It’s my pleasure to present these results on behalf of the investigators, EV-201, enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer in patients previously treated with platinum and immune checkpoint inhibitors.
We know that about 18,000 patients will die of urothelial cancer that will consist of cancers of the upper urinary tract, renal pelvis, bladder and ureter. First line therapy for most patients remains platinum based chemotherapy, however, nearly all patients will progress and receive subsequent treatment. Second line therapy that is approved by the FDA includes one of five checkpoint inhibitors, unfortunately the response rates for these checkpoint inhibitors are anywhere between 13-21% and most patients will require further therapy due to progressive disease. Unfortunately there is no standard therapy for patients who have progressed after platinum based chemotherapy or PD1 or PD-L1 inhibitor.
Enfortumab vedotin is an antibody-drug complex that targets Nectin-4 and this is a therapeutic target that’s expressed in multiple solid tumours and expressed at low levels in normal tissue. It’s expressed at a high level in urothelial cancers.
This diagram explains the process with the action of enfortumab vedotin. This is a monoclonal antibody that’s linked to an anti-tubulin agent called MMAE. This recognised Nectin-4 on the bladder cancer cell, it’s internalised, the lysis uncleaves that complex and then the anti-tubulin agent hits tubulin and causes cell death and cancer death.
The EV-201 trial is a two cohort study. This morning I’ll be presenting cohort 1 which, as I mentioned before, are the previously treated patients with platinum or checkpoint inhibitors. Cohort 2 is ongoing and this includes patients who are ineligible to receive platinum and who have had a prior PD-L1 inhibitor. The drug is administered at 1.25mg/kg on days 1, 8 and 15. Our primary endpoint was objective response as measured by a central review committee. Duration of response, progression free survival, overall survival and safety were our secondary endpoints.
This is a representative population of this type of patient with urothelial carcinoma - predominantly male, median age of 69, ECOG performance status 85%, 68% being 1. Poor prognostic factors are seen in about half of patients. 90% of patients had disease in the viscera and 40% of patients had disease in the liver. If we look at the PD-L1 staining it’s about 35% which is what you would expect from this population of patients.
These are our response rates – 44% of patients had a confirmed objective response with 12% of patients demonstrating a complete response. In an area that’s very, very difficult to treat, metastases to the liver, we had a 38% response rate. When we look at all different subgroups the confidence limits overlapped showing that there was no one group that seemed to benefit more than the other. When we perform the waterfall plots we see that 84% of patients had some form of tumour shrinkage and when we look at the various progression Kaplan-Meier curves, including duration of response, the median is 7.6 months, progression free survival 5.8 months and then also the overall survival is 11.7 months. The lower limit for the confidence levels is 9.1 months and we have not reached the upper limit at this particular point.
The drug was well tolerated, the majority of side effects were grade 1 and grade 2. These included fatigue, alopecia, decreased appetite, dysgeusia, peripheral sensory neuropathy. Overall about 12% of patients discontinued treatment due to toxicities and the most commonly encountered grade 3 or higher side effect was neutropenia.
So, in conclusion, there’s a high unmet need for patients with advanced metastatic urothelial cancer. Enfortumab vedotin is the first novel therapeutic agent to demonstrate substantial clinical activity in patients who progressed after platinum chemotherapy or a PD-1 or PD-L1 inhibitor. We had a 44% objective response rate and a 7.6 month median duration of response. We saw responses across all subgroups of patients and this was irrespective of their previous response to PD-L1 inhibitors. Again, we had a high level of response in liver, 38%, and that confirmed our observations in the phase I trial. It was tolerable with a manageable safety profile and, as I mentioned before, these results were similar to our phase I experience. We feel that both of these trials support the submission to the FDA for accelerated approval. There is a large randomised trial that is now ongoing in the same patient population that we’re presenting this morning comparing enfortumab vedotin to dealer’s choice chemotherapy and that will be our pivotal phase III trial with this particular drug. We’re also looking at various combinations. So we’re very, very excited about this data this morning. Thank you.