PD-1/L1 Inhibitors: Treatment Efficacy In Urothelial Carcinoma
Overview
Programmed cell death‐1/ligand 1 (PD-1/PD-L1) inhibitors represent a novel therapeutic approach for advanced urothelial carcinoma, prompting the need for a comparative assessment of their effectiveness and safety in comparison to traditional chemotherapy. To address this, a comprehensive meta-analysis of randomized controlled trials conducted until July 2021 was undertaken, involving an examination of various databases. The primary focus was on overall survival, while secondary outcomes included progression‐free survival, objective response rate, and treatment-related adverse events. The analysis, which encompassed 3584 patients across five studies, revealed that PD-1/PD-L1 inhibitors exhibited a statistically significant association with inferior progression‐free survival and adverse objective response rates when compared to first-line chemotherapy (p<0.001 for both). However, there was no statistically significant disparity in overall survival outcomes (p=0.33). Conversely, when juxtaposed with second‐line chemotherapy, PD-1/PD-L1 inhibitors demonstrated a significant enhancement in overall survival (p<0.001), with no notable differences in progression‐free survival (p=0.89) or objective response rate (p=0.34). Furthermore, PD-1/PD-L1 inhibitors exhibited favorable tolerability profiles compared to chemotherapy, regardless of whether they were employed as first-line or second-line treatments (p<0.001 for both).
Introduction
Bladder cancer poses a significant health burden, with a substantial number of new cases and deaths reported in 2020, primarily attributed to urothelial carcinoma (UC). Regrettably, the 5-year survival rate for locally advanced or metastatic UC remains dishearteningly low, emphasizing the urgency for improved therapeutic options. Cisplatin has long held the status of the most effective cytotoxic treatment for advanced UC; however, its development has stagnated over the past four decades, with no notable advancements in standard chemotherapy regimens. Moreover, second-line chemotherapy has yielded unsatisfactory outcomes, offering a median overall survival (OS) of only 5-7 months and minimal objective response rates. In response to these challenges, immunotherapy has emerged as a promising approach, garnering FDA approval for several programmed cell death-1/ligand 1 (PD-1/L1) inhibitors, such as atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab, particularly for patients who have experienced platinum-based chemotherapy failure. Some recent randomized clinical trials have, however, reported conflicting findings regarding the efficacy and safety of PD-1/L1 inhibitors. To address this disparity and provide guidance for clinical practice, a systematic review and meta-analysis were conducted, aiming to elucidate the comparative effectiveness and safety of PD-1/L1 inhibitors versus both first- and second-line chemotherapy in the treatment of advanced UC.
Methods
The inclusion criteria for the study encompassed several key aspects to ensure rigorous and relevant research selection. These criteria were as follows:
- Patient Demographics: Studies focused on patients with advanced urothelial carcinoma (UC) who received treatment with a PD-1/L1 inhibitor were considered.
- Study Design: Only Randomized Controlled Trials (RCTs) were eligible for inclusion, ensuring a high level of scientific rigor and reliability.
- Outcome Measures: Studies needed to report critical outcome data, including median Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), and information on Treatment-Related Adverse Events (TRAEs).
- Comparison Groups: Studies were required to include at least two treatment arms, specifically one for chemotherapy and another for immunotherapy with PD-1/L1 inhibitors. This criterion allowed for direct comparisons between the two treatment modalities.
- Language: Publications in English were included to facilitate data extraction and analysis.
Conversely, studies failing to meet these stringent inclusion criteria were excluded from the analysis. In instances where multiple publications reported on the same study population, preference was given to the most recent and comprehensive data source to ensure the accuracy and completeness of the analysis.
In addition to these inclusion and exclusion criteria, the quality of each included study was assessed meticulously. This evaluation employed the Cochrane Collaboration tool, which scrutinized various aspects of potential bias, such as sequence generation, completeness of outcome data, allocation concealment, selective outcome reporting, blinding of participants, personnel, and outcome assessors, as well as other sources of bias. This comprehensive quality assessment ensured that only studies with a high level of methodological rigor were incorporated into the final analysis, reinforcing the reliability and validity of the research findings.
