Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomised, double-blind, phase 3 trial
Petrylak DP et al., Lancet. 2017 Nov 18;390(10109):2266-2277.
PubMed ID: 28916371
Patients with advanced urothelial carcinoma who fail first line platinum-based chemotherapy face limited treatment options upon disease progression. Tumor angiogenesis is one of the key factors leading to refractory disease. Hence, the use of VEGF inhibitors is a plausible targeted therapy in this subpopulation.
Ramucirurab, an IgG1 monoclonal antibody binds to the extracellular domain of VEGFR-2. Preclinial studies revealed synergy of ramucirumab with docetaxel. A phase II study on patients with advanced urothelial cancer refractory to platinum therapy demonstrated significant improvement in PFS (5.4 v 2.8 mos., HR 0.389; p=0.0002) compared to docetaxel alone (J Clin Oncol 2016; 34: 1500-09). Petrylak and colleagues further investigated the efficacy and safety of this combination in the same patient population in the phase III RANGE trial.
- Patients: Histologically or cytologically confirmed locally advanced, unresectable or metastatic urothelial Ca (pure or predominant transitional cell histology) with primary tumor originating from the bladder, urethra, ureter, or renal pelvis, progression ≤14 mos. after platinum-containing chemotherapy, ECOG 0-1, no untreated brain metastases; previous treatment with one immune-checkpoint inhibitor if relapsed ≤24 mos. from the end of platinum-containing regimen was allowed.
- Study design: Phase III, double-blind RCT
- Experimental: Ramucirumab 10 mg/kg IV
- Docetaxel 75 mg/m2 IV (60 mg/m2 in Korea, Taiwan, and Japan)
- Control: Placebo
- Docetaxel 75 mg/m2 IV (60 mg/m2 in Korea, Taiwan, and Japan)
- All chemo given on day 1 of a 21-day cycle
- Primary: PFS
- Secondary: OS, ORR, DCR, DOR, safety, patient-reported outcomes, PK and immunogenicity of ramucirumab
- 530 patients randomized to ramucirumab + deocetaxel (n=263) and placebo + docetaxel (n=267)
Baseline patient characteristics: median age 66 yrs., 55% ≥65 yrs. old, 81% male, 77% white, 52% ECOG 1, 70% Europe and the rest of the world, 77% pure transitional cell histology, 64% bladder as primary tumor site, 70% visceral disease (41% lung metastases), 56% creatinine clearance ≥ 60, 13% Hgb <10 g/dL, 34% Bellmunt risk factor 1, 61% no previous adjuvant therapy, 64% previous cisplatin-based chemotherapy
- QOL measures were comparable at baseline and were unchanged over time. No difference in QOL was observed between both arms.
- After the first ramucirumab administration, the geometric mean trough concentrations before doses two, three, and five were 15 μg/mL, 23 μg/mL, and 34 μg/mL, respectively
- Anti-ramucirumab antibodies: 19 (10%) had positive samples at baseline, three (2%) had treatment-emergent anti-ramucirumab antibodies.
Table 1: Efficacy Outcomes
- Most frequent any grade side effects: fatigue (43% v 46%, alopecia (24% v 35%), diarrhea (29% v 21%), decreased appetite (28% v 23%), nausea (24% v 20%)
- Most common grade ≥3 adverse event with ramucirumab: neutropenia (15% v 14%), febrile neutropenia (10% v 6), fatigue (8% v 9%)
- Use of G-CSF: 42% v 42%
- Most frequent cause of dose adjustment (dose reduction/delay/omission): febrile neutropenia (4% in each arm)
- Most common cause of treatment discontinuation: sepsis (2% v 0%)
- Most common cause of treatment-related death: sepsis (2% v 0%)
- One patient on ramucirumab died from neutropenic sepsis.
Table 2: Adverse Event and Treatment Summary
- In patients with advanced urothelial Ca who failed platinum-based chemotherapy, ramucirumab with docetaxel significantly delayed disease progression by 1.31 mos. and doubled 12mo. PFS compared to docetaxel alone. OS data was immature at interim analysis.
- Combination therapy improved tumor responses and extended duration of response to therapy compared to chemotherapy alone with docetaxel. More patients on ramucirumab experienced tumor burden reduction. No improvement in QOL was observed in either treatment arm.
- The addition of anti-VEGF targeted therapy (ramucirumab) with chemotherapy (docetaxel) did not appear to compound side effects. Most adverse events were low grade. Side effects related to anti-VEGF therapy were observed in up to 6% (grade ≥3) of patients on ramucirumab. Although rates of neutropenia were similar in both arms, sepsis occurred in 2% on ramucurimab; one patient succumbed to neutropenic sepsis.
- The study provided evidence in favor of ramucirumab with docetaxel as a treatment option in platimun-refractory advanced urothelial Ca. However, certain issues must be addressed. In terms of baseline characteristics, slightly more patients on ramucirumab had liver metastases (30% v 26%) and Belllmunt risk score 3 (18% v 12%). Only 6% received previous immune checkpoint inhibitor therapy, median follow-up was short at 5 mos., with a median treatment duration of 12.1 wks.
- A phase 1 study of avelumab, an anti.PD-L1 monoclonal antibody yielded 17% objective response in patients with advanced urothelial Ca after failing platinum therapy who were followed up for at least 6 mos. (Lancet Oncol, http://dx.doi.org/10.1016/S1470-2045(17)30900-2). This is comparable to ORR of 24.5% in the RANGE trial.
- Pembrolizumab has been approved as 2nd line treatment for advanced urothelial cancer based on results from a phase III trial that demonstrated improvement in OS (10.3 vs 7.4, HR= 0.73, P = 0.002) and 21% ORR, despite shorter PFS compared to placebo (N Engl J Med 376:1015-1026, 2017). Similar results were observed for nivolumab in the 2nd line setting (Oncol 2017;18: 312-22). At least 19% achieved an objective tumor response at a median follow-up of 7 mos. and the benefit was observed regardless of PD-L1 expression.
- Although results from the RANGE study are encouraging, further investigation on combination therapy with ramucirumab is needed before it can be recommended.
- The cost of treatment with the addition of ramuciraumab to chemotherapy is a concern, given its marginal advantage over monotherapy. With available targeted treatment options in this setting, determining the most effective drug or combination with the best safety profile remains a challenge.
More GU Cancer Updates