First-line treatment of mUC
When deciding among frontline treatment options, we start by assessing eligibility for platinum-based chemotherapy. For platinum-eligible patients, a cisplatin-based regimen should be offered (or a carboplatin-based regimen, if the patient is unable to receive cisplatin because of comorbidities or frailty), followed by maintenance therapy with the anti-PD-L1 immune checkpoint inhibitor (CI) avelumab.1 In the phase 3 randomized JAVELIN 100 Bladder trial, maintenance avelumab therapy significantly improved overall survival (OS) among patients with mUC whose disease had not progressed after first-line platinum-based chemotherapy (1-year OS: 71% vs. 58%; hazard ratio [HR] for death, 0.69; 95% CI, 0.56 to 0.86).2 This study provides practice-changing, level 1 evidence to support maintenance treatment with avelumab following platinum-based chemotherapy for eligible patients.
The real question, however, is how best to identify patients who are not candidates for platinum. This is necessary because these patients comprise approximately 10% of patients with mUC seen in academic centers and about 20% of those seen in community practice. Thus far, studies have used varying definitions for platinum ineligibility, which can complicate the extrapolation of their findings to treatment selection and prognostication in the real world. At the 2019 ASCO Genitourinary Cancers Symposium (ASCO GU 2019), we saw data supporting a definition of platinum ineligibility based on having at least one of these five parameters: Eastern Cooperative Oncology Group performance status (ECOG PS) of 3 or higher; grade 3 or higher peripheral neuropathy; creatinine clearance rate less than 30 mL per minute; New York Heart Association (NYHA) Heart Failure Class greater than 3; ECOG performance status of 2 with creatinine clearance less than 30 mL per minute.3 Although this was a somewhat rudimentary, consensus-based definition that was based on a survey of genitourinary medical oncologists, it nonetheless represents meaningful progress. Researchers are now undertaking further studies to refine the definition of platinum ineligibility, so stay tuned for more on this topic.
For most platinum-ineligible patients with mUC, the most appropriate first-line treatment is CI therapy with either the PD-L1 inhibitor atezolizumab or the PD-1 inhibitor pembrolizumab.1 This recommendation is based on data from the multicenter phase 2 IMvigor 210 and KEYNOTE 0-52 trials,4,5 which have been widely discussed since their initial publication in 2017 and which I will not review in detail here. Note, however, that there is no need to assess PD-1 expression before selecting CI therapy for platinum-ineligible patients, since CI is their best treatment option.
As a next step, researchers are investigating whether we can improve on the outcomes we see with first-line CI monotherapy in mUC. At ASCO GU 2022, we saw results from the randomized, double-blind, phase 3 LEAP 011 trial, in which adding the kinase inhibitor lenvatinib to pembrolizumab did not improve progression-free survival (PFS) or OS compared with pembrolizumab alone in patients with advanced urothelial cancer.6 Fully 80% of study participants were platinum-ineligible, making these findings quite relevant. Additional studies of first-line CI-based combinations are underway and should provide intriguing results in the near future.
In preclinical studies, PARP inhibitors (PARPi) have shown some evidence of synergistic activity when combined with CIs, prompting clinical trials of first-line combinations. Data reported thus far have been fairly underwhelming when we consider the overall population of patients with advanced mUC,7,8 but subgroup analyses have sparking interest in identifying biomarkers to predict treatment response. In the randomized phase 2 BAYOU trial of 154 platinum-ineligible patients with previously untreated mUC, adding the PARPi olaparib to durvalumab did not improve PFS compared with durvalumab alone; however, a preplanned subgroup analysis suggested a PFS benefit among individuals with HRR alterations (median PFS, 5.6 months with olaparib/durvalumab, vs. 1.8 months with placebo/durvalumab; HR for progression or death, 0.18; 95% CI, 0.06 to 0.46).9 Combination durvalumab/olaparib therapy also was associated with significantly prolonged OS in the HRR altered subgroup but not in the intention-to-treat population. These findings were presented at ASCO GU 2022.
