Thomas Powles, MD, MBBS, MRCP

Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology, director of the Bart Cancer Centre, and lead for Solid Tumour Research at Cancer Research UK, discusses the implications of the positive outcome of the phase 3 EV-301 trial (NCT03474107) of enfortumab vedotin (Padcev) in patients with urothelial cancers.

The EV-301 trial investigated the monoclonal antibody enfortumab vedotin as a targeted therapy in patients who had previously received platinum-based chemotherapy and progressed during or after receiving a PD-1 or PD-L1 inhibitor. Investigators found an overall survival (OS) benefit to enfortumab of 12.88 months versus 8.97 months (HR, 0.70; 95% CI, 0.56-0.89; 

According to Powles, this trial is the third to show a signal of OS in patients with urothelial cancer, following the KEYNOTE-045 trial (NCT02256436) of second-line pembrolizumab (Keytruda) and the JAVELIN Bladder 100 trial (NCT02603432) of maintenance avelumab (Bavencio). Powles anticipates that enfortumab will be a standard-of-care regimen with potential as a second-line treatment, though it is currently approved following chemotherapy and a PD-1/PD-L1 inhibitor.

 This research is practice changing. We've not had many OS signals in urothelial cancer over the last 40 years. We know chemotherapy is active, but there weren't really randomized trials to show that. We had a survival signal for second-line pembrolizumab. We had a survival signal for maintenance avelumab, but we haven't really had any other survival signals in bladder cancer. So, this is the third time we've achieved that with a new class of drugs in a very heavily-treated population.

And so, I think this is going to make a massive difference. I think it's going to be a standard of care. I think, for me, the standard of care currently is platinum-based chemotherapy and maintenance avelumab and giving [enfortumab] on progression, which would be a second-line agent essentially, so we’ll be reaching toward this very quickly.

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Thomas Powles, MD, MBBS, MRCP, discusses the implications of the positive outcome of the phase 3 EV-301 trial of enfortumab vedotin in patients with urothelial cancers. 

Enfortumab Trial For Bladder Cancer Has Practice-Changing Implications 

Thomas Powles, MD, MBBS, MRCP, a professor of genitourinary oncology, director of the Bart Cancer Centre, and lead for Solid Tumour Research at Cancer Research UK, discusses the results of the phase 3 EV-301 trial (NCT03474107) for enfortumab vedotin (Padcev) in patients with urothelial cancer.

The EV-301 study of patients with locally advanced or metastatic urothelial cancer led to an FDA approval of enfortumab in July 2021 after demonstrating survival benefit and tolerable safety profile.

EV-301 was a 1:1 randomized study of 608 patients who had previously received platinum-based chemotherapy and experienced disease progression during or after PD-1/PD-L1 treatment. They were administered either enfortumab vedotin or standard docetaxel, paclitaxel, or vinflunine chemotherapy. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, a cell adhesion molecule that is highly expressed in urothelial cancer.

The trial’s primary end point was overall survival (OS). After a follow-up of 11.1 months, the median OS was 12.9 months for those who received enfortumab vedotin compared with 9.0 months with chemotherapy—an increase of 3.9 months with a hazard ratio of 0.70. Overall response rate (ORR) for enfortumab vedotin was also significantly higher (40.6% vs 17.9%).

In terms of tolerability, the rate of treatment-related adverse events (TRAEs) was comparable in general. For serious TRAEs, patients who received enfortumab vedotin had a rate of serious TRAEs of 22.6% versus 23.4%, and grade 3 or higher TRAEs were around 50% in both groups. Certain TRAEs were more common in each group: maculo-papular rash in the group that received enfortumab vedotin and decreased neutrophil count and white blood cell count in the group that received chemotherapy.

 The EV-301 study is a large, randomized phase 3 study that incorporates patients who have progressed on platinum-based chemotherapy and immune checkpoint inhibitors. It's a 650-patient study, which is robust, and it showed a significant survival advantage for enfortumab vedotin versus chemotherapy. The chemotherapy choice was docetaxel, paclitaxel, or vinflunine, which are standard.

The hazard ratio was 0.70, which was statistically significant, showing a 30% reduction in the risk of death. OS in the enfortumab vendotin arm was approximately 13 months, which is long in this setting. The ORR was 40% versus 18%. The hazard ratio for PFS also favored enfortumab vendotin significantly, so the efficacy signal was consistent, and [that is] really important. And when we give this drug to my patients, this is reinforced. We see really great responses and patients’ pain reducing with therapy. So it's clearly a very active therapy in urothelial cancer.

People obviously asked, “Well, it's a new class of drug, what's the toxicity profile like?” The toxicity profile is manageable. In fact, in the adverse event profile, the percentage of grade 3 or 4 adverse events were about 50% in both groups.

Thomas Powles, MD, MBBS, MRCP, discusses the results of the phase 3 EV-301 trial for enfortumab vedotin in patients with urothelial cancer.

Enfortumab Vedotin Improves Survival Outcomes in Urothelial Cancer

Thomas Powles, MD, MBBS, MRCP, director, Barts Cancer Institute, discusses how researchers are working to optimize treatment with immune checkpoint inhibitors for patients with urothelial carcinoma.

This is the big question he has been asked over the last 12 months, Powles says, with the latest development of new therapies for patients with urothelial carcinomas. The movement of checkpoint inhibitors has primarily been in the perioperative and neoadjuvant spaces, and the story of checkpoint inhibitors has been primarily in metastatic disease.

Checkpoint inhibition has proven itself effective with durable, long-term remissions in about a fifth of patients, but Powles says that we want to improve upon this further. This can be done with 3 different strategies, which include combination therapy, the use of biomarkers, and bringing the therapy earlier on in the disease course. So far, immunotherapy combinations have not been successful in this setting, and biomarkers are often quite complex in the metastatic space, which makes this a major challenge in moving the checkpoint inhibitors forward.

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Thomas Powles, MD, MBBS, MRCP, discusses how researchers are working to optimize treatment with immune checkpoint inhibitors for patients with urothelial carcinoma.

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