It’s both an honour and a pleasure to be able to present this data to you this morning and I’d like to thank the organisers of ESMO. So these are my disclosures.
Bladder cancer, or urothelial carcinoma, arises from the urinary tract; this could be from the kidneys, from the uterus, from the bladder. For patients who are metastatic chemotherapy is a standard of care for front line treatment. Unfortunately, durable survivals are not common, about 5% of patients will survive five years with systemic chemotherapy. Thus, for second line treatment options are needed. Chemotherapy itself as a second line treatment generally gives a median survival of about seven months. In the laboratory we found that an anti-angiogenesis agent called ramucirumab, which targets VEGFR2, has activity in combination with docetaxel, in fact it’s synergistic and showed in animal models better outcomes than docetaxel alone.
So we went forth with a randomised phase II which we published in 2016 which demonstrated a doubling of the progression free survival in patients who were treated with ramucirumab and docetaxel compared to docetaxel alone. Thus the RANGE trial came out of that initial study which randomised patients to ramucirumab at 10mg/kg combined with docetaxel and that compared it to docetaxel at 75mg/m2. These were patients with locally advanced or unresectable metastatic bladder cancer; they had to progress within 14 months of their prior chemotherapy and they were permitted to receive prior immune checkpoint therapy. The other reason for this trial is the fact that we do see dramatic responses with immune therapy but that’s only in about 25% of patients so alternative treatments are needed to be developed for this state of disease.
This is the primary endpoint – progression free survival as assessed by the investigators. As we see here, the median progression free survival for the combination therapy was 4.07 months compared to 2.76 months for those patients who received docetaxel alone. When we look at this from an independent blinded assessment we see a very, very similar pattern – a progression free survival of 4.04 months for the ramucirumab and docetaxel and 2.46 months for the combination therapy. As we see, at one year 11.9% of patients were without progression versus 4.5% of patients in the control arm with docetaxel alone.
These are the objective responses. We’ve seen approximately a doubling of the objective response rate when ramucirumab and docetaxel are combined and compared to docetaxel alone; a 4.2% complete response rate in the combination arm compared to a 1.4% complete response rate in the monotherapy arm.
Despite administration of a second drug we really did not see any degradation of the quality of life parameters that we measured, either by the EORTC QLQ C30 or the EQ-5D-5L index. Again, as we see, consistently throughout all cycles patients seemed to maintain their quality of life when ramucirumab was added to docetaxel.
Thus we conclude that RANGE is the first phase III trial to demonstrate a progression free survival advantage over chemotherapy alone in platinum refractory advanced or metastatic urothelial carcinoma. Most patients were poor prognosis; 61% had at least two adverse prognostic risk factors at baseline so this is a sick group of patients. The progression free survival outcomes were consistent across a variety of different patient subgroups and the trial is designed to look at an overall survival secondary endpoint and that is still maturing at this particular time. As I mentioned before, there’s a doubling of the objective response rate. We did not see additive toxicity with the combination and this is a new treatment option for the treatment of patients with platinum refractory metastatic urothelial carcinoma. So I thank you for your attention.