At the same meeting, we also saw interesting data from the randomized phase 2 ATLANTIS trial, in which maintenance treatment with the PARPi rucaparib after platinum-based chemotherapy produced a trend toward improved PFS among patients with at least a 10% loss of heterozygosity in genes associated with DNA repair deficiency and/or germline BRCA1 or BRCA2 alterations (hazard ratio for PFS, 0.53; 80 CI, 0.30-0.92; P = 0.07).10 This analysis included only 40 patients, but its findings, together with subgroup results from the BAYOU trial, spark some degree of enthusiasm for further investigations of PARPi in mUC. Also, the ongoing phase 1b/2 JAVELIN PARP Medley study (NCT03330405) evaluates different doses of avelumab plus the oral PARPi talazoparib in patients with locally advanced or metastatic solid tumors, including urothelial cancer. Findings for the mUC cohort have not yet been reported.
Several other studies of novel first-line mUC combinations are underway. These include Checkmate 901 (NCT03036098), which compares nivolumab/ipilimumab (a dual-CI regimen), nivolumab/platinum-based chemotherapy, and platinum-based chemotherapy alone; NILE (NCT03682068), in which patients receive durvalumab/platinum-based chemotherapy, two CIs (durvalumab and tremelimumab) plus platinum-based chemotherapy, or platinum-based chemotherapy alone; and EV302 (NCT04223856), which compares the antibody-drug conjugate enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy. In addition, the randomized phase 2 PRESERVE3 study (NCT04887831) explores the addition of the CD 4/6 inhibitor trilaciclib to platinum-based chemotherapy followed by avelumab maintenance therapy. This list is not exhaustive, but it highlights a few studies that are especially notable in the front-line setting.
Later-line treatment of mUC
Historically, second-line single-agent chemotherapy in mUC produces objective responses in only about 10% of patients.11-13 Fortunately, we now have high-level evidence supporting the use of more effective therapies. Those with robust data include the CI pembrolizumab, the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib, and the antibody-drug conjugates enfortumab vedotin-ejfv and sacituzumab govitecan-hziy.
The 542-patient Keynote-045 trial provides level 1 evidence for the use of pembrolizumab over vinflunine, paclitaxel, or docetaxel in eligible patients whose mUC has progressed or recurred after platinum-based chemotherapy.14 Although pembrolizumab did not significantly improve PFS in this study, it was associated with an approximately 3-month prolongation in the coprimary endpoint of OS (HR for death, 0.73, 95% CI 0.59-0.91), regardless of tumor PD-L1 expression. Pembrolizumab also was—and generally is—more tolerable than chemotherapy. The results of Keynote-045 led to the FDA approval of pembrolizumab for treating mUC that has progressed on or after platinum-based chemotherapy. As with all CIs, patients should be educated about and monitored for immune-related adverse events throughout the course of treatment.
Erdafitinib is a small-molecule FGFR inhibitor and the first targeted therapy to be approved in mUC. In the single-arm, phase 2 BLC2001 trial of erdafitinib monotherapy in 101 patients with prespecified FGFR activating mutations or fusions, the objective response rate (ORR) was 40%, median duration of response was 6 months, median PFS was 5.5 months, and median OS was 11.3 months.15 These findings led to an accelerated FDA approval and a breakthrough therapy designation in April 2019. The FDA simultaneously approved an FGFR RGQ RT-PCR companion diagnostic kit to identify candidates for erdafitinib therapy. In support of a full FDA approval, the currently enrolling, randomized, phase 3 THOR study is comparing second or later-line erdafitinib with chemotherapy (vinflunine or docetaxel) or pembrolizumab in patients with selected FGFR mutations.16 Primary results are expected in 2024. The most common grade 3 or higher toxicities with erdafitinib therapy are onycholysis, stomatitis, and palmar-plantar erythrodysesthesia syndrome. Patients also should be monitored for hyperphosphatemia while on treatment.
