Abstract

Introduction Currently, there are no guidelines for the management of locally advanced unresectable or metastatic urothelial carcinoma (mUC) from an Indian perspective. There is a lack of consensus on the utility of treatment options in firstline (1L) and second-line (2L) settings, especially in cisplatin- and platinum-unfit mUC patient subgroups.

Objective This articles aims to develop evidence-based practical consensus recommendations for the management of mUC in Indian settings.

Methods Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 medical oncologists from India constituted the panel. Twelve clinically relevant questions were grouped into five categories for presentation and discussion: (1) cisplatin and platinum ineligibility criteria; (2) programmed death ligand 1 and fibroblast growth factor receptor (FGFR) testing in mUC patients; (3) treatment options in 1L settings; (4) role of switch maintenance; and (5) treatment options in 2L. Statements that reached high (80%) and moderate (60–79%) levels of consensus in the first round (electronic survey) did not undergo the second Delphi round. The questions that received a low level of consensus (< 60>

---

Results Renal impairment (creatinine clearance [CrCl] < 60> 3 or severe renal impairment (CrCl < 30>

Key Points

• In 1L settings, the experts preferred gemcitabine and platinum with cisplatin over carboplatin in mUC patients.

• In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible (cisplatin and carboplatin) may be considered for immunotherapy (atezolizumab or pembrolizumab) in 1L. Post-induction chemotherapy, those who do not progress should be strongly considered for avelumab switch maintenance. 

• Erdafitinib was recommended in FGFR-positive mUC patients in 2L.

• In FGFR-negative patients, platinum-based chemotherapy was suggested in 2L for those relapsing late, immunotherapy (pembrolizumab, nivolumab, or avelumab) for those who did not receive targeted immunotherapy in 1L, and single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine) for other mUC patients. 

Introduction

Carcinoma of the urinary bladder is a common urological malignancy that causes substantial morbidity and mortality. As per the Global Cancer Observatory: CANCER TODAY (GLOBOCAN) statistics, bladder cancer (BC) ranked 10th in incidence, with approximately 573,000 new cases and 213,000 deaths in 2020.1 Urothelial carcinoma (UC) is the predominant histologic type of BC and accounts for nearly 90%. of all BC cases globally.2 BC has a wide spectrum of disease severity from low-grade non–muscle-invasive BC (NMIBC) to muscle-invasive disease stage and metastatic lesions associated with poor outcomes.3 The majority of muscle-invasive tumors are high-grade UCs. A high probability of local/systemic recurrences of muscle-invasive tumors within 36 months after local treatment of primary tumor has been observed.4 BC diagnosed at earlier stages carry a greater chance of 5-year relative survival compared to later disease stages (►Table 1).5 Overall, 5-year relative survival rate for patients diagnosed with distant metastatic UC (mUC) is roughly 6%.5 In India, BC is ranked 17th in incidence and 19th in mortality, with significant heterogeneity in incidence rates across different regions of India.6 The overall incidence rate of BC in India as per the National Cancer Registry Programme report is 2.25 per 100,000 annually (males: 3.67 and females: 0.83).7 In India, BC patients are more often diagnosed with locally advanced diseases, resulting in poor outcomes. A study by Prakash et al assessed the stage distribution of patients presenting with BC (N ¼ 419) to a tertiary care cancer center in Mumbai.8 The median age of patients at diagnosis was 59 (18–88) years.8 Around 47% of patients had NMIBC, 36% had muscle-invasive and locally advanced disease, and 17%. had metastatic disease.8 The most common sites of distant metastasis were

Table 1 Five-year relative survival rates of bladder cancer 

Stage at diagnosis	5-year relative survival (%)
Stage 0: Noninvasive papillary carcinoma and carcinoma in situ	96
Stage 0–I: Localized (confined to primary sites)	70
Stage III–IV: Regional (spread to regional lymph nodes)	38
Stage IV: Distant (metastasis to lungs, liver, or bones)	6

Abbreviation: SEER: Surveillance, Epidemiology, and End Results. Note: Adapted from: National Cancer Institute. SEER Cancer Stat Facts for bladder cancer.5

bone, lung, liver, pelvic peritoneum, adrenal glands, and nonregional lymph nodes.8

The National Comprehensive Cancer Network (NCCN) guidelines recommend either gemcitabine–cisplatin combination chemotherapy or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) with growth factor support for cisplatin-eligible mUC patients in first-line (1L) settings.3 Subsequent switch maintenance may be considered in patients with a nonprogressive disease on 1L platinumbased chemotherapy.3 However, a substantial proportion of mUC patients are unfit to receive cisplatin-based chemotherapy in 1L settings due to advanced age, poor performance status, impaired renal function, and presence of multiple comorbidities. Currently, there are no defined criteria to establish cisplatin and platinum ineligibility in India, and it varies among different physicians and institutes. In addition, there is a lack of consensus on the utility of different treatment options in cisplatin- and platinum-unfit patients in 1L settings and treatment options in second-line (2L) settings. In this article, we have attempted to summarize expert opinions and recommendations on (1) cisplatin and platinum ineligibility criteria, (2) programmed death ligand 1 (PD-L1) and fibroblast growth factor receptor (FGFR) testing, (3) treatment options in 1L settings, (4) role of switch maintenance after 1L platinumcontaining chemotherapy, and (5) treatment options in 2L settings based on the available efficacy and safety data.

Methodology

Panel Selection

A panel of 15 medical oncologists with significant experience in managing BC patients participated in the development of the consensus article.

