Abstract
Background
The addition of immune checkpoint inhibitors (ICIs) and antibody–drug conjugates into the metastatic urothelial cancer (mUC) treatment landscape has advanced therapeutic strategies beyond platinum-based chemotherapy (PBT). We evaluated real-world treatment patterns and overall survival (OS) among mUC patients during the period between maintenance avelumab (maintA) and enfortumab vedotin plus pembrolizumab approvals in the United States.
Materials and methods
This retrospective cohort study utilized structured and chart review data from iKnowMed, a United States community oncology electronic health record database, to identify adult mUC patients initiating first-line (1L) anticancer treatment (index date) between April 2020 and September 2022. Patients were followed from the index date until March 2023, the last patient visit, or death, whichever occurred first. Descriptive statistics were used to report treatment patterns. Kaplan–Meier methods were used to assess OS.
Results
A total of 597 patients initiated 1L treatments (ICI monotherapy: 47.9%, PBT: 40.7%, other: 11.4%). The median age at diagnosis was 74 years, and 76.9% were male. Among patients receiving 1L PBT, 39.5% received maintA. Among those who were not on prior treatment at the end of the follow-up, 32.7% and 11.3% of 1L-treated patients received second-line and third-line treatment. The median OS from the index date for 1L-treated patients was 11.8 months (95% confidence interval 10.4-14.2 months).
Conclusions
Despite the approval of maintenance therapy, prognoses for mUC patients remained poor. ICI monotherapy continues to be a common option in 1L. Many 1L patients did not have an opportunity to receive subsequent treatment, highlighting the continuing unmet need for mUC patients.
Key words: metastatic urothelial cancer, maintenance therapy, treatment patterns, overall survival, avelumab
Highlights
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Immunotherapy is often selected (48%) to treat mUC.
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Immunotherapy is preferentially used (60%) for older adults (aged 75+ years).
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Real-world use of maintA post-platinum chemotherapy is modest (40%).
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Less than one-third received any subsequent therapy after 1L treatment.
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mUC patients have poor OS, highlighting continuing unmet need.
Introduction
Bladder cancer is the 10th most common type of cancer globally, with incidence and mortality rates of 3.1% and 2.3%, respectively.1 The prognosis for patients with metastatic urothelial carcinoma (mUC) is particularly poor, with the 5-year overall survival (OS) estimated to be <10%.2 Recently, the integration of immune checkpoint inhibitors (ICIs) and antibody–drug conjugates into the treatment paradigm for mUC represents a significant advancement beyond platinum-based chemotherapy (PBT). In June 2020, the United States Food and Drug Administration (FDA) approved avelumab as a first-line (1L) maintenance treatment for patients whose disease had not progressed on 1L PBT, based on results from the JAVELIN Bladder 100 trial.3 Subsequently, the treatment landscape underwent a further transformation with the FDA’s accelerated approval of enfortumab vedotin plus pembrolizumab (EV + P) in April 2023 for 1L cisplatin-ineligible patients,4 followed by full approval in December 2023 for all 1L patients.5 In March 2024, the FDA approved nivolumab (Opdivo) in combination with frontline cisplatin and gemcitabine for 1L cisplatin-eligible patients. These options have been reflected in the latest National Comprehensive Cancer Network (NCCN) guideline.6
Given the rapid changes in the treatment landscape, a better understanding of the comprehensive treatment strategies for patients with mUC in a real-world setting is important. We described the real-world treatment patterns and OS among mUC patients within the United States community oncology setting following the approval of maintenance avelumab (maintA), but before the accelerated approval of EV + P in April 2023.
Materials and methods
Data source
The US Oncology Network’s electronic health record (EHR) system, iKnowMed (iKM), includes over 1.2 million patients treated annually by 1400 affiliated physicians operating in >450 geographically diverse community-based outpatient practices throughout the United States. Structured iKM data, supplemented with unstructured data on patients’ treatment history and physician-assessed response abstracted from medical charts, were analyzed. The Social Security Administration’s Death Master File (LADMF) and other publicly available death record data were used to supplement data available in iKM with respect to vital status and death date. This study was granted an exception and waiver of informed consent by The US Oncology Inc. Institutional Review Board.
