Immune checkpoint blockade therapy by blocking PD-1/PD-L1 axis signaling is approved in advanced urothelial cancers in a few settings: (1) first-line therapy for platinum-ineligible patients, (2) first-line therapy in cisplatin-ineligible patients with high PD-L1 expression, (3) maintenance therapy for patients who do not progress with first-line chemotherapy, and (4) as subsequent therapy for patients progressing after cisplatin-based first-line therapy. Approvals for settings #1 and #2 are based on single-arm phase 2 data, with setting #3 based on the JAVELIN-100 Bladder randomized control trial.
To explore the efficacy of combining anti-PD-1 therapy with chemotherapy in platinum-eligible patients as first-line therapy, KEYNOTE-361 was designed as a randomized trial with the schema below. Pembrolizumab maintenance therapy was given up to two years. Dual primary endpoints were progression-free and overall survival (OS).
This trial utilized a sequential statistical analysis, first examining progression-free survival, then overall survival, as shown below. It is important to note that because one of the interim PFS analyses was negative, considerable alpha was spent prior to the overall survival analysis, and thus overall survival analysis of pembrolizumab monotherapy compared to chemotherapy was not possible.
A total of 1010 patients were randomized on this trial.
The treatment arms were balanced.
Beginning in February 2018, based on changes in the United States Federal Drug Administration (FDA) approval of pembrolizumab, only patients with PD-L1 positivity were eligible to enroll in the pembrolizumab only arm, resulting in slightly lower numbers of patients.
With regards to progression-free survival (PFS), combination pembrolizumab and chemotherapy was associated with a median PFS of 8.3 months versus 7.1 months (HR 0.78, 0.65-0.93, p = 0.0033). The p-value did not meet the significance cutoff (p < 0.0019).
Median OS for combination therapy was 17 months versus 14.3 months for chemotherapy alone (HR 0.86, 0.72-1.02, p = 0.0407). The p-value for this comparison did not meet the significance threshold of p < 0.0142.
Rates of subsequent anti-cancer therapy, which influences overall survival especially in first-line clinical trials, are shown below. Approximately half of the patients receiving standard of care chemotherapy in the first line went on to receive anti-PD-1 axis therapy. As an exploratory analysis, the OS analysis was adjusted for subsequent therapy, but this approach also did not show a significant advantage for combination IO/chemo.
As mentioned above, pembrolizumab monotherapy relative to chemotherapy was not able to be tested statistically due to prior analyses in the sequential testing plan being negative. As an exploratory analysis, survival data from pembrolizumab alone versus chemotherapy are shown below.
With regards to response rate, chemotherapy had a higher overall response rate (~45%) relative to pembrolizumab alone (~30%). Combination pembrolizumab and chemotherapy had an overall response rate of 54.7%. Importantly, immunotherapy responders seemed to have more durable responses relative to chemotherapy-alone responders.
Adding pembrolizumab to chemotherapy did not cause major differences in safety profile.
In summary, the addition of pembrolizumab to platinum-chemotherapy for first-line treatment of advanced urothelial cancer did not provide a statistically significant benefit for progression-free or overall survival. Importantly, patients who did respond to first-line immunotherapy did have more durable responses, suggesting a subset of patients who may not require aggressive therapy to induce disease regression may benefit longer from immunotherapy, but how to identify these patients remains very unclear.
Presented by: Ajjai Alva, MBBS, Associate Professor of Medicine and Medical Oncologist at the University of Michigan Medical Center, Ann Arbor, Michigan
Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020
Read the Invited Discussion on this Topic: ESMO Virtual Congress 2020: Invited Discussant KEYNOTE-361 (LBA23) and DANUBE (697O)
Updates on Bladder Cancer Clinical Trials ASCO GU 2020 - Matthew Galsky
The Dynamic Advancements in Personalized Treatments for Metastatic Urothelial Cancer - Andrea Apolo
Update on Phase 3 KEYNOTE-361 Trial Evaluating Pembrolizumab as Monotherapy and in Combination with Chemotherapy in Patients with Advanced or Metastatic Urothelial Carcinoma