Evidence Review 

A literature review was carried out based on data from the PubMed database toidentify relevant articles between January 2001 and March 2022 using keywords such as “urothelial carcinoma,” “bladder cancer,” “first-line,” “second-line,” “maintenance,” “guidelines,” and “management.” Twelve clinically relevant questions (►Supplementary Material) belonging to five major domains were drafted.

    • Cisplatin/platinum ineligibility criteria.

    • PD-L1 and FGFR testing.

    • Treatment pattern in 1L settings.

    • Role of switch maintenance.

    • Treatment pattern in 2L settings and subsequent therapy.

An electronic survey link to these questions was sent to all the participants to record their views. Key articles were shortlisted and circulated among the participants before the survey. The “Oxford Centre for Evidence-Based Medicine: Levels of Evidence (LOE)” was used to define the grade or LOE of each recommendation (►Table 2A).9

Consensus Process

Modified Delphi consensus methodology was considered to arrive at a consensus.10 ►Table 2(B) lists the grades of recommendation (GOR) used during the electronic voting.11 The level of consensus (LOC) was considered “high” when 80%. of participants agreed/strongly agreed or disagreed/ strongly disagreed with a particular statement (►Table 2C).12 A “moderate” LOC was achieved when 60 to 79%. of participants agreed/strongly agreed or disagreed/ strongly disagreed with a particular statement.12 All the statements that reached a “moderate” and “high” LOC in the first round did not undergo the second Delphi round. The questions that received a “low” LOC (< 60>

Results

The experts (N ¼ 15) analyzed evidence, including randomized clinical trials (RCTs), systematic literature reviews, and meta-analyses through a systematic search of MEDLINE (via PubMed), Cochrane Library, and guidelines (NCCN) on mUC management published between January 2001 and March 2022. Experts made their decisions based on the available evidence and current practices in India (during Delphi rounds 1 and 2).

Cisplatin Ineligibility Criteria in Locally Advanced Unresectable UC or mUC

Assessment of performance status and renal function is of utmost importance for treatment selection. The Eastern Cooperative Oncology Group performance status (ECOG PS) 2 criterion can strongly predict poor outcomes (increased toxicity and decreased efficacy) in mUC patients treated with cisplatin-based regimens (LOE: 1a).13 The presence of renal impairment (creatinine clearance [CrCl] < 60>

Consensus/recommendations: Initial clinical evaluation should involve an assessment of medical history, hydration status, urinary obstruction, infection, and metabolic derangement. It is important that these factors are identified early and treated appropriately before deciding on eligibility for cisplatin-based chemotherapy. Experts agreed that renal impairment (CrCl < 60>

Table 2 Definitions: (A) Oxford LOE grading system, (B) grades of recommendation, and (C) level of consensus

(A) Oxford Centre for Evidence-Based Medicine: Level of evidence (LOE)
LOE	Therapy/prevention, etiology/harm	Prognosis
1a	Systematic review (with homogeneity) of RCTs	A systematic review (with homogeneity) of inception cohort studies; clinical decision rule validated in different populations
1b	Individual RCT (with narrow CI)	Individual inception cohort study with > 80%. follow-up; clinical decision rule validated in a single population
1c	All or none	All or no case series
2a	Systematic review (with homogeneity) of cohort studies	A systematic review (with homogeneity) of either retrospective cohort studies or untreated control groups in RCTs
2b	Individual cohort study (including low-quality RCTs, < 80>	Retrospective cohort study or follow-up of untreated control patients in an RCT; derivation of clinical decision rule or validated on split-sample only
2c	“Outcomes” research and ecological studies	“Outcomes” research
3a	Systematic review (with homogeneity) of case–control studies
3b	Individual case–control study
4	Case series (and poor-quality cohort and case–control studies)	Case series (and poor-quality prognostic cohort studies)
5	Expert opinion without an explicit critical appraisal, or based on physiology, bench research, or “first principles”	Expert opinion without an explicit critical appraisal, or based on physiology, bench research, or “first principles”
(B) Grade of recommendation (GOR)
++	This investigation or therapeutic intervention is highly beneficial for patients, can be recommended without restriction, and should be performed
+	This investigation or therapeutic intervention is of limited benefit for patients and can be performed
+/-	This investigation or therapeutic intervention has not shown benefit for patients and may be performed only in individual cases. According to current knowledge, a general recommendation cannot be given
-	This investigation or therapeutic intervention can be of disadvantage to patients and might not be performed
--	This investigation or therapeutic intervention is of clear disadvantage to patients and should be avoided or omitted in any case
(C) Level of consensus (LOC)
High	When 80%. of participants agree/strongly agree or disagree/strongly disagree with a statement
Moderate	When 60–79%. of participants agree/strongly agree or disagree/strongly disagree with a statement
Low	When < 60>

Abbreviations: CI, confidence interval; RCTs, randomized controlled trials. Adapted from: Oxford Centre for Evidence-Based Medicine: Levels of Evidence,9 Scharl et al, 2013,11 and Jünger et al, 2012.12

Platinum Ineligibility Criteria in Locally Advanced Unresectable UC or mUC 

Patients with ECOG PS > 3, CrCl < 30> 3, NYHA heart failure class > 3, and a combination of ECOG PS 2 and CrCl < 30>

Consensus/recommendations: Experts agreed that patients are unfit for any platinum-based chemotherapy in case of ECOG PS > 3 or severe renal impairment (CrCl < 30> 3 peripheral neuropathy, NYHA class > 3 heart failure, or the combination of ECOG PS 2 and CrCl < 30>

