Enfortumab Vedotin Plus Pembrolizumab Leads to Shifts in Frontline Metastatic Urothelial Cancer Management

Janaki Neela Sharma, MD

The combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) has reshaped the way that patients with locally advanced or metastatic urothelial cancer are treated in the frontline setting, according to Janaki Neela Sharma, MD, who added that emerging data across the first-line therapy space have added key decisions for this patient population

In an interview with OncLive®, Sharma expanded on the road to the FDA approval of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer, highlighted first-line data for other regimens such as nivolumab (Opdivo) plus chemotherapy or avelumab (Bavencio) maintenance, and contextualized how all of the emerging data have affected treatment decision-making in clinical practice. Sharma serves as an assistant professor of clinical medicine in Genitourinary Medical Oncology at the University of Miami Health Systems, in Florida.

OncLive: How has the integration of enfortumab vedotin into the frontline setting for advanced urothelial cancer affected the current treatment landscape of bladder cancer?

Sharma: We haven't seen drugs with that kind of high [overall] response rate [ORR], durability of response, and overall survival [OS] benefit [in bladder cancer]. It's pretty unusual in many solid tumors to see that kind of ORR, and to see it in bladder cancer was outstanding.

Initially, getting [FDA accelerated] approval [of frontline enfortumab vedotin plus pembrolizumab] for cisplatin-ineligible patients [in 2023] was a great first step, and it was fascinating for the patients because there was a short period of time where cisplatin-ineligible patients could [receive the combination], but cisplatin-eligible patients couldn't. In that scenario, it was better to be a cisplatin-ineligible patient because you could get this combination of drugs.

Now that we have [full] approval [for the frontline combination] for all comers with metastatic bladder cancer—one with a pretty tolerable adverse effect profile—people are switching over to [using this as a standard] first-line therapy. However, this complicates the landscape for second-line and beyond. There is a question of what the ORR looks like for traditional chemotherapy such as cisplatin/gemcitabine after patients already received enfortumab vedotin plus pembrolizumab. Those are some questions that we don't have the answers to yet.

In terms of optimal sequencing down the line, we also don't know if enfortumab vedotin plus pembrolizumab in the first line is better than gemcitabine, cisplatin, and nivolumab in the frontline. Clearly, the results of [phase 3 EV-302] trial [NCT04223856] look better than the results of the [phase 3 CheckMate 901 study (NCT03036098), which supported the FDA approval of frontline nivolumab plus chemotherapy in March 2024]. However, without a head-to-head comparison [between enfortumab vedotin plus pembrolizumab vs nivolumab plus chemotherapy], evidence-based medicine practitioners are not going to [call] one superior to the other.

Outside of data from enfortumab vedotin plus pembrolizumab, what other trials have led to shifts in the bladder cancer treatment landscape?

The phase 3 JAVELIN Bladder 100 trial [NCT02603432] is a bit of an older trial that first read out in 2020. JAVELIN Bladder 100 took patients with metastatic bladder cancer, and after they had received standard [frontline] chemotherapy [without disease progression], investigators randomly assigned patients to receive maintenance immunotherapy with avelumab plus best supportive care [BSC] or BSC alone. The primary end point in this trial was OS. It turned out that there was a significant OS benefit with [maintenance avelumab] after chemotherapy. After 2020, the standard of care was to use immunotherapy as maintenance after up-front chemotherapy.

We didn't see any real advances beyond [avelumab] until 2023, and that's when the enfortumab vedotin data read out from the phase 1b/2 EV-103/KEYNOTE-869 trial [NCT03288545]. That was a dose-escalation and -expansion trial with multiple arms. Patients with frontline metastatic bladder cancer who were cisplatin-ineligible [experienced] progression-free survival and OS benefits.

The OS with enfortumab vedotin in the frontline [setting] for cisplatin-ineligible patients ended up being 26.1 months, which is almost one-third higher than what we were seeing with traditional chemotherapy.¹ The most exciting [part] of this was that the ORR was [77.3%] in this cisplatin-ineligible [population], whereas previous ORRs with traditional chemotherapy were closer to 30% or 40%.

How did data from EV-302 further define the role of frontline enfortumab vedotin plus pembrolizumab in patients with advanced urothelial cancer, irrespective of cisplatin eligibility?

EV-302 read out [in 2023], and that was looking at the combination of enfortumab vedotin plus pembrolizumab in all comers with [previously untreated] metastatic bladder cancer, including both cisplatin-eligible or -ineligible patients. The control arm was standard-of-care chemotherapy with gemcitabine and cisplatin. [Data from this study] led to the eventual full FDA approval for [treatment with this combination] in patients with bladder cancer in the frontline [setting].

We saw the same OS benefit [in a cisplatin-eligible and -ineligible population]. [Data presented at the 2023 ESMO Congress showed] the median OS for enfortumab vedotin plus pembrolizumab was 31.5 months.² The survival benefit didn't change much between cisplatin-ineligible vs -eligible patients in the pre-planned subgroup analysis.

We again saw that high ORR in EV-302, [where] enfortumab vedotin plus pembrolizumab generated a confirmed ORR of 67.7%, whereas standard-of-care chemotherapy had an ORR of 44.4%.

What were the key data from the CheckMate 901 trial, and where does nivolumab plus chemotherapy fit into the frontline treatment setting for advanced urothelial cancer?

Along with [enfortumab vedotin plus pembrolizumab], there was another frontline immunotherapy trial that also read out [at the 2023 ESMO Congress] called CheckMate 901, which [evaluated] the combination of traditional chemotherapy, such as platinum plus gemcitabine, and nivolumab followed by nivolumab maintenance. This was a large phase 3 trial. Patients were randomly assigned to receive [nivolumab or placebo plus chemotherapy, followed by nivolumab or placebo maintenance].

[Data showed nivolumab plus chemotherapy elicited] a median OS of 21.7 months.³ This was better than traditional chemotherapy where your median OS is approximately 18 to 20 [months], which was consistent with this trial [where the median OS was 18.9 months in the control arm].

However, when we look at CheckMate 901, we saw an ORR of 57.6% with the combination of [nivolumab] and chemotherapy, whereas you were approaching 70% with enfortumab vedotin plus pembrolizumab [in EV-302]. Although you can't compare between trials and there were similar improvements in efficacy [with nivolumab plus chemotherapy vs enfortumab vedotin plus chemotherapy], we have seen a larger percentage of patients have a response to the enfortumab vedotin and pembrolizumab combination, which is why I think it is in the forefront of most providers’ treatment armamentarium.

References

1. 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
2. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
3. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial. Ann Oncol. 2023;34(suppl 2):S1341. doi:10.1016/j.annonc.2023.10.107