Study design and population
This retrospective observational cohort study included adult (≥18 years of age) patients with a documented diagnosis of mUC, which included patients with stage IV disease at initial diagnosis and patients diagnosed with earlier stages who later developed evidence of metastatic disease. Patients initiating 1L treatments between 30 April 2020 and 30 September 2022 were included (Figure 1). The index date was defined as the date of initiation of 1L treatment after the confirmed diagnosis of mUC. Patients were excluded if they had less than two vital visits (i.e. physical encounters with the practice, detected by vital sign records) observed after the index date to demonstrate a continuity of care within The US Oncology Network, were enrolled in interventional clinical trials, or received treatment for other documented primary cancer diagnoses (except for basal cell carcinoma of the skin, squamous-cell carcinoma of the skin, or cervical carcinoma in situ) during the study observation period. Patients were initially identified through eligibility criteria available in structured fields of the EHR and then all patients underwent a targeted chart review to confirm their eligibility. Eligible patients were followed longitudinally through the end of the study observation period (31 March 2023), or until date of last visit or death, whichever occurred first.
Figure 1.
Study design. X = additional visit at qualifying US Oncology Network clinic or record of death. aLast visit = last physical encounter.
Study variables
Patient characteristics
Structured data are available for demographic characteristics, including age, sex, race, and practice location, and most clinical characteristics such as cancer stage, histology, body mass index (BMI), tobacco use, Eastern Cooperative Oncology Group (ECOG) performance status, and creatinine clearance. Documentation of muscle invasion, de novo metastatic status, presence of visceral metastases, selected comorbidities, and Charlson Comorbidity Index (CCI) were obtained from chart abstraction. Age, documentation of muscle invasion, and de novo metastatic status were captured at diagnosis, and other demographic and clinical characteristics were assessed at baseline (i.e. within 6 months before the index date).
Treatment patterns
Treatment patterns included the distribution and sequence of regimens received in the metastatic setting. To establish line of therapy sequencing, the first systemic treatment regimen received after the initial mUC diagnosis was considered as 1L. The treatment line was advanced to the next line when there was a provider-documented disease progression, as noted during the chart review. Maintenance therapy was identified based on explicit documentation in physician notes or records, administered after the completion of 1L PBT, and without evidence of disease progression.
OS
OS was defined as the interval between the index date and the date of death due to any cause. Patients who did not die within the study observation period were censored at the end of study observation period or the last visit date, whichever occurred first.
Data management and quality control
Structured data were extracted through programmatic queries of the iKM EHR data and an external repository of mortality data. Chart abstractors with oncology research experience received specialized study-specific training to manually capture additional information contained in unstructured EHR fields. The process of chart abstraction was executed with a 21 CFR Part 11-compliant electronic data capture system, OpenClinica, which employed skip logic and error flags to standardize data entry. The data were subsequently exported for quality checks, and any uncertainties during chart reviews were resolved through a standardized procedure, involving escalation to senior study members as needed.
Quality control measures were integrated into all phases of data collection and analysis, utilizing a statistical sampling approach to identify and correct errors. Note, given the retrospective and observational design of the study, follow-up with treating providers was not possible. Instead, potential data errors underwent source data verification to ensure accuracy, and a quality control metric report was compiled to evaluate accuracy rates. Variables with success rates <80% prompted additional abstractor training. Finally, analytic quality control checks were conducted on the final dataset to identify and amend any inaccuracies, to promote the reliability and integrity of the study findings.
Statistical analysis
We conducted descriptive analyses to summarize demographic and clinical characteristics for patients overall and stratified by 1L treatment categories (ICI monotherapy, PBT, and others). Continuous variables were described using mean, standard deviation, median, and interquartile range (IQR). Categorical variables were described by patient counts and percentages. Treatment patterns were summarized descriptively using patient counts and percentages, stratified by 1L treatment category. All cell counts with fewer than five patients were suppressed (reported as <5 in Table 1) due to data privacy regulations. OS was estimated using the Kaplan–Meier product limit method, overall and stratified by 1L treatment categories. We assessed median survival times with 95% confidence intervals (CIs) and survival probabilities (with 95% CIs) at 6, 12, 18, and 24 months. All statistical analyses were carried out using SAS v.9.4 (SAS Institute Inc, Cary, NC) with a priori significance level of P value of <0.05.
