Enfortumab vedotin plus pembrolizumab improves overall survival for advanced bladder cancer

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Published: 22 Oct 2023
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Prof Thomas Powles - Barts Cancer Centre, London, UK

Dr Powels talks to ecancer at ESMO 2023 in Madrid about his presentation on the phase 3 EV-302 clinical trial, also known as KEYNOTE-A39, evaluating the combination of enfortumab vedotin-ejfv and pembrolizumab compared to chemotherapy, for patients with previously untreated locally advanced or metastatic urothelial cancer.

The study showed improvements in overall survival (OS) and progression-free survival (PFS).

Patients receiving enfortumab vedotin and pembrolizumab had a median OS of 31.5 months compared to 16.1 months with chemotherapy. OS risk reduced by 53% with the combination therapy. Median PFS was 12.5 months compared to 6.3 months in the chemotherapy arm, reducing the risk of cancer progression or death by 55%, and the study showed consistent OS results across various patient subgroups.

Common Grade 3 or higher adverse events related to the combination therapy included rash, hyperglycaemia, neutropenia, neuropathy, diarrhoea, and anaemia, with no new safety concerns identified.

Enfortumab vedotin plus pembrolizumab improves overall survival for advanced bladder cancer

Prof Thomas Powles - Barts Cancer Centre, London, UK

The EV-302 study is a study looking at enfortumab vedotin and pembrolizumab versus first line standard chemotherapy in advanced urothelial cancer, or bladder cancer. It’s a first-line trial for patients with advanced disease who haven’t previously received chemotherapy. Urothelial cancer is one of the top ten common cancers. First-line treatment for advanced disease has been chemotherapy based for forty years. It’s never been beaten, actually, before, since gemcitabine cisplatin or gemcitabine carboplatin, but outcomes are poor, median survival is between 12-14 months. While we’ve tried to introduce immunotherapies, they tend to be used later in the disease setting.

The randomised phase III study takes two really promising drugs – enfortumab vedotin and pembrolizumab. Enfortumab vedotin is an antibody drug conjugate – it targets nectin-4, it has MMAE as the payload. Pembrolizumab is a well-known PD-1 inhibitor. Both of the drugs have activity on their own in urothelial cancer in platinum refractory disease, in those patients whose cancers progressed after chemotherapy. We did a phase II study where we combined the two drugs together and we showed really impressive activity - 68% response rates. Chemotherapy comes in at about 45%, and so with those promising results with that combination, we launched this large randomised phase III study. This study compared enfortumab vedotin and pembrolizumab versus gemcitabine cisplatin and gemcitabine carboplatin chemotherapy in first line, previously untreated patients.

The results of the trial were really striking and, dare I say it, transformative for this disease. We randomised 850 patients, 440 in each arm, and we showed a 55% reduction in the risk of progression of disease, doubling median progression free survival from six months to twelve months. We showed a 68% response rate, significantly better than chemotherapy. We also showed a 30% CR rate, where radiologically, the cancer disappeared altogether, which we hadn’t really seen before in this disease. As I said before, the vast majority of patients relapse and die from their disease quite quickly.

Most importantly we showed a 53% reduction in the  risk of death with a hazard ratio of 0.47 which is highly statistically significant. These results underpin the activity of these two drugs being significantly superior to platinum-based chemotherapy. Two caveats – the first is that 30% of patients in the chemotherapy arm went on to receive maintenance avelumab, which recently has become the standard of care, which is actually a respectable number. Secondly a high proportion of patients in the control arm got subsequent immunotherapy, about 68%, so it’s representative of patients getting subsequent immunotherapy, which underpinned the impressive results. Also, the benefits were seen irrespective of gemcitabine cisplatin or gemcitabine carboplatin, irrespective of the chemotherapy, irrespective of the PD-L1 biomarker, irrespective of whether the patient’s had liver metastasis or lymph node disease, so it was effective across broad subgroups of patients.

I think it’s important to talk about the toxicity profile of the drug also. Chemotherapy is associated with a 70%, in this study, a 70% grade 3 or 4 adverse event profile. The EV pembrolizumab, enfortumab vedotin and pembrolizumab, was associated with a 56% risk of grade 3 or four 4. That doesn’t mean it was better tolerated, because toxicity is different. Most of the chemotherapy toxicity was focused around nausea, fatigue, standard chemotherapy toxicity, neutropenia, anaemia. Enfortumab vedotin and pembrolizumab had some adverse effects of special interest – skin toxicity, peripheral neuropathy, and hyperglycaemia. There were no treatment related deaths associated with these three special adverse events of special interest which I think is important, but also we noticed these were in line with what we’d seen in previous trials; the toxicity profile was manageable. I think there’s education and training around the toxicity of a new combination, as is always the case with a cancer medicine,, but my personal experience is it’s a regime which is manageable for our patients and incredibly active.

Could you comment on the safety profile?

The safety profile of the drug is important because the drug is given until progression of disease. The median number of cycles that patients had was ten, so that’s a significant period of therapy. The adverse events, the special interest, the skin toxicity tends to occur quite quickly. The cessation of therapy when it does occur is important and you can rechallenge the drug at a lower dose, and that’s important. The peripheral neuropathy tends to accumulate with time and, again, the key there is to dose-reduce or stop the therapy, and then you can rechallenge potentially at a reduced dose. When hyperglycaemia occurs patients would require glucose monitoring and glucose treatment therapy, diabetic treatment therapy.

Anything else to add?

The treatment of urothelial cancer has been chemotherapy based for forty years, it’s not been beaten. The EV-302 study with enfortumab vedotin and pembrolizumab reduces the risk of death compared to chemotherapy by 50%. It’s the first time we’ve beaten chemotherapy, and potentially transforms this disease.