KEYNOTE-045 was a phase III clinical trial assessing pembrolizumab vs chemotherapy for patients with recurrent, advanced urothelial cancer. In the initial report of this trial, pembrolizumab was associated with significantly longer overall survival (OS) compared to either paclitaxel, docetaxel, or vinflunine chemotherapy (median 10.3 vs 7.4 months; HR 0.73, 95%CI 0.59-0.91) .
Dr. De Wit’s study found that with additional follow-up of KEYNOTE-045 patients, OS with pembrolizumab vs chemotherapy (paclitaxel, docetaxel, or vinflunine) continued to show significant differences (HR 0.70 vs 0.73 at first reporting - Sept 7, 2016). Additionally, pembrolizumab continued to have a superior safety profile compared with chemotherapy in these patients with recurrent, advanced urothelial carcinoma. Dr. Petrylak’s study found that in a subgroup analysis of patients in the KEYNOTE-045 trial, pembrolizumab was associated with longer OS, higher antitumor activity, and lower incidence of toxicities than single-agent paclitaxel, docetaxel, or vinflunine in patients with advanced urothelial carcinoma. According to Dr. De Santis, these two studies of KEYNOTE-045 highlight several points, (i) longer follow-up of these patients confirms previous findings that there is a significant benefit for pembrolizumab compared to chemotherapy in the second-line setting, (ii) post-hoc analysis of the control arm vs chemotherapies, although statistically significant, has limited additional information, considering there are low numbers in each subgroup, an imbalance in risk factors, and the fact that significant differences in outcome between paclitaxel, docetaxel and vinflunine is unlikely.
Dr. Necchi’s study found that patients in IMvigor210 (platinum-treated locally advanced or urothelial carcinoma) who continued atezolizumab beyond progressive disease derived prolonged clinical benefit including tumor burden reduction and longer OS compared to patients who discontinued atezolizumab post-progressive disease. According to Dr. Necchi and his co-authors, an important future challenge in the post-progressive disease setting will be to identify patients most likely to respond to atezolizumab and appropriate sequencing of chemotherapy agents thereafter. Dr. De Santis notes that when assessing treatment beyond progression, particularly in the immunotherapy trials, significant biases are introduced since treating physicians have selected patients with favorable clinical presentation.
Furthermore, there are questions with regards to what is true progression? Dr. De Santis notes that pseudo-progression may occur secondary to initial tumor enlargement with delayed shrinkage in the setting of response of a target lesion in the presence of a new lesion. These issues hopefully will be alleviated with the indoctrination of the immune modified RECIST criteria. Dr. De Santis also notes that there are issues with regards to treatment strategies for patients with urothelial cancer who progress on checkpoint inhibitor therapy. When these patients need to change treatment, should they revert back to chemotherapy, receive taxane chemotherapy + VEGF targeted therapy, or switch to another immunotherapy agent? Dr. De Santis highlights that the results from this post-hoc analysis are hypothesis generating and that post-progression treatment with a checkpoint inhibitor seems to be a valid concept in selected patients with favorable prognostic factors and/or suspected pseudo-progression.
Speaker: Maria De Santis, Clinical Trials Unit, University of Warwick, Coventry, United Kingdom
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
1. De Wit R, Vaughn DJ, Fradet Y, et al. Pembrolizumab versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer: mature results from the phase 3 KEYNOTE-045 trial. ESMO 2017 abstr LBA37.
2. Petrylak D, Vogelzang NJ, Fradet Y, et al. Subgroup Analyses from KEYNOTE-045: Pembrolizumab Versus Individual Investigator’s Choice of Chemotherapy (paclitaxel, docetaxel, or vinflunine) in Recurrent, Advanced Urothelial Cancer. ESMO 2017 abstr 851.
3. Necchi A, Joseph RW, Loriot Y, et al. Atezolizumab in Platinum-Treated Locally Advanced or Metastatic Urothelial Carcinoma: Post-Progression Outcomes from the Phase 2 IMvigor210 Study. ESMO 2017 abstr 852.
4. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.