PD-L1 Testing in Locally Advanced Unresectable UC or mUC

The NCCN guidelines recommend early molecular/genomic testing to facilitate treatment decision-making in patients with locally advanced unresectable UC or mUC.3 A systematic review by Rouanne et al highlighted the use of PD-L1 testing with use of atezolizumab (IMvigor130 [N ¼ 851; SP142 assay], IMvigor210 [N ¼ 119 cisplatin ineligible; SP142]), and pembrolizumab (KEYNOTE 052 [N ¼ 370 cisplatin ineligible; 22C3]) in 1L settings (LOC: 1a).19 Currently, the use of PD-L1 testing before 1L therapy is advised in mUC patients who are cisplatin ineligible and have no contraindications to the use of immunotherapy. Immune checkpoint inhibitors (ICIs) used in the 1L include atezolizumab and pembrolizumab.3 However, in platinumineligible patients, checkpoint inhibitor (CPI) can be administered irrespective of PD-L1 status.3 The NCCN guidelines do not recommend PD-L1 testing before the maintenance phase. This is based on the JAVELIN 100 phase 3 trial that was not powered to assess progression-free survival/overall survival (PFS/OS) in the PD-L1-negative mUC patients in maintenance settings (LOE: 2b).3,20,21 In the 2L setting, PD-L1 testing is not required when assessing eligibility for treatment with ICIs (LOE: 1a).3,19,22

Consensus/recommendations: Experts agreed that PD-L1 testing before 1L systemic therapy can be performed in mUC patients who are ineligible to receive cisplatin chemotherapy (GOR: þ; LOC: “high”). In platinum-ineligible patients, CPI can be administered irrespective of PD-L1 status (GOR: þ; LOC: “high”). PD-L1 testing is not required when assessing eligibility for treatment in maintenance and 2L settings (GOR: þ/–; LOC: “high”).

FGFR Testing in Locally Advanced Unresectable UC or mUC

Studies have shown that FGFR3 mutation or FGFR2/3 fusion plays a significant role in the development of mUC.23–25 Currently, FGFR testing (FGFR3 mutation or FGFR2/3 fusion) is recommended after progression on platinum-based chemotherapy by the NCCN group to plan for optimal treatment (FGFR inhibitor or PD-L1 inhibitor [for FGFR-negative patients]) based on the eligibility criteria (LOE: 1a).3,23–25

Consensus/recommendations: FGFR mutation testing has not shown benefit for mUC patients in 1L settings. Experts strongly opined that it is important to screen mUC patients for FGFR3 alterations or FGFR2/3 fusion before 2L systemic therapy to plan for optimal treatment (FGFR inhibitor or PD-L1 inhibitor) (GOR: þþ; LOC: “high”).

►Table 3 lists recommendations on cisplatin/platinum ineligibility criteria and biomarker testing for management of locally advanced unresectable or mUC.

Treatment Pattern in 1L Settings

Patients eligible for cisplatin-based chemotherapy: The NCCN guidelines recommend either gemcitabine–cisplatin chemotherapy or ddMVAC with growth factor support for cisplatineligible mUC patients in 1L settings.3

Patients ineligible to receive cisplatin-based chemotherapy: Carboplatin–gemcitabine combination chemotherapy is recommended in cisplatin-ineligible mUC patients in 1L based on the results of phase 1/2 randomized EORTC 30986 trial (overall response rate [ORR]: 41.2%; median OS: 9.3 months) (LOE: 2b).26 Treatment with an ICI (atezolizumab [PD-L1 inhibitor] or pembrolizumab [PD-1 inhibitor]) could be an alternative option.3 Currently, the use of PD-L1 testing before 1L therapy is advised in mUC patients who are cisplatin ineligible and have no contraindications to the use of immunotherapy.3 In phase 2, IMvigor210 cohort study, atezolizumab conferred significant clinical benefits in untreated cisplatin-ineligible mUC.27 Scoring criteria designated tumors based on tumor-infiltrating immune cells (ICs): (1) IC0 (PD-L1 expression on < 1>

Table 3 Cisplatin-/platinum-ineligibility criteria and biomarker testing in mUC patients

(A) Cisplatin/platinum ineligibility criteria: Summary of expert recommendations
Expert recommendations on cisplatin-ineligibility criteria
• ECOG PS 2 (LOE: 1a; GOR: þþ; LOC: 66.7%).
• CrCl < 60>
• Grade 2 peripheral neuropathy (LOE: 2c; GOR: þþ; LOC: 60%)
• NYHA class 3 heart failure (LOE: 2c; GOR: þþ; LOC: 80%)
• Grade 2 hearing loss (LOE: 2c; GOR: þ; LOC: 80%)
Expert recommendations on platinum (cisplatin and carboplatin)-ineligibility criteria
• ECOG PS > 3 (LOE: 2c; GOR: þþ; LOC: 80%)
• CrCl < 30>
• Grade > 3 peripheral neuropathy (LOE: 2c; GOR: þþ; LOC: 60%)
• NYHA class > 3 heart failure (LOE: 2c; GOR: þþ; LOC: 60%)
• ECOG PS 2 and CrCl < 30>
• Grade 2 hearing loss (LOE: 2c; GOR: þ; LOC: 80%)
(B) Biomarker testing in mUC: Summary of expert recommendations
PD-L1 testing before 1L systemic therapy can be performed in mUC patients who are ineligible to receive cisplatin chemotherapy. PD-L1 testing before 1L systemic therapy is not required for those who are ineligible to receive any platinum-based chemotherapy (LOE: 1a; GOR: þ; LOC: 80%)
PD-L1 testing is not required when assessing eligibility for ICI maintenance in patients who have not progressed with platinum-containing chemotherapy (LOE: 2b; GOR: þ/ ; LOC: 80%)
PD-L1 testing is not required when assessing eligibility for treatment in 2L settings. According to current knowledge, a general recommendation cannot be given (LOE: 1a; GOR: þ/ ; LOC: 80%)
FGFR mutation testing has not shown benefit for mUC patients in 1L settings. A general recommendation regarding FGFR testing before 1L systemic therapy cannot be given (LOE: 2b; GOR: þ/ ; LOC: 80%)
It is important to screen mUC patients for FGFR alterations before 2L systemic therapy to plan for optimal treatment (LOE: 1a; GOR: þþ; LOC: 80%)