Table 1.
Characteristics of patients diagnosed with mUC initiating 1L treatment
| Characteristics | Overall (n = 597) |
ICI monotherapy (n = 286) | PBT ± maintA (n = 243) | Other treatments (n = 68) | P value |
|---|---|---|---|---|---|
| Age at diagnosis (years) | <0.0001 | ||||
| Mean (SD) | 73.6 (10.1) | 76.5 (10.2) | 71.0 (8.9) | 70.8 (10.2) | |
| Median (IQR) | 74 (67-80) | 77 (70-83) | 71 (65-77) | 70 (65-77) | |
| Age at diagnosis (years), n (%) | <0.0001 | ||||
| <65 | 111 (18.6) | 40 (14.0) | 55 (22.6) | 16 (23.5) | |
| 65-74 | 211 (35.3) | 82 (28.7) | 103 (42.4) | 26 (38.2) | |
| 75+ | 275 (46.1) | 164 (57.3) | 85 (35.0) | 26 (38.2) | |
| Sex, n (%) | 0.4762 | ||||
| Female | 138 (23.1) | 66 (23.1) | 60 (24.7) | 12 (17.6) | |
| Male | 459 (76.9) | 220 (76.9) | 183 (75.3) | 56 (82.4) | |
| Race, n (%)a | 0.6168 | ||||
| White or Caucasian | 439 (89.4) | 212 (90.2) | 173 (87.8) | 54 (91.5) | |
| Other race | 52 (10.6) | 23 (9.8) | 24 (12.2) | 5 (8.5) | |
| Not documented | 106 | 51 | 46 | 9 | |
| Practice region, n (%) | 0.6536 | ||||
| Midwest/northeast | 201 (33.7) | 92 (32.2) | 86 (35.4) | 23 (33.8) | |
| South | 208 (34.8) | 108 (37.8) | 76 (31.3) | 24 (35.3) | |
| West | 188 (31.5) | 86 (30.1) | 81 (33.3) | 21 (30.9) | |
| BMI (kg/m2) | 0.0001 | ||||
| Mean (SD) | 26.5 (5.3) | 25.5 (5.1) | 27.6 (5.4) | 26.8 (4.7) | |
| Median (IQR) | 25.5 (23.0-29.9) | 25.0 (22.3-28.2) | 26.6 (23.8-31.2) | 27.5 (22.4-30.4) | |
| BMI, n (%)a | 0.0007 | ||||
| Underweight/normal (≤24.9 kg/m2) | 203 (41.9) | 117 (49.2) | 65 (34.0) | 21 (37.5) | |
| Overweight (25-29.9 kg/m2) | 165 (34.0) | 83 (34.9) | 64 (33.5) | 18 (32.1) | |
| Obese (≥30 kg/m2) | 117 (24.1) | 38 (16.0) | 62 (32.5) | 17 (30.4) | |
| Not documented | 112 | 48 | 52 | 12 | |
| Tobacco use, n (%)a | 0.1899 | ||||
| No history of tobacco use | 231 (41.2) | 117 (44.3) | 96 (41.2) | 18 (28.1) | |
| Current | 73 (13.0) | 30 (11.4) | 33 (14.2) | 10 (15.6) | |
| Former | 257 (45.8) | 117 (44.3) | 104 (44.6) | 36 (56.3) | |
| Not documented | 36 | 22 | 10 | 4 | |
| Provider documentation of muscle invasion, n (%)a | 0.1201 | ||||
| Yes | 290 (57.5) | 153 (61.9) | 104 (52.3) | 33 (56.9) | |
| No | 214 (42.5) | 94 (38.1) | 95 (47.7) | 25 (43.1) | |
| Not documented | 93 | 39 | 44 | 10 | |
| De novo metastatic status, n (%) | <0.0001 | ||||
| Yes | 203 (34.0) | 68 (23.8) | 118 (48.6) | 17 (25.0) | |
| No | 394 (66.0) | 218 (76.2) | 125 (51.4) | 51 (75.0) | |
| Presence of visceral metastases, n (%) | 0.8351 | ||||
| Yes | 294 (49.2) | 139 (48.6) | 123 (50.6) | 32 (47.1) | |
| No | 303 (50.8) | 147 (51.4) | 120 (49.4) | 36 (52.9) | |
| ECOG performance status, n (%)a | 0.0109 | ||||