Nectin-4 is a transmembrane adhesion molecule that is expressed in the majority of urothelial carcinomas. Enfortumab vedotin, an anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE), is approved by the FDA for the second or later-line treatment of mUC in platinum-ineligible patients and patients who have previously received a CI and platinum-based chemotherapy. In the single-arm, phase 2 EV 201 study of 89 cisplatin-ineligible patients whose mUC had progressed on first-line CI treatment, enfortumab vedotin achieved an impressive ORR of 52%, including a complete response rate of 20% and a partial response rate of 31%.17 Building on these findings, the randomized phase 3 EV 301 study evaluated third-line enfortumab vedotin in patients who had received both platinum-based chemotherapy and a CI. Enfortumab vedotin improved OS by a median of approximately 4 months (HR for death, 0.70; 95% CI, 0.56 to 0.89) and PFS by a median of approximately 1.84 months (HR for progression or death, 0.62; 95% CI, 0.51-0.75) when compared with chemotherapy with docetaxel, vinflunine, and paclitaxel.18
Enfortumab vedotin has a distinct toxicity profile characterized by lower rates of cytopenias and increased risk for neuropathy, potentially severe hyperglycemia, and rash—including, in rare cases, Stevens-Johnson syndrome/toxic epidermal necrolysis, a known on-target toxicity due to nectin-4 expression in the skin. Patients receiving enfortumab vedotin should be educated about and monitored for hyperglycemia and cutaneous toxicities, with early involvement of endocrinology and dermatology as needed. As always, the choice of oncolytic(s) should be based on shared decision-making that incorporates overall performance status, comorbidities, prior treatment history, individual drug toxicity profiles, the level of evidence from relevant studies, and patient preference.
Sacituzumab govitecan-hziy (sacituzumab) targets a transmembrane glycoprotein known as TROP-2 that is upregulated in urothelial carcinoma and many other types of cancer. The multicohort, phase 2, open-label TROPHY-U-01 study (NCT03547973) evaluated sacituzumab monotherapy in patients who had progressed after platinum-based chemotherapy and a CI.19 The ORR was 27% and median OS was 10.9 months, which is noteworthy considering the heavily pretreated nature of this population—it is likely that many participants had already received erdafitinib or enfortumab. These findings led to the accelerated FDA approval of sacituzumab for treating mUC in post-platinum patients who had also previously received a PD-1 or PD-L1 inhibitor.
Cohort 3 of the TROPHY trial combined sacituzumab with pembrolizumab in platinum-experienced patients who were naïve to CI therapy; interim findings presented at ASCO GU 2022 included an ORR of 34% after a median follow-up time of approximately 6 months.20 The most common grade 3 or higher toxicities were diarrhea, anemia, and febrile neutropenia, in line with the individual safety profiles of these two therapies. These results are not practice-altering, but they are intriguing and deserve further investigation, particularly considering the heavily pretreated nature of the TROPHY population. Currently, the phase 3, randomized multicenter, TROPiCS-04 study (NCT04527991) is comparing sacituzumab with investigator’s choice of non-platinum, single-agent chemotherapy in patients whose mUC has progressed after platinum-based and CI therapies.21
The CIs avelumab and nivolumab also are FDA-approved for treating mUC that progresses during or after platinum-based chemotherapy, and both these therapies are being evaluated as part of combination regimens in the later-line mUC setting. At ASCO GU 2022, we saw data from a small phase 1b study that combined nivolumab with fam-trastuzumab deruxtecan-nxki in patients whose HER2-expressing mUC had progressed on or after platinum-based chemotherapy.22 The reported ORR was nearly 37%, but almost one-third of patients stopped treatment due to adverse events, including pneumonitis, a known toxicity of both agents. The currently recruiting phase 3 randomized MAIN-CAV study (NCT05092958) explores the addition of the tyrosine kinase inhibitor cabozantinib to avelumab in platinum-experienced patients with mUC.23
With respect to combinations of targeted therapies, a currently recruiting phase 1b trial (NCT04963153) is evaluating third-line treatment with erdafitinib plus enfortumab vedotin in patients with mUC and FGFR2/3 alterations who previously have received platinum-based chemotherapy and CI therapy.24 Primary results are anticipated next year. Researchers also are evaluating RC48 (disitamab vedotin), a novel antibody-drug conjugate that targets HER2. In 2020, the FDA granted disitamab a breakthrough therapy designation in mUC based on the results of a small phase 2 study of disitamab monotherapy in patients who had progressed on at least one prior line of systemic therapy.25 Objective response rates were 60.5% overall and 70.6% among patients with HER2 positivity on fluorescent in situ hybridization or immunohistochemistry. The toxicity profile was regarded as acceptable, and most adverse events were graded as 1 or 2. Another phase 2 study (NCT04879329) of disitamab in HER2-expressing mUC is recruiting; patients will receive disitamab alone or in combination with pembrolizumab.