Abbreviations: 1L, first-line; 2L, second-line; CrCl, creatinine clearance; ECOG PS: Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; GOR, grade of recommendation; ICI, immune checkpoint inhibitor; LOC, level of consensus; LOE, level of evidence; mUC, metastatic urothelial carcinoma; NYHA, New York Heart Association; PD-L1, programmed death-ligand 1.

locally advanced or mUC (cisplatin-unfit patients with PD-L1 CPS 10 or patients who are not eligible for any platinumcontaining chemotherapy regardless of PD-L1 status) to a full approval and revised the indication to only cover the treatment of patients who are not eligible for any platinumcontaining chemotherapy.35 Based on the FDA approvals and evidence, the recent 2022 NCCN guideline has recommended: (1) atezolizumab (for patients not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression); or (2) pembrolizumab (for patients who are not eligible for any platinum-containing chemotherapy) (LOE: 2b).3,27,28,30,31,35

Consensus/recommendations: Experts agreed that they would prefer carboplatin–gemcitabine chemotherapy followed by avelumab maintenance over ICI monotherapy (atezolizumab or pembrolizumab) in mUC patients with positive PD-L1 status unfit for cisplatin-based regimens in 1L settings (GOR: þþ; LOC: “high”). Experts preferred ICI monotherapy (atezolizumab or pembrolizumab) over BSC in patients ineligible for any platinum-based chemotherapy (GOR: þþ; LOC: “high”). BSC should be strongly preferred over ICI therapy in patients with: (1) poor performance status, (2) multiple uncontrolled comorbidities, and/or (3) poor access to therapies (GOR: þþ; LOC: “high”).

Role of ICI–chemotherapy combination therapy: Two trials investigated the relevance of ICI (atezolizumab or pembrolizumab) plus platinum-based chemotherapy combination in 1L settings. The first trial to report was IMvigor130, where atezolizumab plus platinum-based chemotherapy provided PFS benefit (8.2 vs. 6.3 months; p ¼ 0.007); however, OS was not significant after a median follow-up of 11.8 months compared to placebo plus platinum-based chemotherapy.36 The KEYNOTE 361 study had a similar design and investigated pembrolizumab plus platinum–gemcitabine versus chemotherapy plus placebo in 1L settings.37 The study revealed no benefit of this combination in terms of PFS or OS.37

Consensus/recommendations: Experts agreed that immunotherapy (atezolizumab or pembrolizumab) plus platinum–gemcitabine chemotherapy is not suitable in mUC patients in 1L settings (GOR: ; LOC: “high”).

Role of Switch Maintenance in Locally Advanced Unresectable UC or mUC After Platinum-Based Chemotherapy

The JAVELIN Bladder 100 phase 3 RCT explored the impact of switch maintenance with PD-L1 inhibitor avelumab plus BSC versus BSC alone in mUC not progressed with 1L platinumcontaining chemotherapy (complete or partial response vs. stable disease).21 Patients were categorized as having PD-L1- positive status if at least one of the three criteria were met: (1) at least 25% of tumor cells stained for PD-L1, (2) at least 25% of ICs stained for PD-L1 if more than 1% of the tumor area contained ICs, or (3) 100% of ICs stained for PD-L1 if no more than 1% of the tumor area contained ICs.21 Addition of maintenance avelumab to BSC significantly prolonged median OS (21.4 months; 95% CI: 18.9–26.1) as compared with BSC alone (14.3 months [95% CI: 12.9–17.9]; p ¼ 0.001) (LOE: 1b).21 With extended follow-up ( 38 months), median OS remained significantly longer in the avelumab plus BSC (23.8 months [95% CI: 19.9–28.8]) as compared to BSC alone (15.0 months [95% CI: 13.5–18.2]; p ¼ 0.0036) in unresectable locally advanced UC or mUC without disease progression.38 Another phase 2 RCT investigated the impact of switch maintenance with PD-1inhibitor pembrolizumabinmUC patients achieving at least stable disease on 1L platinum-based chemotherapy. In this study, the OS was not significantly different (22 vs. 18.7 months) in patients randomly assigned to maintenance pembrolizumab versus placebo (LOE: 2b).39

Consensus/recommendations: Experts strongly recommended avelumab switch maintenance plus BSC in mUC patients with nonprogressive disease after 4 to 6 cycles of 1L platinum-containing chemotherapy (GOR: þþ; LOC: “high”). They would not prefer pembrolizumab switch maintenance due to no significant OS benefit in mUC patients (GOR: ; LOC: “high”). They would consider BSC alone in patients with poor performance status and lack of access to immunotherapies (GOR: þ/ ; LOC: “high”).