| 0-1 | 244 (82.4) | 112 (74.7) | 103 (92.8) | 29 (82.9) | |
| 2+ | 52 (17.6) | 38 (25.3) | 8 (7.2) | 5 (14.3) | |
| Not documented | 301 | 136 | 132 | 33 | |
| Creatinine clearance (ml/min) | <0.0001 | ||||
| Patients with available data | 241 | 112 | 102 | 27 | |
| Mean (SD) | 60.8 (29.1) | 52.6 (25.0) | 69.0 (30.7) | 63.6 (30.4) | |
| Median (IQR) | 52.4 (41.6-72.4) | 46.6 (37.2-61.1) | 61.2 (47.7-82.5) | 56.2 (40.9-79.2) | |
| Comorbidities, n (%)b | |||||
| Renal disease | 142 (39.9) | 82 (44.3) | 40 (30.3) | 20 (51.3) | 0.0130 |
| Chronic obstructive pulmonary disease | 109 (30.6) | 63 (34.1) | 34 (25.8) | 12 (30.8) | 0.2870 |
| Cerebrovascular disease | 49 (13.8) | 27 (14.6) | 19 (14.4) | 3 (7.7) | 0.5547 |
| Congestive heart failure | 39 (11.0) | 25 (13.5) | 12 (9.1) | 2 (5.1) | 0.2492 |
| Diabetes mellitus | 106 (29.8) | 52 (28.1) | 38 (28.8) | 16 (41.0) | 0.2634 |
| Diabetes with sequelae | 21 (5.9) | 11 (5.9) | 8 (6.1) | 2 (5.1) | 1.000 |
| History of myocardial infarction | 28 (7.9) | 15 (8.1) | 11 (8.3) | 2 (5.1) | 0.9196 |
| Peripheral vascular disease | 72 (20.2) | 34 (18.4) | 32 (24.2) | 6 (15.4) | 0.3202 |
| Modified CCI, n (%) | 0.0643 | ||||
| 0 | 241 (40.4) | 101 (35.3) | 111 (45.7) | 29 (42.6) | |
| 1-2 | 242 (40.5) | 123 (43.0) | 96 (39.5) | 23 (33.8) | |
| 3+ | 114 (19.1) | 62 (21.7) | 36 (14.8) | 16 (23.5) | |
| Follow-up duration (months) | 0.0615 | ||||
| Median (95% CI) | 13.1 (11.4-15.6) | 11.0 (8.9-14.4) | 16.4 (13.0-19.0) | 12.9 (9.9-19.1) |
1L, first-line; CCI, Charlson Comorbidity Index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; IQR, interquartile range; maintA, maintenance avelumab; mUC, metastatic urothelial carcinoma; PBT, platinum-based chemotherapy; SD, standard deviation.
Percentages and P values are calculated among patients with non-missing data.
Charlson comorbidities with <5% were not included in the table. This included acute myocardial infarction, dementia/Alzheimer disease, human immunodeficiency virus/acquired immunodeficiency syndrome, mild liver disease, paralysis, peptic or gastric ulcer, and rheumatic or connective tissue.
Results
Demographics and clinical characteristics for the overall population
Among overall 597 mUC patients initiating 1L anticancer treatments (flow diagram of study cohort derivation described in Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2024.100110), the median (IQR) age was 74 years (67-80 years) at mUC diagnosis. Most (76.9%) were male, 89.4% were Caucasian, and many (60%) had comorbidities. Visceral metastases were present in 294 (49.2%) patients, and 203 (34.0%) had de novo disease at diagnosis. The median duration of follow-up from index date was 13.1 (95% CI 11.4-15.6) months (Table 1).