Immune checkpoint inhibitors, kinase inhibitors, and antibody-drug conjugates are rapidly altering the treatment landscape for patients with advanced and metastatic urothelial cancer. Patients who are post-platinum or platinum-ineligible particularly stand to benefit, but these treatments are likely to be used more broadly in the future, including as alternatives to platinum-based chemotherapy or in earlier-stage disease. Current and planned studies should help elucidate which novel agents, combinations, and biomarkers show the greatest potential for use in the clinic. Given the increasing range of approved treatment options in mUC, it is crucial to pursue shared decision making based on a thoughtful consideration of patient and tumor characteristics as well as the toxicity profile and level of evidence for each treatment.
Written by: Petros Grivas, MD, Ph.D., Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 1.2022 – February 11, 2022.
- 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.
- Gupta S, Sonpavde G, Grivas P, et al. Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). J Clin Oncol. 2019;7_suppl:451-451.
- Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
- 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.
- Loriot Y, Grivos P, De Wit R, et al. First-line pembrolizumab (pembro) with or without lenvatinib (lenva) in patients with advanced urothelial carcinoma (LEAP-011): A phase 3, randomized, double-blind study. J Clin Oncol. 2022;40(6_suppl):432-432.
- Grivas P, Loriot Y, Morales-Barrera R, et al. Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS). BMC Cancer. 2021;21(1):593.
- Powles T, Carroll D, Chowdhury S, et al. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med. 2021;27(5):793-801.
- Rosenberg JE, Park HS, Dao TV, et al. BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC). J Clin Oncol. 2022;40:6_suppl:437-437.
- Crabb SJ, Hussain SA, Soulis E, et al. A randomized, double blind, biomarker selected, phase II clinical trial of maintenance PARP inhibition following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS rucaparib arm. J Clin Oncol. 2022;40(6_suppl):436-436.
- Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27:4454-4461.
- McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15:1853-1857.
- Vaughn DJ, Broome CM, Hussain M, et al. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002;20:937-940.
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
- Siefker-Radtke AO, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma (mUC): Long-term outcomes in BLC2001. J Clin Oncol. 2020;38(15_suppl):5015-5015.
- Siefker-Radtke AO, Imkamp F, Necchi A, et al. A phase 3 study of erdafitinib compared with vinflunine or docetaxel or pembrolizumab in patients with metastatic or surgically unresectable urothelial carcinoma and selected FGFR gene alterations. Poster presented at: The 70th Congress of the German Society of Urology (DGU); September 26-29, 2018; Dresden, Germany.
- Yu EY, Petrylak DP, O'Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):872-882.
- 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.
- 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 platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485.
- Grivas P, Poussel D, Chandler HP. TROPHY-U-01 cohort 3: sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. J Clin Oncol. 2022;40(6_suppl):434-434.
- Grivas P, Tagawa ST, Bellmunt J, et al. TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy. J Clin Oncol. 2021;39(6_suppl):TPS498.
- Galsky MD, Del Conte G, Foti S, et al. Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC). J Clin Oncol. 2022;40(6_suppl):438-438.
- Gupta S, Ballman KV, Galsky MD, et al. MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients with metastatic urothelial cancer (mUC) (Alliance A032001). J Clin Oncol. 2022;40(16_suppl): TPS4607-TPS4607.
- Jain RK, Kim Y, Rembisz J, et al. Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs). J Clin Oncol. 2022;40(6_suppl): TPS595- TPS595.
- Sheng X, Zhou AP, Shi Y, et al. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2019;37(15_suppl):4509-4509.
Published Date: June 2022