Patient profiles suitable for avelumab switch maintenance: Avelumab switch maintenance plus BSC provided an OS and PFS benefit in patients with PD-L1-positive or PD-L1-negative tumors, with a potentially greater benefit in patients with PD-L1-positive tumors.21 Avelumab maintenance significantly prolonged OS in the PD-L1-positive mUC patients; OS at 1 year was 79.1% in the avelumab group versus 60.4% in the control group (BSC alone; p < 0>

Consensus/recommendations: Experts agreed that avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with ECOG 0/1, age < 65>

►Table 4 lists the recommendations for 1L systemic therapy and switch maintenance after 1L platinum-containing chemotherapy.

Treatment Pattern in 2L and Subsequent Therapy

In the phase 3 KEYNOTE-045 RCT, pembrolizumab conferred significant OS benefits in 2L (10.3 vs. 7.4 months; p ¼ 0.002) as compared to the chemotherapy group (paclitaxel, docetaxel, or vinflunine) in mUC patients who progressed during or after the receipt of platinum chemotherapy (LOE: 1b).40 Nivolumab, a fully human immunoglobulin G4 PD-1 ICI, demonstrated clinical benefit (ORR was 19·6% [95% CI: 15.0–24.9]) in a phase 2, single-arm study in mUC patients whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen (LOE: 2b).41 Recently, the efficacy and safety of avelumab in 2L were assessed in phase 1b JAVELIN Solid Tumor study. Avelumab therapy resulted in a median OS of 7.0 months and a 24-month OS rate of 20.1% (LOE: 2b).42 For management of mUC patients with FGFR alternations, the NCCN guideline recommends erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, in 2L based on the promising result from the phase 2 BLC2001 study.43 The confirmed response rate to erdafitinib therapy was 40% and the median OS was 13.8 months. Among patients who had undergone prior immunotherapy, the response rate was 59% (LOE: 2b).43 The indication of atezolizumab was withdrawn by the FDA in March 2021 in mUC patients previously treated with platinum-based chemotherapy based on the results of the phase 3 IMvigor211 trial.44 The trial failed to meet its primary endpoint of OS benefit in mUC patients with positive PD-L1 status (IC2/3; 11.1 vs. 10.6 months; p ¼ 0.41) as compared to chemotherapy (vinflunine, paclitaxel, or docetaxel).44,45 The NCCN guidelines recommend: (1) rechallenge with gemcitabine and cisplatin or carboplatin or MVAC in patients who relapse after a year of last platinum exposure, (2) erdafitinib in patients with FGFR3 or FGFR2 genetic alterations, or (3) ICI therapy (pembrolizumab, nivolumab, or avelumab) in patients who have not received ICI in 1L settings.3

Consensus/recommendations: Experts recommended erdafitinib in FGFR-positive mUC patients in 2L settings (GOR: þþ; LOC: “high”). Experts agreed that in FGFR-negative patients, ICIs (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine).

Table 4 First-line systemic therapy and switch maintenance for locally advanced or mUC

(A) 1L systemic therapy for locally advanced unresectable UC or mUC: Summary of expert recommendations
Treatment of cisplatin-ineligible mUC patients with positive PD-L1 status   Carboplatin–gemcitabine chemotherapy is preferred over ICI monotherapy (atezolizumab or pembrolizumab) in mUC patients with positive PD-L1 status deemed unfit for cisplatin-based therapy in 1L settings (LOE: 2b; GOR:   þþ; LOC: 80%)  Treatment of mUC patient ineligible for any platinum-based chemotherapy (cisplatin and carboplatin ineligible)   • ICI monotherapy (atezolizumab or pembrolizumab) can be preferred over BSC in patients ineligible for any platinum-based chemotherapy (LOE: 2b; GOR: þþ; LOC: 80%)   • BSC is strongly preferred over ICI therapy in patients with: (1) poor performance status; (2) multiple uncontrolled comorbidities; and/or (3) poor access to immunotherapies (LOE: 2c; GOR: þþ; LOC: 80%)  Scope of immunotherapy–chemotherapy combination in 1L treatment settings  • Immunotherapy (atezolizumab or pembrolizumab) plus platinum–gemcitabine chemotherapy is not suitable in mUC patients in 1L treatment settings (LOE: 1b; GOR: ; LOC: 80%)
(B) Switch maintenance for locally advanced unresectable UC or mUC patients after 1L platinum-containing chemotherapy:      Expert recommendations
Switch maintenance in the general population   • Avelumab switch maintenance plus BSC is strongly recommended in mUC patients with the nonprogressive disease after 4–6 cycles of 1L platinum-containing chemotherapy (LOE: 1b; GOR: þþ; LOC: 100%)   • Pembrolizumab switch maintenance is not suitable after 1L platinum-containing chemotherapy due to no OS benefit in mUC patients (LOE: 2b; GOR: ; LOC: 80%)   • BSC instead of switch maintenance can be considered in patients with poor performance status and lack of access to immunotherapies (LOE: 2c; GOR: þ/ ; LOC: 80%)
Patient profiles suitable for avelumab switch maintenance therapy   PD-L1 status  • Avelumab switch maintenance plus BSC is strongly recommended in PD-L1-positive mUC patients with the nonprogressive disease after 4–6 cycles of 1L platinum-containing chemotherapy (LOE: 1b; GOR: þþ; LOC: 86.7%)  • Avelumab switch maintenance plus BSC can be performed in PD-L1-negative mUC patients with the nonprogressive disease after 4–6 cycles of 1L platinum-containing chemotherapy (LOE: 2b; GOR: þþ; LOC: 80%)  Prior chemotherapy regimen  • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients not progressed on 1L gemcitabine–carboplatin or gemcitabine–cisplatin-based chemotherapy (LOE: 1b; GOR: þþ; LOC: 93.3%)  Response to chemotherapy  • Avelumab switch maintenance therapy is beneficial and recommended in mUC patients with partial and complete response after 1L platinum-containing chemotherapy (LOE: 1b; GOR: þþ; LOC: 86.7%)  • Avelumab maintenance therapy is also recommended in mUC patients with stable disease after 1L platinum-containing chemotherapy (LOE: 1b; GOR: þþ; LOC: 66.7%)  Type of metastases  • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with nonvisceral metastasis after 1L platinum-containing chemotherapy (LOE: 1b; GOR: þþ; LOC: 86.7%)  • Avelumab switch maintenance therapy is beneficial in mUC patients with visceral metastasis after 1L platinum-containing chemotherapy (LOE: 1b; GOR: þþ; LOC: 73.3%)  ECOG status  Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with ECOG status 0/1 (LOE: 1b; GOR: þþ; LOC: 93.3%)  CrCl  Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients regardless of CrCl (< 60>  Age  • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with age < 65>  • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with age 65 years (LOE: 1b; GOR: þþ; LOC: 66.7%)

