(1) The context before RANGE
Until 2016, the management and prognosis for metastatic urothelial carcinoma was quite dismal. Cisplatin-eligible patients received either dose-dense MVAC or cisplatin-gemcitabine, while cisplatin-ineligible patients received carboplatin-gemcitabine. For platinum-resistant metastatic urothelial cancer there was no standard chemotherapy, however vinflunine and taxanes were options. Angiogenesis is associated with stage and poor prognosis, with VEGF as a key mediator of angiogenesis in urothelial carcinoma. Preclinical models have demonstrated that VEGF inhibitors combined to chemotherapy increases antitumor activity. There have been several trials in the first line setting assessing angiogenesis inhibitors in metastatic urothelial carcinoma (all n<100), with no specific remarkable outcomes, however with noted toxicity in these patients with significant comorbidities. In the second line, Dr. Petrylak previously showed in a phase II study (n=45) that the VEGF2 receptor antagonist ramucirumab plus docetaxel significantly improved median progression-free survival (PFS) over docetaxel alone (5.4 vs 2.8 months; HR, 0.389; 95% CI, 0.235-0.643), with no unexpected toxicities . These results provided the rationale for a phase III trial.
(2) The data
As Dr. Loriot notes, both arms of this trial were well balanced with 2/3 of patients having visceral disease, balance between patients having poor risk factors, and few patients having prior immune checkpoint inhibitor therapy (<10%). The study met its PFS primary endpoint with a statistically significant HR favoring ramucirumab plus docetaxel of 0.757. However, as Dr. Loriot points out this only translates to an absolute difference of 1.31 months PFS advantage, with a smaller PFS difference than reported in the phase II trial. Furthermore, he notes that (i) OS interim results were planned at final PFS analysis, but are yet to be reported, (ii) there was better objective response rate (ORR) in the ramucirumab plus docetaxel arm, but the significance has yet to be tested, and (iii) there was no improvement in quality of life metrics, however this is with limited data after cycle 3 of treatment. Importantly, there was better tolerance in the phase III trial than the phase II trial, with no significant additive toxicity in this population of patients with cardiovascular and renal comorbidities.
Dr. Loriot provided a concise strengths/weaknesses summary slide for the results of this trial. Strengths included (i) the study meeting its primary endpoint, (ii) this is the best ORR reported in a phase III trial in unselected patients, (iii) safety is manageable in this population of complex and frail patients, and (iv) ramucirumab may be the best angiogenic inhibitor ever investigated in urothelial carcinoma. Weaknesses included (i) PFS as a primary endpoint is not surrogate for OS in metastatic urothelial carcinoma, (ii) the benefit of PFS is quite small, (iii) interim analysis for OS is not reported, (iv) there was no improvement in quality of life metrics for these patients often complaining of symptoms in the second-line setting, (v) there was no biomarker data reported as of yet.
(3) The context after RANGE
How this data translates in clinical practice for metastatic urothelial carcinoma is the most important question to be answered. Dr. Loriot notes that pembrolizumab in the second line is the only non-chemotherapy agent to prolong OS (KEYNOTE-045 ). Additionally, with improved EORTC QLQ-C30 scores for pembrolizumab, Dr. Loriot surmises that pembrolizumab and other immune checkpoint inhibitors may be the preferred option in the second line for the majority of clinicians. He feels that ramucirumab + docetaxel may be the treatment chosen post-immune checkpoint inhibitor therapy for clinicians, however there are several issues: (i) there is an insufficient number of patients in the subgroup analysis to suggest that ramucirumab + docetaxel may be active in this setting, considering only 10% of patients received prior immune checkpoint inhibitor therapy, (ii) many patients (~60%) do not receive any subsequent treatment after immune checkpoint inhibitor failure, (iii) there is no evidence for efficacy of ramucirumab on visceral disease, and (iv) whether ramucirumab is active and well-tolerated in unselected patients in daily practice remains to be seen, considering that inclusion criteria for the trial were quite restrictive (performance status 0-1, no untreated brain metastasis, no recent cardiovascular events, no thromboembolic events within six months of treatment). Given the early crossing of OS survival curves in the KEYNOTE-045 (up to 6 months), Dr. Loriot wonders if ramucirumab + docetaxel may be active in patients in whom immune checkpoint inhibitor treatment has no activity and when these regimens even induce “hyper-progression”. Furthermore, ramucirumab + docetaxel may be a better option for basal tumors that were poor responders in prior immune checkpoint inhibitor trials (ie. atezolizumab ), although translational investigations will be key.
(4) The outlook
Dr. Loriot concluded this presentation with outlining what the outlook is in 2017 for patients with metastatic urothelial carcinoma. First-line treatment remains platinum-based chemotherapy, with immune checkpoint inhibitor therapy for a potential subset of patients. These recommendations may also change pending results IO-IO and IO-chemotherapy trials. For patients with platinum-resistant disease, most patients will likely receive immune-checkpoint inhibitor therapy followed by docetaxel + ramucirumab. A subset of platinum-resistant patients (those with short response to first-line treatment, no visceral metastasis, ineligible for immune-checkpoint inhibitor therapy) likely will go straight to docetaxel + ramucirumab for second-line treatment.
1. Petrylak DP, Chi KN, Drakaki A, et al. RANGE: A randomized, double-blind, placebo controlled phase 3 study of docetaxel with or without ramucirumab in platinum refractory advanced or metastatic urothelial carcinoma. ESMO 2017 abstr LBA4.
2. Petrylak DP, Tagawa ST, Kohli M, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: An open-label, three-arm, randomized controlled phase II trial. J Clin Oncol 2016;34(13):1500-1509.
3. 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.
4. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016;387(10031):1909-1920.
Speaker: Yohann Loriot, Gustave Roussy, University of Paris Saclay, Villejuif, France
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