Statistical Analysis
The meta-analysis incorporated several essential endpoints to evaluate the efficacy and safety of the treatments under scrutiny. These endpoints encompassed the following key measures:
- Median Overall Survival (OS): This parameter assessed the duration of survival among patients who received the different treatment modalities. It provided critical insights into the impact of PD-1/L1 inhibitors and chemotherapy on patients’ overall survival.
- Median Progression-Free Survival (PFS): PFS determined the length of time patients remained free from disease progression while undergoing treatment. It offered valuable information regarding the treatment’s ability to control the advancement of urothelial carcinoma.
- Objective Response Rate (ORR): ORR quantified the proportion of patients who exhibited a positive response to the treatments, indicating tumor regression or stabilization. This metric gauged the therapeutic efficacy of PD-1/L1 inhibitors and chemotherapy.
- Treatment-Related Adverse Events (TRAEs): TRAEs were meticulously examined to assess the safety profiles of the treatments. This encompassed monitoring the frequency and severity of adverse events associated with both PD-1/L1 inhibitors and chemotherapy.
To present these critical findings effectively, forest plots were employed as visual aids, offering a concise summary of survival data and dichotomous outcomes. The presentation of results was accompanied by 95% confidence intervals (CIs), which served to establish the precision and reliability of the reported findings.
Statistical heterogeneity among various studies was rigorously assessed using the two-sided Q-statistic and I2 test. Significance was attributed to p-values of ≤0.05, indicating substantial heterogeneity. To select the appropriate statistical model for data synthesis, two distinct models were considered:
- Fixed-Effects Model: This model was chosen in the absence of significant heterogeneity between studies. It assumed that the true effect size across all studies was constant.
- Random-Effects Model: When substantial heterogeneity was detected among studies, the random-effects model was employed. This model accounted for the variability in effect sizes between studies and provided a more conservative estimate of the treatment effects.
By systematically employing these analytical methods and statistical models, the meta-analysis ensured a robust and evidence-based assessment of the comparative outcomes and safety profiles of PD-1/L1 inhibitors versus chemotherapy in treating advanced urothelial carcinoma.
Results
The analysis encompassing data from five studies involving 3,584 patients evaluated several key aspects in the treatment of advanced urothelial carcinoma. Firstly, in terms of Median Overall Survival (OS), the results showed no statistically significant difference between immunotherapy and first-line chemotherapy (odds ratio [OR] = 0.94, 95% CI: 0.84–1.06, p= 0.33, I2= 0%). Further subgroup analyses for specific immunotherapy agents (durvalumab, atezolizumab, and pembrolizumab) also indicated no significant differences. In contrast, immunotherapy exhibited a significant improvement in OS compared to second-line chemotherapy (OR = 0.81, 95% CI: 0.71–0.92, p< 0.001, I2= 21%), with both pembrolizumab (OR = 0.73, 95% CI: 0.59 to 0.91, p= 0.004) and atezolizumab (OR = 0.85, 95% CI: 0.73–0.99, p= 0.04) subgroups demonstrating significant results.
Progression-Free Survival (PFS) data was derived from four studies, two each in the first- and second-line chemotherapy groups, encompassing 1,349 and 1,473 patients, respectively. PD-1/L1 inhibitors resulted in a significantly lower PFS than first-line chemotherapy (OR = 1.32, 95% CI: 1.15–1.51, p< 0.001, I2= 0%). This trend persisted regardless of whether durvalumab or pembrolizumab was used. However, there was no statistically significant difference in PFS when comparing PD-1/L1 inhibitors with second-line chemotherapy (OR = 0.99, 95% CI: 0.84–1.16, p= 0.89, I2= 0%), a result consistent with subgroup analyses.