Abbreviations: 1L, first-line; BSC, best supportive care; CrCl, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; GFR, glomerular filtration rate; GOR, grade of recommendation; ICI, immune checkpoint inhibitor; LOC, level of consensus; LOE, level of evidence; mUC, metastatic urothelial carcinoma; PD-L1, programmed death-ligand 1; UV, urothelial carcinoma.

Patient eligibility should be determined before therapy based on the available efficacy and safety data. On the other hand, chemotherapy (paclitaxel, docetaxel, or vinflunine) can be considered in patients who are not eligible for ICI therapy or have poor access to ICI therapy. Experts strongly opined that pembrolizumab can be preferred as it has strong phase 3 clinical evidence with OS benefit (GOR: þþ; LOC: “high”) as compared to nivolumab (GOR: þ; LOC: “high”).

Patient profiles suitable for ICI in 2L: Experts agreed that ICI therapy (pembrolizumab, nivolumab, or avelumab) is suitable and can be recommended in patients with ECOG status 0/1 (GOR: þþ; LOC: “high”). In addition, ICI therapy can be considered in patients with: (1) prior cisplatin chemotherapy, (2) PDL1 (IC 2/3), and (3) visceral disease (GOR:þþ; LOC: “moderate”). Scope of antibody–drug conjugates (ADCs): In phase 3 EV-301 trial, the efficacy of enfortumab vedotin, a nectin-4-directed ADC, was assessed in patients previously treated with platinum-containing chemotherapy and a PD-1 or PD-L1inhibitor.46 The study demonstrated that median OS was significantly longerin the enfortumab vedotin treatment arm (12.88months [95%. CI: 10.58–15.21) as compared to the chemotherapy group (docetaxel, paclitaxel, or vinflunine) (8.97 months [95%. CI: 8.05–10.74]; p¼ 0.001) (LOE: 1b).46 Another phase 2, openlabel (TROPHY-U-01) cohort study investigated the role of TROP-2-directed ADC sacituzumab govitecan in mUC patients who progress on platinum-based combination chemotherapy and ICI therapy.47 The median OS achieved with sacituzumab govitecan therapy was 10.9 months (95% CI: 9.0–13.8 months) (LOE: 2b).47

Consensus/recommendations: Experts agreed that enfortumab vedotin is a suitable treatment option in patients who have previously received platinum-containing chemotherapy and progressed during or after treatment with a PD-1 or PD-L1 inhibitor (GOR: þþ; LOC: “moderate”). Currently, enfortumab vedotin is available only on a compassionate basis in India. Sacituzumab govitecan is another treatment option in patients who have previously received platinum-containing chemotherapy and progressed during or after treatment with a PD-1 or PD-L1 inhibitor (GOR: þþ; LOC: “low”).

OS improvement from the start of 1L therapy: Experts opined that 1L platinum-based chemotherapy (4–6 cycles) followed by avelumab switch maintenance with BSC is most useful in terms of OS improvement from the start of 1L therapy and can be recommended (GOR: þþ; LOC: “high”).

►Table 5 lists the recommendations for 2L systemic therapy for the management of mUC.

Discussion

Clinical and Research Implications

Treatment of UC has evolved over the last few years with improved outcomes across different disease stages. ICI and targeted therapies have emerged as new options for the treatment of persistent diseases. In India, there are no country-specific guidelines or recommendations for the management of locally advanced unresectable or mUC. Furthermore, due to the scarcity of RCTs conducted in India and the lack of local guidelines or recommendations, oncologists rely on data from the Western world. Currently, there are no defined criteria to establish cisplatin and platinum ineligibility in India, and it varies among different physicians and institutes. There is a lack of consensus on the utility of treatment options, especially in cisplatin- and platinumunfit mUC patient subgroups. To the best of our knowledge, this is the first evidence-based practical consensus document to guide clinicians on the management of mUC in Indian settings. This consensus document will offer expert guidance to Indian oncologists and help achieve consistency in mUC management across various healthcare settings.

Strengths: The members of the panel (in the space of genitourinary oncology) were selected to best represent the breadth of knowledge and clinical expertise in the field from all over India. There was no selection bias during the development of the expert committee. All experts actively participated during the consensus process. The responses of all panelists were generated in the form of graphs (GOR vs. response in percentage) to ensure the protection of participants’ data.

