunohistology, information on the quantity of the prevailing immune cell types and their spatial information can be gained, which allows judging the immune status and therapeutic choices. Considering the complexity of the immune response, shown by the cancer immunity cycle, the antitumor response can be halted at many steps, each one requiring specific corrective measures to restart the cycle and push it forward. Checkpoint inhibition monotherapy is expected to be successful only in a minority of patients who have T cell-positive tumors and a TME permissive for T cell reactivity (no inhibitory cells). The current knowledge suggests that the immune landscape of BC is complex with the presence of T cells and multiple suppressor mechanisms, including PD-L1, macrophages, Treg cells, and loss of MHC. Therefore, combination therapies of checkpoint therapeutics with other agents that address the patient’s individual TME composition are required for most patients. Regarding the choice of combination partners for checkpoint inhibitors, seemingly “inactive” substances in monotherapy should not be excluded. In monotherapy, their activity may be concealed because the T cells’ brakes are active, but synergistic activity can be expected in combination with checkpoint inhibition. New developments are on the horizon, such as the analysis of urine lymphocytes [31], and radiolabeled antibodies or radiopharmaceuticals [32][33]. These non-invasive tools may allow dynamically assessing the BC immune TME and imaging an agent’s potential effectiveness. Non-effective therapies may then be discontinued earlier and patients transferred faster to hopefully more beneficial therapies.

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