ESMO 2018: RANGE, A Phase 3, Randomized, Placebo-Controlled, Double-Blind Trial of Ramucirumab and Docetaxel In Platinum-Refractory Urothelial Carcinoma: Overall Survival Results

Munich, Germany ( Until the introduction and, ultimately, approval of multiple immune checkpoint inhibitors in the setting of platinum-refractory metastatic urothelial carcinoma (mUC), docetaxel was the standard of care 2nd line therapy. However, at the time of initiation of the RANGE study, ICI’s had not yet been introduced nor had they been approved.

The biologic rationale for adding ramucirumab (RAM), a monoclonal antibody against the VEGF-receptor itself (rather than the ligand, as is the case with bevacizumab), was a dual-agent therapy to potentiate docetaxel efficacy alone. RANGE was a phase 3 RCT comparing docetaxel (DOC) alone or docetaxel with RAM in patients who had failed platinum-based chemotherapy. RANGE had already met its primary endpoint; RAM+DOC improved PFS (median 4.1 vs 2.8 mo; HR 0.76; p = 0.0118) and objective response rate (ORR; 24.5% vs 14%) without significant additive toxicity or compromise in quality of life compared to DOC alone (Petrylak et al. Lancet 2017). In this abstract, they authors report overall survival (OS) results, which was a secondary endpoint.

530 pts were randomized to RAM+DOC (n = 263) or DOC alone (n = 267). Median follow-up time was 7.4 months. With regards to the secondary endpoint of interest (OS), there was a trend toward improved OS for patients treated with RAM+DOC, but it did not meet statistical significance (median, 9.4 vs 7.9 months; HR, 0.89; 95% CI, 0.72-1.09; p = 0.2461).

Interestingly, they did do a subgroup analysis of patients based on the location of the primary tumor – either bladder, renal pelvis or ureter. There have now been numerous retrospective studies that have demonstrated that these may, in fact, be slightly different disease processes with unique clinical and genomic differences. In this study, the authors found that patients with primary bladder tumors did slightly better with RAM+DOC than DOC alone, though it wasn’t statistically significant (median, 9.7 vs 7.0 months; HR, 0.78; p = 0.0521). There was no difference in patients with upper tract disease.

Previously reported PFS and ORR results were confirmed (PFS, median 4.1 vs 2.8 mo; HR 0.70; p = 0.0002; ORR, 25.9% [95% CI, 20.6-31.1] vs 13.9% [95% CI, 9.7-18.0]). Grade ≥3 adverse events were reported at a similar frequency in both arms with no unexpected toxicities.

Based on this, the authors conclude that adding RAM to DOC in platinum-refractory mUC showed statistically superior PFS, improved ORR, and a trend toward improved OS compared to Docetaxel alone.

Invited Discussant
In his discussion, Dr. Jones made the following important points:
1) The relevance of the study has diminished, as numerous ICI’s have supplanted docetaxel as the 2nd line therapy of choice
2) Failure to demonstrate OS will limit enthusiasm for RAM utilization anyway

However, there remains an unmet need for survival prolonging therapies in patients who have had platinum-based chemotherapy and ICI’s – and this may serve a role in this setting.

Presented by:
Daniel P. Petrylak, Medical Oncology, Internal Medicine, Yale, New Haven Hospital, New Haven, CT, US
Invited Discussant: Rob Jones, MD, Professor, the University of Glasgow, Glasgow, Great Britain

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, twitter: @tchandra_uromd, @TjuUrology at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany

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