A new exploratory analysis of the phase III KEYNOTE-361 clinical trial has provided insights into potential biomarkers for predicting response to immunotherapy in patients with advanced urothelial carcinoma. The study, published on December 1, 2024 in Clinical Cancer Research, examined the association between tumor mutational burden (TMB), PD-L1 expression, and clinical outcomes in patients treated with pembrolizumab alone or in combination with chemotherapy versus chemotherapy alone.
KEYNOTE-361 was a randomized, open-label study conducted across 201 medical centers globally. Funded by Merck & Co., the trial enrolled 993 patients with locally advanced, unresectable, or metastatic urothelial carcinoma who had not received prior systemic treatment. Patients were randomized 1:1:1 to receive pembrolizumab monotherapy, pembrolizumab plus platinum-based chemotherapy, or chemotherapy alone.
The primary objective of this prespecified exploratory analysis was to evaluate the association of TMB and PD-L1 combined positive score (CPS) as continuous variables with clinical outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Secondary objectives included assessing outcomes based on prespecified cutoffs for TMB (≥175 mutations/exome) and PD-L1 CPS (≥10).
Of the 993 treated patients, 820 (82.6%) had evaluable TMB data and all 993 had evaluable PD-L1 CPS data. Baseline characteristics were generally well-balanced between treatment arms. The analysis revealed that TMB as a continuous variable was significantly associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively). For pembrolizumab plus chemotherapy, TMB was associated with PFS and OS (one-sided P = 0.007 and P = 0.010, respectively). In the chemotherapy arm, TMB showed a significant association only with OS (two-sided P = 0.040).
PD-L1 CPS as a continuous variable showed less consistent associations, with significant results only for PFS in the pembrolizumab monotherapy arm (one-sided P = 0.006) and ORR in the pembrolizumab plus chemotherapy arm (one-sided P = 0.042). The correlation between TMB and PD-L1 CPS was modest across all treatment arms (Spearman ρ ranging from 0.15 to 0.22).
When evaluating outcomes based on prespecified biomarker cutoffs, patients with TMB ≥175 mutations/exome treated with pembrolizumab monotherapy showed improved median PFS (9.9 vs 7.8 months; HR, 0.81; 95% CI, 0.54-1.21) and OS (28.3 vs 15.5 months; HR, 0.69; 95% CI, 0.45-1.04) compared to chemotherapy. Similar trends were observed for pembrolizumab plus chemotherapy versus chemotherapy alone in the high TMB subgroup.
Interestingly, the subgroup of patients with both high TMB (≥175 mutations/exome) and high PD-L1 expression (CPS ≥10) showed the most substantial improvements in PFS and OS with pembrolizumab-based treatments compared to chemotherapy alone. This suggests a potential synergistic effect of these biomarkers in predicting immunotherapy response.
The study has several limitations, including its exploratory nature and the evolving landscape of first-line treatments for advanced urothelial carcinoma. Recent positive results from trials evaluating enfortumab vedotin plus pembrolizumab and nivolumab plus cisplatin-based chemotherapy have changed the standard of care, potentially impacting the clinical relevance of these findings. Additionally, the lack of information on histologic variants and pathologic stages limits the comprehensiveness of the analysis.
The authors concluded that TMB appears to be associated with improved clinical outcomes for pembrolizumab monotherapy and, to a lesser extent, for pembrolizumab plus chemotherapy in patients with advanced urothelial carcinoma. They suggest that the combination of high TMB and high PD-L1 expression may identify patients most likely to benefit from pembrolizumab-based treatments.
The potential clinical impact of these findings is significant, as they may help guide treatment selection and patient stratification in advanced urothelial carcinoma. However, the authors emphasize the need for continued evaluation of these biomarkers in light of emerging first-line immunotherapy-based treatments. The study underscores the importance of integrating multiple biomarkers to optimize patient selection for immunotherapy in this challenging disease setting.
As the field of immuno-oncology continues to evolve, this analysis provides valuable insights into the complex interplay between tumor biology and treatment response. While further validation is needed, the results suggest that a multi-biomarker approach incorporating TMB and PD-L1 expression may enhance our ability to predict immunotherapy outcomes in advanced urothelial carcinoma. Clinicians and researchers alike will be closely watching for prospective studies that can confirm and extend these findings, potentially leading to more personalized treatment strategies for patients with this aggressive malignancy.
References
Fléchon A, Morales-Barrera R, Powles T, et al. Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma. Clin Cancer Res. 2024;30(23):5353-5364. doi:10.1158/1078-0432.CCR-23-3518