For the Objective Response Rate (ORR) analysis, data from three studies in the first-line chemotherapy group and two studies in the second-line chemotherapy group were included, comprising a total of 2,105 and 1,465 patients, respectively. PD-1/L1 inhibitors exhibited a lower pooled ORR of 26.1% compared to 45.8% for first-line chemotherapy. Subgroup analyses demonstrated that each PD-1/L1 inhibitor had a significantly lower ORR than first-line chemotherapy (p< 0.001 for each subgroup). Conversely, the pooled ORR of PD-1/L1 inhibitors and second-line chemotherapy was 16.3% versus 12.4%, respectively (OR = 1.42, 95% CI: 0.69–2.92, p= 0.34, I2= 82%), with atezolizumab not significantly different from second-line chemotherapy, while pembrolizumab exhibited a higher ORR (OR = 2.08, 95% CI: 1.29–3.34, p= 0.002).
In terms of Treatment-Related Adverse Events (TRAEs), all studies reported data. PD-1/L1 inhibitors were associated with a significantly lower incidence of all-grade TRAEs (first-line chemotherapy: OR = 0.12, 95% CI: 0.09–0.16, p< 0.001, I2= 0%; second-line chemotherapy: OR = 0.22, 95% CI: 0.14–0.36, p< 0.001, I2= 61%) and grade 3/4+ TRAEs (first-line chemotherapy: OR = 0.05, 95% CI: 0.04–0.07, p< 0.001, I2= 93%; second-line chemotherapy: OR = 0.27, 95% CI: 0.21–0.34, p= 0.03, I2= 80%) compared with chemotherapy. Subgroup analyses also demonstrated consistent results. The most common TRAEs for patients receiving PD-1/L1 inhibitors were fatigue, pruritus, and anemia, whereas chemotherapy was associated with a greater risk of neutropenia and reductions in white blood cell and platelet counts.
Conclusion
This systematic meta-analysis represents the first comprehensive exploration of the merits and drawbacks of immunotherapy when compared to both first- and second-line chemotherapy in the context of advanced urothelial carcinoma (UC). The analysis drew from a cohort of 3,584 patients encompassing five well-structured Randomized Controlled Trials (RCTs), indirectly comparing various clinically relevant immunotherapy options. The study revealed several significant findings:
- Survival Outcomes: Immunotherapy with PD-1/L1 inhibitors did not show a statistically significant difference in Overall Survival (OS) compared to first-line chemotherapy, although it significantly improved OS when compared to second-line chemotherapy. Notably, PD-1/L1 inhibitors demonstrated a significant survival benefit in patients with advanced UC who had progressed after a platinum-containing regimen.
- Progression-Free Survival and Objective Response Rate: PD-1/L1 inhibitors resulted in a significantly lower Progression-Free Survival (PFS) and Objective Response Rate (ORR) when compared to first-line chemotherapy. However, when compared to second-line chemotherapy, PD-1/L1 inhibitors did not exhibit a statistically significant difference in PFS and ORR.
- Safety Profile: Immunotherapy with PD-1/L1 inhibitors was significantly better tolerated than both first- and second-line chemotherapy. All-grade Treatment-Related Adverse Events (TRAEs) were notably less frequent with PD-1/L1 inhibitors than with chemotherapy. Grade 3/4+ TRAEs were also less common in patients treated with PD-1/L1 inhibitors.
The study’s findings highlight the role of PD-1/L1 inhibitors in advanced UC treatment, where they demonstrate notable benefits in terms of OS compared to second-line chemotherapy. However, they do not exhibit superior OS to first-line chemotherapy. Importantly, the safety profile of immunotherapy is favorable, making it an attractive option for patients, especially when considering its tolerability in contrast to the cytotoxic effects of chemotherapy.
The study also sheds light on the potential of combination therapies, such as the combination of cytotoxic chemotherapy and immunotherapy, which has shown promise in improving survival rates. Additionally, targeted therapy combined with immunotherapy, such as FGFR inhibitors and PD-1/L1 inhibitors, is an emerging field with ongoing trials to maximize survival benefits for patients with advanced bladder cancer.
Despite the successes of immunotherapy, challenges remain in achieving a cure for cancer. A substantial proportion of patients do not respond to immunotherapy, and some may experience tumor progression after an initial response. Understanding the mechanisms of primary and secondary immune escape is crucial for developing targeted treatments. Safety considerations are also pivotal, with immunotherapy generally exhibiting a more favorable safety profile compared to chemotherapy.
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