1L treatment patterns
Among all 1L-treated mUC patients, 286 (47.9%) received ICI monotherapy, 243 (40.7%) received PBT (with or without maintA), and the remaining 68 (11.4%) patients received other treatments (including ICI–chemotherapy combinations, non-platinum-based single-agent or combination chemotherapies; Figure 2). Among 243 1L PBT-treated patients, 99 (41%) received cisplatin-based regimens, 131 (54%) received carboplatin-based regimens, and 13 (7.6%) received other platinum-based regimens; 96 (39.5%) received maintA after 1L PBT. The most common treatments among the 286 1L ICI monotherapy-treated patients were pembrolizumab (85.3%) and atezolizumab (13.3%).
Figure 2.
1L treatment patterns for mUC patients following maintA approval (n = 597).a 1L, first-line; ICI, immune checkpoint inhibitor; maintA, maintenance avelumab; mUC, metastatic urothelial cancer; PBT, platinum-based therapy. aThis includes patients diagnosed from May 2020 to September 2022, with follow-up until March 2023, last patient record, or death, whichever occurred first. Among 1L PBT-treated patients, six received maintenance pembrolizumab or maintenance atezolizumab. Other treatments included other chemotherapy, ICI–chemotherapy combination, and non-chemotherapy/non-ICI treatments.
Patients receiving 1L ICI monotherapy were older (median age 77 versus 71 years) and had lower BMI (median BMI 25.0 versus 26.6 kg/m2) compared with patients receiving 1L PBT (with or without maintA). Additionally, a greater proportion of patients who received 1L ICI monotherapy had recurrent versus de novo mUC (76.2% versus 51.4%), comorbidities (64.7% versus 54.3%), and renal disease (44.3% versus 30.3%) compared with those who received 1L PBT (with or without maintA; Table 1).
The use of 1L ICI monotherapy increased with age, ranging from 36% among those aged <65 years to 60% among those ≥75 years of age. Additionally, 1L ICI monotherapy use constituted the majority of anticancer treatments utilized for those with a modified CCI ≥3 (54% versus 42% for a CCI of 0; Figure 3).
Figure 3.
1L treatment patterns for mUC patients following maintA approval by baseline age category and modified Charlson Comorbidity Index. 1L, first-line; ICI, immune checkpoint inhibitor; maintA, maintenance avelumab; mUC, metastatic urothelial cancer; PBT, platinum-based therapy.
Treatment sequencing post-1L treatments
Of all 597 1L-treated patients, 47 patients were continuing 1L treatment and 37 patients were continuing second-line (2L) treatment at the end of the study period, and therefore were ineligible for subsequent treatment. Among those who were not on prior treatment at the end of follow-up, 32.7% (n = 180 out of 550) and 11.3% (n = 58 out of 513) of 1L-treated patients received 2L and third-line (3L) treatments, respectively (data not shown). Overall, the most common 2L treatments were EV monotherapy (39.4%) and pembrolizumab monotherapy (27.8%), and the most common 3L treatments were EV monotherapy (39.7%) and sacituzumab govitecan (20.7%). Subsequent treatment patterns for patients who initiated selected 1L treatments following maintA approval are presented (Figure 4).
Figure 4.
Subsequent treatment patterns for patients diagnosed with mUC initiating selected 1L treatments following maintA approval.a 1L, first-line; 2L, second-line; 3L third-line; EV, regimens containing enfortumab vedotin; ICI, immune checkpoint inhibitor; maintA, maintenance avelumab; mUC, metastatic urothelial cancer; PBT, platinum-based therapy; SG, sacituzumab govitecan. aSeventy-four patients who received treatments other than 1L ICI monotherapy or PBT were omitted from this diagram to present the most commonly observed treatment sequences more fully. Patients who were continuing 1L/2L treatment at the end of the study period were included in the figure within the ‘no treatment’ group for 2L/3L treatment.
