The American Society of Clinical Oncology (ASCO) recently held its 2023 Genitourinary Cancers Symposium in San Francisco, California. The meeting focused on multidisciplinary approaches in genitourinary (GU) cancer treatment, research, and care. Highlights included new data in both localized and advanced urothelial carcinoma (UC). Herein are the latest results from clinical trials of first-line treatments in locally advanced or metastatic UC.

IMvigor130: Final Overall Survival Results With Atezolizumab Combo

The primary analysis of the phase III IMvigor130 trial showed a progression-free survival (PFS) benefit with first-line atezolizumab plus platinum chemotherapy/gemcitabine (Arm A) vs. placebo plus platinum chemotherapy (Arm C) in patients with locally advanced or metastatic UC. Interim data showed improved overall survival (OS) in Arm A; however, the threshold for significance was not crossed. Exploratory analysis indicated that OS was improved when atezolizumab was combined with cisplatin compared with carboplatin, regardless of PD-L1 status. At ASCO GU 2023, Enrique Grande, MD, PhD (MD Anderson Cancer Center Madrid, Madrid, Spain) presented the final OS data from Arm A and Arm C.

The median OS in Arm A was 16.1 months (95% CI: 14.2, 18.8) vs. 13.4 months (95% CI: 12.0, 15.3) in Arm C (HR, 0.85; 95% CI: 0.73, 1.00; P = 0.023). Despite the trend toward improved OS with atezolizumab plus platinum chemotherapy/gemcitabine, the pre-specified boundary for efficacy in patients with metastatic UC was not crossed (P = 0.021). The 2-year OS rate in Arm A was 38% (95% CI: 33.1, 42.4) vs. 32% (95% CI: 27.6, 37.2) in Arm C. The 3-year OS rate in Arm A was 26% (95% CI: 21.6, 30.0) vs. 22% (95% CI: 17.4, 26.0) in Arm C.

The trend toward improved OS continued when the atezolizumab regimen was combined with cisplatin vs. carboplatin. The HR with cisplatin was 0.76 (95% CI: 0.57, 1.01) vs. 0.89 (95% CI: 0.74, 1.08) with carboplatin. PD-L1 status did not differ significantly between the two subgroups; the authors suggest that further mechanistic investigations are warranted. No new safety signals were reported.

IMvigor130: Final OS Results with Atezolizumab Monotherapy

Arm B of the IMvigor130 trial consisted of patients with locally advanced or metastatic UC who received atezolizumab monotherapy. Two interim OS analyses from IMvigor130 had previously demonstrated a non-statistically significant OS benefit with atezolizumab monotherapy (Arm B) vs. placebo plus gemcitabine/platinum (investigator choice of carboplatin or cisplatin; Arm C) in patients with high PD-L1 expression on tumor-infiltrating immune cells (IC2/3). In an exploratory analysis of cisplatin-ineligible patients with PD-L1 IC2/3 tumors, atezolizumab monotherapy improved OS. At ASCO GU 2023, Aristotelis Bamias, MD, PhD (National and Kapodistrian University of Athens, Athens, Greece) presented final OS data comparing Arm B and Arm C.

Overall, in the intention-to-treat population, there was no OS benefit for patients who received atezolizumab monotherapy compared with patients who received chemotherapy: median OS was 15.2 months (Arm B; 95% CI: 13.1, 17.7) vs. 13.3 months (Arm C; 95% CI: 11.9, 15.6), respectively (HR, 0.98; 95% CI: 0.82, 1.16). The 2-year OS rates were 34% in Arm B and 32% in Arm C. Exploratory efficacy analysis suggested a clinical benefit with first-line atezolizumab monotherapy in cisplatin-ineligible patients with PD-L1 IC2/3 tumors: the median OS was 18.6 months vs. 10.0 months in Arm C (unstratified OS HR, 0.56; 95% CI: 0.34, 0.91). 

Atezolizumab showed a favorable tolerability profile compared with placebo plus chemotherapy, with no new safety findings. The authors suggest that the benefit-risk ratio of atezolizumab vs. chemotherapy supports the use of atezolizumab as first-line treatment for cisplatin-ineligible patients with PD-L1 IC2/3 metastatic UC.

JAVELIN Bladder 100: First-Line Avelumab for Advanced UC

As shown in the phase III JAVELIN Bladder 100 trial, avelumab first-line maintenance plus best supportive care (BSC) significantly extended OS and PFS vs. BSC alone in patients with advanced UC who had not progressed on first-line platinum chemotherapy. These results led to the approval of avelumab in many countries for this indication. At ASCO GU 2023, Srikala S. Sridhar, MD, MSc, FRCPC (Princess Margaret Cancer Centre, University Health Network, Toronto, Canada) presented post hoc data showing long-term outcomes after at least 2 years of follow-up in JAVELIN Bladder 100’s subgroups defined by their first-line chemotherapy regimen.

With a median follow-up of ≥38 months in both arms in subgroups treated with first-line cisplatin plus gemcitabine or carboplatin plus gemcitabine, OS and PFS were longer in the avelumab plus BSC arm than in the BSC alone arm. In the cisplatin subgroup, median OS was 25.1 months (95% CI: 19.3, 30.9) vs. a median OS of 17.5 months (95% CI: 13.7, 24.2) in the BSC group (HR 0.78 [95% CI: 0.607, 1.008]). In the carboplatin subgroup, the median OS was 20.8 months (95% CI: 17.9, 28.7), while the median OS was 13.0 months (95% CI: 9.4, 16.1) in the BSC group (HR 0.70 [95% CI: 0.523, 0.929]).

In the overall population, the median OS measured from the start of first-line chemotherapy was 29.7 months (95% CI: 25.2, 34.0) in the avelumab plus BSC arm and 20.5 months (95% CI: 19.0, 23.5) in the BSC alone arm (HR, 0.77 [95% CI: 0.635, 0.921]). The authors concluded that these results further support avelumab as the standard of care in patients with advanced UC who have not progressed following first-line platinum-based chemotherapy.

Immune Checkpoint Inhibitors (ICI) in the First-Line Treatment of Advanced UC

Andrea B. Apolo, MD (National Cancer Institute, Bethesda, Maryland, US) discussed the future of ICI in the first-line treatment of metastatic UC. She highlighted that trials investigating the combination of chemotherapy plus ICI as first-line treatment for patients with metastatic UC, such as IMvigor130 with atezolizumab (PD-L1 inhibitor) and KEYNOTE-361 with pembrolizumab (PD-1 inhibitor), have been negative for clinical benefit. She noted that ICI monotherapy is no longer an FDA-approved standard of care option for the first-line treatment of platinum-eligible patients. Dr. Apolo summarized that in the first-line setting for patients with metastatic UC most patients are able to receive platinum-based chemotherapy and, if they respond, they go on to receive maintenance avelumab. If the patient does not respond, second-line and beyond treatment may include pembrolizumab, nivolumab, avelumab, erdafitinib, enfortumab vedotin, or sacituzumab govitecan. Clinical trials are ongoing assessing the efficacy of antibody-drug conjugates (ADC) plus ICI vs. chemotherapy in the metastatic and neoadjuvant setting.