Table 5 Second-line systemic therapy for locally advanced or mUC

2L systemic therapy for locally advanced unresectable UC or mUC: Expert recommendations
• Erdafitinib is recommended in FGFR-positive mUC patients in 2L settings (LOE: 2b; GOR: þþ; LOC: 80%)   • In FGFR-negative patients, ICI (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine) in 2L settings. Pembrolizumab has strong phase 3 data in terms of OS and   can be preferred (LOE: 1b; GOR: þþ; LOC: 80%) over nivolumab (LOE: 2b; GOR: þ; LOC: 80%) in 2L settings  • Enfortumab vedotin is a suitable treatment option in mUC patients who have previously received platinum-containing chemotherapy and progressed during or after treatment with a PD-1 or PD-L1 inhibitor (LOE: 1b; GOR: þþ;   LOC: “moderate”). Currently, enfortumab vedotin is available only on a compassionate basis in India  • Sacituzumab govitecan is another treatment option in patients who have previously received platinum-containing chemotherapy and progressed during or after treatment with a PD-1 or PD-L1 inhibitor (LOE: 2b; GOR: þþ;   LOC: “low”)
Patient profiles suitable for ICI in 2L settings  • ECOG PS status: ICI therapy (pembrolizumab, nivolumab, or avelumab) is suitable and can be recommended in patients with ECOG status 0/1 in 2L settings (GOR: þþ; LOC: 86.7%)  • PD-L1 status: ICI therapy (pembrolizumab, nivolumab or avelumab) can be considered in PD-L1 (IC 2/3 [GOR: þþ; LOC: 60%] and IC 1 [GOR: þ; LOC: 73.3%]) in 2L settings  • First-line chemotherapy: ICI therapy (pembrolizumab, nivolumab, or avelumab) is suitable in patients with prior cisplatin chemotherapy in 2L settings (GOR: þþ; LOC: 73.3%)  • Extent of involvement: ICI therapy (pembrolizumab, nivolumab, or avelumab) can be considered in patients with visceral disease in 2L settings (GOR: þþ; LOC: 60%)
OS improvement from the start of therapy: Expert recommendations
1L platinum-based chemotherapy (4–6 cycles) followed by avelumab switch maintenance with BSC is most useful in terms of OS improvement from the start of 1L therapy and can be recommended (GOR: þþ; LOC:   100%)

Abbreviations: 2L, second-line; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; GOR, grade of recommendation; ICI, immune checkpoint inhibitor; LOC, level of consensus; LOE, level of evidence; mUC, metastatic urothelial carcinoma; OS, overall survival; PD-L1, programmed death-ligand 1; UV, urothelial carcinoma. 

Limitation: The patient’s voice was not included in the consensus process.

Conclusion 

In this article, we have attempted to summarize the Indian consensus on the management of locally advanced unresectable UC or mUC. Patients with treatment-naive mUC should be classified according to cisplatin and platinum eligibility based on clear definitions. In a 1L setting, the experts preferred gemcitabine and platinum with cisplatin over carboplatin. Selected patients who are platinum ineligible may be considered for atezolizumab or pembrolizumab. Post-induction chemotherapy, those who do not progress should be strongly considered for avelumab maintenance. Experts recommended screening mUC patients for FGFR3 alterations or FGFR2/3 fusion before deciding on 2L therapy. Options for 2L therapy include platinum-based chemotherapy for those relapsing late, targeted therapy with erdafitinib for patients with FGFR alterations, ICI (pembrolizumab, nivolumab, or avelumab) for those who have not received ICI in 1L settings, and single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine) for others. Enfortumab vedotin and sacituzumab govitecan should be considered for further lines of therapy. 

Authors’ Contributions 

 All authors have contributed equally to the concept, design, editing, review, and finalization of manuscript.

Funding 

 This study is supported by Pfizer India Ltd.

Conflict of Interest

None declared.

Acknowledgment 

We would like to thank BioQuest Solutions Pvt Ltd for their editorial support.

References 

1 Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(03):209–249

2 Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of bladder cancer. Med Sci (Basel) 2020;8(01):15

3 NCCN Clinical Practice Guidelines Version 1 (2022) for Bladder Cancer. Accessed April 12, 2022, at: https://www.nccn.org/guidelines/guidelines-detail?category¼1&id¼1417

4 Valderrama BP, González-Del-Alba A, Morales-Barrera R, et al. SEOM-SOGUG clinical guideline for localized muscle invasive and advanced bladder cancer (2021). Clin Transl Oncol 2022;24(04): 613–624

5 National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) on survival rates for bladder cancer. Accessed April 26, 2022, at: https://www.cancer.org/cancer/bladder-cancer/detection-diagnosis-staging/survival-rates.html

6 Mishra V, Balasubramaniam G. Urinary bladder cancer and its associated factors – an epidemiological overview. Indian J Med Sci 2021;73:239–248

7 Abid A, Sen S, Bandyopadhyay R. Clinicopathological study of urothelial neoplasms in urinary bladder with special reference to expression of Her2/neu and Ki-67 in malignant lesions. Indian J Pathol Oncol 2021;8:369–376

8 Prakash G, Pal M, Odaiyappan K, et al. Bladder cancer demographics and outcome data from 2013 at a tertiary cancer hospital in India. Indian J Cancer 2019;56(01):54–58

9 Oxford Centre for Evidence-Based Medicine: levels of evidence. Accessed April 29, 2022, at: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009

10 Nasa P, Jain R, Juneja D. Delphi methodology in healthcare research: how to decide its appropriateness. World J Methodol 2021;11(04):116–129