Clinical outcomes
Of all 597 1L-treated mUC patients, 317 (53.1%) died during the follow-up. The median OS (mOS) among all 1L-treated patients was 11.8 months (95% CI 10.4-14.2 months), with a 24-month survival probability of 32.3% (95% CI 27.4% to 37.4%). The mOS was 9.9 months (95% CI 7.7-12.9 months) for ICI monotherapy and 14.5 months (95% CI 11.5-17.1 months) for PBT (Figure 5 and Supplementary Table S1, available at https://doi.org/10.1016/j.esmorw.2024.100110).
Figure 5.
Kaplan–Meier estimates of OS for patients diagnosed with mUC initiating 1L treatments. 1L, first-line; CI, confidence interval; ICI, immune checkpoint inhibitor; maintA, maintenance avelumab; mUC, metastatic urothelial cancer; OS, overall survival; PBT, platinum-based therapy.
Discussion
We evaluated treatment patterns and OS among 1L mUC patients following the United States approval of maintA, but before 1L approvals of both EV + P and nivolumab in combination with cisplatin and gemcitabine, with several notable findings. ICI monotherapy and PBT were the primary treatment options in 1L. This study and previous studies7,8 suggest a modest uptake of maintA in the United States community oncology settings: around 25%-40% among 1L PBT-treated mUC patients. Previously, we reported that ICI monotherapy constituted the majority of systemic treatments utilized in the 1L setting for those aged ≥75 years and for those with poor ECOG status during the post-immunotherapy era (and before maintA became available).9 Similarly, ICI monotherapy continued to fill the therapeutic gap in 1L mUC patients after maintA approval, especially for older and/or frail patients presenting with comorbidities. Although EV or P is commonly used after 1L treatment, only one-third of 1L-treated patients went on to receive 2L treatments, consistent with previous reports (ranging from 34% to 39%).10, 11, 12, 13, 14 This indicates a low chance that patients may receive 3L treatments. The mOS for 1L mUC patients overall and by treatment options was consistent with previous reports and patient prognoses remained poor. These findings highlight the high unmet need for more effective and tolerable treatments in the 1L setting. The recent approval of EV + P in 1L represents a major advance in meeting this need.
Our study had several limitations. The iKM EHR database is used for clinical practice purposes and not designed specifically for research; therefore, data standardization collection methods and instruments could be influenced by physician reporting practices. Practices within The US Oncology Network may not be generalizable to academic practices. Future research is warranted to provide critical insight into the real-world evolution of practice patterns and clinical outcomes after 1L approvals of EV + P15,16 and nivolumab in combination with cisplatin and gemcitabine.17,18 This study has several strengths, including robust sample size (n = 597), a nearly 3-year study period that enabled us to describe the changing treatment landscape from 1L United States approval of maintA to right before 1L EV + P accelerated approval, and the comprehensive data captured by the iKM EHR database on clinical characteristics (such as cancer staging and histology) and patient care, particularly with patient eligibility and maintA use confirmed via chart review based on physician notes and records.
Conclusions
The prognoses remain poor for mUC patients, and even after maintA became available, ICI monotherapy continues to be a prevalent option in 1L, especially for older patients and those presenting with comorbidities. The uptake of maintA has been modest among 1L PBT-treated patients. Many 1L-treated mUC patients do not have an opportunity to receive 2L+ treatment, continuing to demonstrate a high unmet need for more effective and tolerable treatments in the 1L setting. ICIs have become central in 1L, and future studies will help understand their utilization patterns and impact on patient survival in this evolving landscape.
Acknowledgments
Funding
This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) (no grant number). The sponsor participated in the study design, the interpretation of the data, the writing of the manuscript, and the decision to submit the article for publication. The sponsor had no role in the collection and analysis of the data.
Disclosure
HL, AB, SF, and PS are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. SS, LH, JG, and PC are employees of Ontada, a company that has provided paid services to MSD. PC has received grant funding from Pfizer, BMS, MSD, and Aptos. RM has received grant funding (to institution) from MSD and Astellas, and consulting fees from MSD, BMS, and Seagen. MB has received consulting fees from MSD, AstraZeneca, Xencor, Pfizer, Agendia, Exelixis, and Janssen, and reports a leadership or fiduciary role with Exelixis.
Supplementary data
References
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