Temporal changes in treatment patterns by age group and functional status before and after PD-1/L1 inhibitor approvals in advanced urothelial carcinoma

Introduction Metastatic urothelial carcinoma (mUC) has poor prognosis. A high unmet need exists for novel treatment for those who are unfit for platinum-based chemotherapy. Methods We aimed to describe real-world temporal changes in patient characteristics and 1L treatment selection for mUC patients in the United States following the approval of anti-PD-1/L1 treatments. This study was a retrospective, observational study using anonymized and structured oncology electronic medical record (EMR) data from IQVIA and the US Oncology Network iKnowMed (USON). Results After approval of 1L anti-PD-1/L1 treatment for mUC, there is a marked increase in the use of 1L anti-PD-1/L1 monotherapies, accompanied by a proportional decrease in 1L platinum-based treatments and non-guideline-based therapy; particularly among the elderly (> 75 years) and those with poor ECOG performance status (ECOG PS 2+). Discussion Anti-PD-1/L1 monotherapies fulfill the prior unmet need of frail mUC patients who are ineligible for platinum-based therapies.


Introduction
Metastatic urothelial carcinoma (mUC) disproportionately affects the elderly and typically is incurable, poor prognosis.Platinum-containing chemotherapy remains the first-line (1L) standard-of-care treatment for mUC patients (1).
Approximately 40-60% of 1L mUC patients are not eligible for cisplatin-based chemotherapy due to poor performance status (ECOG PS) or renal impairment (2)(3)(4).Many 1L mUC patients are not eligible for carboplatin-based chemotherapy, due to ageassociated comorbidity or medical frailty, or decline treatment due to perceptions of treatment-related toxicity (5).For platinumineligible mUC patients, no approved drug was available until the approval of anti-PD-1/L1 immuno-oncology (IO) treatments.As such, many 1L mUC patients were not offered any treatment or were treated with non-guideline-based therapies (2)(3)(4).
Pembrolizumab and atezolizumab were approved in 2017 and are currently recommended by The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer (v3.2023) (6) as monotherapies specifically in the setting of 1L cisplatin-ineligible (atezolizumab only for patients whose tumors express PD-L1) or platinum-ineligible patients (pembrolizumab and atezolizumab irrespective of PD-L1 status).Very limited prior data have described the impact of IO treatment availability on 1L treatment landscape among mUC patients.This study aimed to describe real-world temporal changes in patient characteristics and 1L treatment selection following the approval of anti-PD-1/L1 treatments for mUC.

Methods
This study was a retrospective, observational study using anonymized and structured oncology electronic medical record (EMR) data from IQVIA and the US Oncology Network iKnowMed (USON).IQVIA Oncology EMR contains data from multiple oncology specific EMR data sources across a consortium of health care provider locations in the US that include community practices, hospitals, and academic medical centers (>1.1 million oncology patients across 41 states).The US Oncology Network iKnowMed (USON) EMR is an oncology-specific system that captures outpatient community practice encounter history for patients under care within the US Oncology Network (~10% of newly diagnosed cancer patients in the US annually across 19 states and 480 sites).
The study included patients (≥18 years of age) with a diagnosis of mUC (during 01/01/2012-09/30/2020 in IQVIA EMR & 01/01/ 2010-09/30/2020 in USON) who had ≥2 visits and initiated 1L systemic anticancer therapy.Patients were excluded if they had a non-UC primary tumor (excepting non-melanoma skin cancer and in-situ or benign neoplasms).First-line systemic treatments were grouped as: cisplatin-based chemotherapy, carboplatin-based chemotherapy, anti-PD-1/L1 monotherapy (pembrolizumab, atezolizumab, and others), and other treatments (including noncarboplatin/non-cisplatin platinum-based chemotherapy, nonplatinum chemotherapy, anti-PD-1/L1combination with chemotherapy, and non-chemotherapy/non-immunotherapy treatment).The first regulatory approval of an anti-PD-1/L1 treatment for 1L advanced/metastatic UC occurred in April 2017.The analyses were conducted separately in two distinct time-periods (before and in/after April 2017) and included descriptive statistics of demographic and clinical characteristics, and 1L treatment choice, overall and by age and ECOG performance score at 1L treatment start.

Discussion
To our knowledge, this is the first study to evaluate the temporal changes in mUC patient characteristics and 1L treatment receipt following the approval of anti-PD-1/L1 treatments.We demonstrate, over the last decade, an increasing proportion of mUC patients older than 75 years of age and with ECOG PS of 2 or higher among those treated in the 1L setting, reflecting an older and frailer population.Further, after approval of 1L anti-PD-1/L1 treatment for mUC, there is a decrease in platinum-based treatments and non-NCCN recommended therapies as 1L treatment, and a marked increase in the use of anti-PD-1/L1 monotherapy.Finally, anti-PD-1/L1 monotherapy constituted the majority of systemic treatment starts in the 1L setting for patients 75 years of age or older and for those with ECOG PS 2 or higher.
mUC predominantly affects the elderly.Older patients are much more likely to present with increased comorbidities and decreased renal function, which may affect treatment choices and willingness to accept treatment toxicity.In this population, data from two large U.S. cohorts suggest that the anti-PD-1/L1 monotherapies are therapies of choice and fulfill a critical unmet need among older and frailer mUC patients who are ineligible for platinum-based therapies.This has several limitations.Data from USON and IQVIA EMR databases are mostly derived from community oncology practices and may not necessarily generalizable to the US population.A considerable group of patients had missing data on ECOG PS.Future studies with updated data are warranted to further understand the 1L changing landscape and outcomes for mUC patients.

Take home message:
This real-world evidence study suggests that recently approved immuno-oncology medications have filled a therapeutic gap in firstline advanced/metastatic urothelial cancer patients, especially for older and/or frail patients.

TABLE 1
Treatment pattern among 1L treated advanced urothelial carcinoma patients.