11 Scharl A, Thomssen C, Harbeck N, Müller V. AGO recommendations for diagnosis and treatment of patients with early breast cancer: update 2013. Breast Care (Basel) 2013;8(03):174–180

12 Jünger S, Payne S, Brearley S, Ploenes V, Radbruch L. Consensus building in palliative care: a Europe-wide Delphi study on common understandings and conceptual differences. J Pain Symptom Manage 2012;44(02):192–205

13 Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol 2011;29(17):2432–2438

14 Park SB, Krishnan AV, Lin CS, Goldstein D, Friedlander M, Kiernan MC. Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem 2008;15(29):3081–3094

15 National Cancer Institute. Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events (CTCAE) version 5. Accessed May 05, 2022, at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x1 /211.pdf

16 Raja W, Mir MH, Dar I, Banday MA, Ahmad I. Cisplatin induced paroxysmal supraventricular tachycardia. Indian J Med Paediatr Oncol 2013;34(04):330–332

17 Gupta S, Bellmunt J, Plimack ER, et al. Defining “platinumineligible” patients with metastatic urothelial cancer (mUC). J Clin Oncol 2019;37:451

18 De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II–results of EORTC study 30986. J Clin Oncol 2009;27(33):5634–5639

19 Rouanne M, Radulescu C, Adam J, Allory Y. PD-L1 testing in urothelial bladder cancer: essentials of clinical practice. World J Urol 2021;39(05):1345–1355

20 Grivas P, Agarwal N, Pal S, et al. Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: applying clinical trial findings to clinical practice. Cancer Treat Rev 2021; 97:102187

21 Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 2020;383(13):1218–1230

22 Rui X, Gu TT, Pan HF, Zhang HZ. Evaluation of PD-L1 biomarker for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatments for urothelial carcinoma patients: a meta-analysis. Int Immunopharmacol 2019;67:378–385

23 Casadei C, Dizman N, Schepisi G, et al. Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors. Ther Adv Med Oncol 2019;11:1758835919890285

24 Kwon WA, Seo HK. Emerging agents for the treatment of metastatic urothelial cancer. Investig Clin Urol 2021;62(03):243–255

25 Kacew A, Sweis RF. FGFR3 alterations in the era of immunotherapy for urothelial bladder cancer. Front Immunol 2020;11:575258

26 De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012;30(02):191–199

27 Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. [published correction appears in Lancet. 26 August 2017;390(10097):848] Lancet 2017;389(10064):67–76

28 FDA alerts health care professionals and oncology clinical investigators about an efficacy issue identified in clinical trials for some patients taking Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as monotherapy to treat urothelial cancer with low expression of PD-L1. Accessed May 18, 2022, at: https://www.fda.gov/ drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-and-oncology-clinical-investigators-about-efficacy-issue

29 ODAC says ‘yes’ to continued approval of atezolizumab for cisplatin-ineligible locally advanced or metastatic UC. Accessed October 7, 2022, at: https://www.targetedonc.com/view/odacsays-yes-to-continued-approval-of-atezolizumab-for-cisplatinineligible-locally-advanced-metastatic-uc

30 Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18 (11):1483–1492

31 Vuky J, Balar AV, Castellano D, et al. Long-term outcomes in KEYNOTE-052: Phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. J Clin Oncol 2020;38(23):2658–2666

32 Hugar LA, Lopa SH, Yabes JG, et al. Palliative care use amongst patients with bladder cancer. BJU Int 2019;123(06):968–975

33 Hugar LA, Wulff-Burchfield EM, Winzelberg GS, Jacobs BL, Davies BJ. Incorporating palliative care principles to improve patient care and quality of life in urologic oncology. Nat Rev Urol 2021;18(10): 623–635

34 Castagneto B, Zai S, Marenco D, et al. Single-agent gemcitabine in previously untreated elderly patients with advanced bladder carcinoma: response to treatment and correlation with the comprehensive geriatric assessment. Oncology 2004;67(01):27–32

35 FDA approves updated indication for Merck’s KEYTRUDA® (pembrolizumab) for treatment of certain patients with urothelial carcinoma (bladder cancer). Accessed Oct 07, 2022, at: https:// www.merck.com/news/fda-approves-updated-indication-formercks-keytruda-pembrolizumab-for-treatment-of-certainpatients-with-urothelial-carcinoma-bladder-cancer/

36 Galsky MD, Arija JÁA, Bamias A, et al; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebocontrolled phase 3 trial. Lancet 2020;395(10236):1547–1557

37 Powles T, Csőszi T, Özgüroğlu M, et al; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol 2021;22(07):931–945

38 Pérez-Valderrama B, Powles T, Sridhar SS, et al. Avelumab firstline (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol 2022;40:4559

39 Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized doubleblind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol 2020;38(16):1797–1806

40 Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376(11):1015–1026

41 Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(03): 312–322

42 Apolo AB, Ellerton JA, Infante JR, et al. Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. J Immunother Cancer 2020;8(02):e001246

43 Loriot Y, Necchi A, Park SH, et al; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381(04):338–348

44 Atezolizumab Indication in US Withdrawn for Previously Treated Metastatic Urothelial Cancer. Accessed May 18, 2022, at: https:// www.cancernetwork.com/view/atezolizumab-indication-in-uswithdrawn-for-previously-treated-metastatic-urothelial-cancer

45 Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. [published correction appears in Lancet. 2018 Oct 20;392 (10156):1402] Lancet 2018;391(10122):748–757

46 Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384(12):1125–1135

47 Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinumbased chemotherapy and checkpoint inhibitors. J Clin Oncol 2021;39(22):2474–2485