Enfortumab Vedotin for Metastatic Urothelial Cancer After Progression on Platinum-Based Chemotherapy

Petros Grivas, MD, PhD, Fred Hutchinson Cancer Center, Seattle, Washington, outlines a treatment plan for a patient with metastatic urothelial cancer who progressed after completing a gemcitabine-cisplatin chemotherapy regimen.

Dr Grivas explains and provides evidence for the next line of treatment a clinician may consider in this particular situation.

Transcript:

I'm Dr Petros Grivas. I'm a medical oncologist in Seattle. I'm a professor of oncology and also serve as a clinical director at the University of Washington for the Genitourinary Cancers Program at the Fred Hutchinson Cancer Center. I'm very excited about the developments in the field of urothelial cancer.

Today, I will present a case for you. A 75-year-old woman with a new diagnosis of metastatic urothelial cancer of the bladder presented with enlarged pelvic and retroperitoneal lymphadenopathy and 2 small metastatic lesions in the left lung. The performance status was ECOG 1. The patient has hypertension, hyperlipidemia, but otherwise good normal organ function and there is no hearing loss, neuropathy or autoimmune disease. Creatine clearance is 60 mL/minute and the PD-L1 score is 15, by composite positive score (CPS) using the 22C3 antibody.

A discussion took place with the patient and because she was deemed to be fit for cisplatin, she received appropriately 6 cycles of gemcitabine-cisplatin chemotherapy, with eventual complete response. There was an interim CT CAP (chest-abdomen-pelvis) that showed partial response after 3 cycles. Patient tolerated chemotherapy well and continued beyond the 3 cycles to receive, as I just said, a total of 6 cycles of chemotherapy. And gemcitabine-cisplatin is the standard chemotherapy for cisplatin-fit patients.

At the CT after 6 cycles, the patient had a complete response. She went on to receive switch maintenance avelumab, an anti-PD-L1 agent, based on the results of the JAVELIN-Bladder-100 trial that showed statistically and clinically significant overall survival and progression-free survival benefit with switch maintenance avelumab plus best supportive care vs best supportive care alone. That has been the standard of care for patients with response or stable disease to first-line platinum-based chemotherapy. The patient tolerated the treatment well with no significant adverse events and had a CT CAP every 2 months, with continued complete response.

However, about 10 months into the avelumab treatment, there was a CT CAP scan that showed the 3 new liver lesions about 1.5 centimeter each. The performance status remains ECOG 1. The patient denies any neuropathy or skin rash or diabetes mellitus and is willing to come to treatment in the cancer center. Next-generation sequencing of the tumor tissue, that was done before at the time of diagnosis of metastatic disease, which is a common scenario, did not reveal the presence of any FGFR alterations.

The question is, what systemic therapy would you recommend? I would particularly pay attention to the fact that the next generation sequencing was negative for activating mutation or fusion, for FGFR2 or FGFR3. So erdafitinib is not indicated in this setting. We have data from the EV-301 phase 3 trial, comparing enfortumab vedotin to either docetaxel, paclitaxel or vinflunine, which showed significant overall survival benefit and progression-free survival benefit and much higher response rates with enfortumab vedotin, 41% with enfortumab and only 18% with other salvage chemotherapy.

Because of that difference in response rates, and also the PFS and significant overall survival benefit, enfortumab vedotin is the Level I evidence-based agent in this setting. This is technically a second-line setting, because the chemotherapy and the avelumab maintenance given in the first-line setting, so here we are in progression, second-line setting. Enfortumab vedotin has that Level I evidence based on what we just discussed: The EV-301 trial, which was published by Dr Thom Powles [MBBS, MDCP, MD, Barts Cancer Centre at Bartholomew’s Hospital, London, United Kingdon] and colleagues in the New England Journal of Medicine and I think that represents the preferred choice, based on level of evidence.

However, there is also data with sacituzumab govitecan, and an accelerated approval by the FDA based on phase 2 trial data, specifically from Cohort 1 of the TROPHY-U-01 trial, that showed very significant activity with this antibody drug conjugate. The response rate of sacituzumab govitecan was 27% in a heavily pretreated population. So, sacituzumab-govitecan is also an option. However, the level of evidence here favors enfortumab vedotin based on the phase 3 trial that led to the regular approval vs the accelerate approval of sacituzumab.

Based on what I discussed before, I would not use another taxane agent at this point. I would reserve taxane for the future. And there is, I would say, no good data for rechallenging with platinum-based chemotherapy. Obviously, there is about 10 months interval since the patient started avelumab, but I think with the existence of antibody drug conjugate, I would probably switch to that category at this point. I would use enfortumab vedotin as a preferred option in this particular case. If the patient had significant grade 2 or higher neuropathy, or maybe uncontrolled diabetes mellitus with high obesity, the case could be made for sacituzumab to be given before enfortumab. But again, at this particular point in this case, with no exclusions or contraindications, enfortumab vedotin has the Level I evidence.

Sacituzumab govitecan should be considered in the treatment paradigm of this patient at some point, and docetaxel, maybe later on. There is an ongoing phase 3 trial that is comparing sacituzumab govitecan with docetaxel or paclitaxel or vinflunine, the TROPIC-04 trial, that's going to answer the question for better survival benefit or not with Sacituzumab govitecan, which already has accelerated approval.

We are excited to have many options in this setting that did not exist even 4 years ago, and we’re waiting for even more options down the road, as well as for validated biomarkers to help select patients in the future.

Thank you so much for attending this case scenario and look forward to having more options for patients in the future. Thank you.

Source:

Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384:1125-1135. doi:10.1056/NEJMoa2035807