Enfortumab Vedotin Plus Pembrolizumab May Address Unmet Need in Advanced Urothelial Cancer

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Jonathan E. Rosenberg, MD, discusses key safety and efficacy data from the EV-103 trial supporting supplemental biologics license applications seeking FDA approval of enfortumab vedotin plus pembrolizumab in patients with advanced urothelial cancer.

Jonathan E. Rosenberg, MD

Jonathan E. Rosenberg, MD

Administration of the antibody-drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) with the PD-L1 inhibitor pembrolizumab (Keytruda) has resulted in durable efficacy with a manageable safety profilein patients with locally advanced or metastatic urothelial carcinoma. Available data with this regimen could lead to accelerated approval in the frontline setting, potentially ameliorating the historically poor prognoses observed in those who are cisplatin ineligible, according to Jonathan E. Rosenberg, MD.

On December 20th, 2022, the FDA granted priority review to supplemental biologics license applications (sBLAs) seeking the approval of enfortumab vedotin and pembrolizumab in combination for patients with locally advanced or metastatic urothelial cancer who are cisplatin ineligible.1

The applications were supported by data from the phase 1b/2 KEYNOTE-869/EV-103 trial (NCT03288545). In the dose-escalation cohort, cohort A, the combination elicited a confirmed overall response rate (cORR) of 73.3% (95% CI, 58.1%-85.4%).2 Updated findings from cohort K presented at the 2023 Genitourinary Cancers Symposium showed that the combination induced a cORR of 64.5% (95% CI, 52.7%-75.1%) in the overall cohort, with a consistent ORR observed across all prespecified subgroups.3 Treatment-related adverse effects (TRAEs) led to treatment interruption or dose reduction in 68.4% and 48.7% of patients, respectively, but were determined to be manageable with close monitoring and dose modifications.

The regulatory agency is expected to decide on both applications by April 21, 2023.

“This combination might be a game changer for the treatment of advanced urothelial cancer. We have not seen regimens that had response rates of over 60% in repeated studies,” said Rosenberg, chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology, Enno W. Ercklentz Chair in Genitourinary Oncology at the Memorial Sloan Kettering Cancer Center (MSKCC), and attending physician at Memorial Hospital at MSKCC, New York City, New York. “[The regimen is] not limited by renal function, which is a major concern for [patients with] advanced bladder cancer.”

In an interview with OncLive®, Rosenberg discussed key safety and efficacy data from the EV-103 trial supporting sBLCAs seeking FDA approval of enfortumab vedotin plus pembrolizumab in patients with advanced urothelial cancer.

OncLive®: What unmet needs prompted the examination of enfortumab vedotin plus pembrolizumab in this population?

Rosenberg: Patients who are cisplatin-ineligible still have suboptimal outcomes, despite the use of sequential chemotherapy and immunotherapy in responders and salvage immunotherapy in non-responders. [Although these approaches are considered to be the] standard of care, it is not really based on overwhelming evidence. Historical studies with carboplatin and gemcitabine showed a survival of about 9 months. In modern studies, [survival] is [around] 13 months with better supportive care, perhaps better patient selection for chemotherapy, and perhaps some patients are not receiving chemotherapy and are going on more modern trials. In patients who respond to treatment, maintenance therapy probably [prolongs survival by] an additional 6 months. We need better options for patients with metastatic disease who are not candidates for cisplatin-based chemotherapy. That was the rationale behind the patient population [selected] in this clinical trial.

Could you expand on the mechanisms of action for these two agents?

Enfortumab vedotin is an antibody-drug conjugate. [The monoclonal antibody] targets nectin-4 and is conjugated through a linker to monomethyl auristatin E [MMAE]; it circulates through the body and binds nectin-4, and it is [then] internalized into the cancer cell and releases MMAE into the lysosome [killing] the cancer cell. There may be bystander effects, as well. Preclinical evidence support the fact that MMAE [can] trigger immunogenic cell death, leading to the production of damage-associated molecular patterns. [These patterns] stimulate dendritic cells, [which then] signal to immune cells.

All of this provides the rationale for using PD-1 inhibitors like pembrolizumab [Keytruda] in this space. The thought is that the PD-1 inhibitor is working within the tumor, allowing immune cells that are trafficked to the tumor to recognize cancer cells and improve the cell kill from enfortumab vedotin. It’s possible that these are additive effects, although data do [indicate] some synergy particularly with regard to response durability. [Historically,] the durability of responses for pembrolizumab monotherapy is very long, and the durability of enfortumab vedotin monotherapy is [only] 6 to 9 months on average. With the combination, we get a high rate of tumor reduction and durability that you might expect from an immunotherapy.

What key efficacy data were reported from cohorts A and K in the EV-103 trial, and what updates were presented at the 2022 Genitourinary Cancers Symposium?

Cohort A was the dose-escalation cohort. [Data] from this cohort were reported in the Journal of Clinical Oncology. [In this group, we observed] an objective response rate [ORR] of 73%. The median duration of response [DOR] and median survival [were both] approaching 2 years. This is unheard of in that patient population. [These data] provided the rationale for the randomized study of enfortumab vedotin and pembrolizumab [as well as] enfortumab vedotin monotherapy. The enfortumab vedotin monotherapy cohort was [examined] to contextualize the relative contribution of enfortumab vedotin to [patient] outcomes. We’ve had large trials of pembrolizumab monotherapy in the first-line setting, but there have not been trials of enfortumab vedotin monotherapy in this setting.

Cohort K was the randomized cohort. Patients who received enfortumab vedotin and pembrolizumab had a response rate of 64.5%, and a response rate of [45.2%] in patients who received enfortumab vedotin alone. [As such,] the [response rate] was numerically higher in the patients who received the combination. It’s important to remember that this was a non-comparative study; it was not really designed to compare the two regimens. The time-to-event end points are maturing.

Data [presented at] the 2023 Genitourinary Cancers Symposium [from cohort K appear] to be similar to [what was seen in] cohort A, [in that] the durability of responses is very long. Overall survival, although [the data are] immature, appears to be quite long as well.

What next steps are planned for this research?

We’re very excited to see more mature data and we hope that these results are maintained over time. There is a randomized phase 3 trial, EV-302 [NCT04223856], comparing enfortumab vedotin and pembrolizumab [with] cisplatin- or carboplatin-based chemotherapy. The study has finished accrual, but [the data] are not mature. We’re looking to see those results in a year or two. If that trial is positive, it will lead to the full approval of [enfortumab vedotin plus pembrolizumab] for bladder cancer, regardless of platinum eligibility.

What should be known about the toxicity profile of this regimen?

The safety profile of enfortumab vedotin and pembrolizumab is relatively similar to each drug’s [individual profile]. We do see more skin rashes than with either drug alone; this is not a surprise because skin toxicity is a risk with both agents. Notably, there were no life-threatening or fatal [toxicities] in cohort K of EV-103. [The profile] seems to be a mix of enfortumab vedotin–mediated toxicity directly to the epidermis from drug deposition and in some patients, immune-mediated toxicity. Most of the time, [these toxicities are] similarly treated with either topical or oral steroids. In general, enfortumab vedotin has a low rate of severe skin toxicity. Providers need to be aware of and monitor for this as they start to use the drug. In my own practice, I see patients from day 1 and day 8 of the cycle for the first several months. [Many] providers will [only] see the patient on day 1 and may miss the signs of early skin toxicity; that may be an early warning sign for more serious AEs.

There was a low rate of pneumonitis, but it might be a bit higher than what you might expect from pembrolizumab; it has been reported with enfortumab vedotin, as well. Peripheral neuropathy [can also occur] with this combination based on the toxicity profile of enfortumab vedotin. [Because] enfortumab vedotin has high antitumor activity and durability, patients [stay] on the drug for a long time and can develop neuropathy. [This] can be a dose-limiting AE of enfortumab vedotin; in my experience, this is not related to or worsened by the pembrolizumab. [This toxicity] may [require] patients to dose reduce, take breaks, or [discontinue treatment]. Providers should be aware of this when using enfortumab vedotin as a monotherapy or in combination.

When thinking about using enfortumab vedotin, it is important to also measure and monitor a patient’s glucose [levels] during treatment, as some patients are susceptible to developing hyperglycemia. Rarely, that toxicity can lead to extreme hyperglycemia, [especially] if other AEs like severe skin toxicity arise. [Extreme hyperglycemia] is rare, [occurring in] only 1% or fewer [patients], but about 20% of patients do experience some degree of hyperglycemia. As such, keeping an eye on patients’ blood sugar is important. Some can be managed with metformin or other diabetic agents. In my limited experience, this toxicity will get better when you stop the enfortumab vedotin. This is another unique toxicity from ADCs that is worth noting.

How would the FDA approval for enfortumab vedotin plus pembrolizumab in urothelial cancer improve the treatment paradigm for this population?

With this regimen, if we’re seeing response rates ranging from 60% to 70%, that means we can quickly palliate disease-related symptoms. The median time to response [for both arms was about 2 months], or by the first imaging, and those responses appeared to be very durable. If we have two-thirds of patients responding to treatment, that is very different from the 35% to 40% of patients responding to treatment with platinum-based chemotherapy.

I suspect that the FDA will [grant] accelerated approval to this regimen based on the available data and I hope to see confirmatory data in the randomized phase 3 [EV-302] trial.

This would be the first time we see an improvement in survival compared with [standard] platinum-based chemotherapy. Other [phase 3 trials of PD-1 inhibitors], such as KEYNOTE-361 [NCT02853305] and IMvigor130 [NCT02807636]…have failed to improve on gemcitabine and platinum in randomized settings.

Editor’s Note: Dr. Rosenberg reports serving as a consultant or on a paid advisory board for Aadi, Alligator, Seagen, Astellas, Boerhinger Ingelheim, EMD-Serono, Gilead, Hengrui, IMVax, NCCN, Merck, Tyra; he received honoraria from Clinical Care Options, OncLive, Mashup Media, Research to Practice; he received lecture fees from speaking at the invitation of a commercial sponsor from EMD-Serono, Pfizer.


  1. Seagen, Astellas, and Merck announce FDA acceptance of sBLAs for Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for the first-line treatment of certain patients with locally advanced or metastatic urothelial cancer. News release. Seagen, Astellas, and Merck. December 20, 2022. Accessed February 24, 2022. https://investor.seagen.com/enfortumab -vedotin-ejfv-with-KEYTRUDA
  2. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol. 2023;41(1):22-31. doi:10.1200/JCO.22.01643
  3. O’Donnell PH, Rosenberg JE, Homes CJ, et al. Enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC): subgroup analyses of confirmed objective response rate (cORR) from EV-103 cohort K. J Clin Oncol. 2023;41(suppl.6):499. doi:10.1200/JCO.2023.41.6_suppl.499
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