In the last 30 years in bladder cancer, no new drug developments had been reported, until the beginning of the immunotherapy era. Bladder cancer is one of the tumors with the highest load of somatic mutations, making it a perfect target for immunotherapy.
In the last few years, five new immunotherapeutic agents were developed - atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab. Immunotherapy in bladder cancer has been initially tested in two settings: prior cis-platinum treatment, or cis-platinum ineligible patients. In the platinum-refractory setting, there has been no head to head comparisons, but initial data has shown an objective response rate of around 20%, a median OS of 7.7-18.2 months, and a median PFS of 1.5-2.1 months for all five immune checkpoint inhibitors. Using analysis of The Cancer Genome Atlas (TCGA), the luminal subtype II was shown to have an objective response rate that was significantly higher than the other subtypes (p=0.0072).
In the Checkmate 275 study, patients with metastatic urothelial carcinoma of the bladder, who progressed on prior cis-platinum-based therapy, were given Nivolumab with the primary endpoint being objective response rate. This trial demonstrated an objective response rate of 19.6% and median OS in all patients was 8.7 months1.
In another trial, the Keynote-045 phase 3 study, similar patients were analyzed, all patients had received 1-2 lines of cis-platinum therapy. These patients were randomized to either pembrolizumab or paclitaxel/docetaxel/vinflunine for two years or until unacceptable toxicity2. This trial showed a clear benefit in overall survival in favor of pembrolizumab of 43.9% vs. 30.7%. A 27% reduction in the risk of death was demonstrated with pembrolizumab2.
Dr. Sternberg then moved on to discuss the checkmate 032 trial, that Dr. Rosenberg presented earlier. Overall 1150 participants were recruited with the model being a parallel assignment. This was a multi-cohort randomized non-comparative phase 2 study. In the Nivo1+IPI3 most patients had 2-3 previous treatments, with 20% having had previous neoadjuvant treatment, and 36% had adjuvant treatment, while 75% had systemic metastatic treatment. These results were, however, like in the Nivo3+IPI1 and Nivo monotherapy arms. The follow-up of this arm (Nivo1+IPI3) was considerably shorter than the other two arms (7.9 months vs. ~37 months).
The best overall response rate per investigator was most impressive in Nivo1+IPI3 arm with 38%, vs. 25.6% and 26.9% in the other two arms. The progression-free survival was also significantly higher in the group of Nivo1+IPI3 (4.9 months vs., ~2.7 months in the other two arms). Lastly, the overall survival was also better among the Nivo1+IPI3 group with a median overall survival of 15.3 months vs. 7.4-9.9 months in the other two arms. Interestingly, the Nivo1+IPI3 patients with PD-l1expression more than 1% had an overall response rate which was much higher than that of the PD-L1 expression <1% (58.1% vs. 23.8%). The adverse effects of this study were quite acceptable, with the main reports of diarrhea, and elevated liver function tests. The adverse effects were slightly higher in the Nivo1+IPI3 group when compared to the other two arms.
There are currently many first-line phases 3 trials of anti-PD-1/PD-L1 antibodies in urothelial cancer (Figure 1), including the Checkmate 901, which will compare Nivolumab+cisplatin+gemcitabine to Cisplatin+Gemcitabine or carboplatin+gemcitabine.
Figure 1: Key first-line phase 3 trials of anti-PD-1/PD-L1 antibodies in urothelial cancer:
In summary, Checkmate 032 is a multicenter phase 1 and two studies and not a randomized trial. We cannot compare the results of this study with other studies. However, this study does reproduce previous results. It demonstrated an objective response rate of 38% for the Nivo1+IPI3 arm, which is quite impressive. Unfortunately, the follow-up is not mature yet. The results demonstrate that tumors with positive PD-L1 tumors probably benefit the most. We need a phase 3 randomized study, which is currently ongoing, the Checkmate 901, comparing Nivolumab and chemotherapy to chemotherapy alone, as first-line treatment in unresectable or metastatic urothelial carcinoma.
Presented by: Cora N. Sternberg, MD, FCAP, Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy
1. Sharma P et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322.
2. Bellmunt J et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015-1026
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, twitter: @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany