EV-302 Regimen Bests Chemo in Advanced Urothelial Cancer

Thomas B. Powles, MBBS, MRCP, MD

Findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) sent shockwaves through all in attendance at the 2023 ESMO Congress––for the first time, the tried-and-true frontline standard of care, platinum-based chemotherapy, had proven less effective in improving survival than its investigational challenger. Based on the results, investigators concluded that the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda; EVP) may become the preferred frontline standard of care for patients with locally advanced or metastatic urothelial cancer regardless of cisplatin eligibility.¹

The data were presented by Thomas B. Powles, MBBS, MRCP, MD, director of the Barts Cancer Centre at St Bartholomew’s Hospital in London.

EV-302 Trial Transforms the Frontline Treatment Landscape

The open-label, EV-302 trial enrolled 886 patients with previously untreated locally advanced or metastatic urothelial cancer eligible for cisplatin- or carboplatin-containing chemotherapy, enfortumab vedotin, and pembrolizumab. Patients were also required to be naïve to PD-(L)1 inhibitors, have a glomerular filtration rate of at least 30 mL/min, and an ECOG performance status of 2 or less.

The median age in both arms was 69 years and about three-fourths of patients were male. Most patients in the trial were White, making up 69.7% and 65.3% of patients in the EVP and control arms, respectively. About 97% of patients in both arms had an ECOG performance status of 0 or 1.

In the EVP arm, the primary tumor location was upper tract for 30.5% of patients and lower tract for 69.0%. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and approximately 72% had visceral metastases. Regarding PD-L1 status, 58% of patients in each arm had high expression (combined positive score [CPS] ≥10), with the remaining 42% having low expression (CPS <10).

Patients were randomly assigned to standard of care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (n = 444) or 1.25 mg/kg of intravenous (IV) enfortumab vedotin on days 1 and 8 and 200 mg of IV pembrolizumab on day 1 of every 3-week cycle (n = 442). The maximum number of pembrolizumab cycles allowed was 35 and there was no maximum number of cycles for enfortumab vedotin. The co-primary end points were OS and PFS per blinded independent central review (BICR).

At a median follow-up of 17.2 months, the median overall survival (OS) was 31.5 months (95% CI, 25.4-not reached [NR]) in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; P < .00001), reducing the risk of death by 53%.

The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin, and was not impacted by PD-L1 status or existence of visceral metastases.¹

Moreover, the combination led to a significant improvement in progression-free survival (PFS) vs chemotherapy, with a median PFS of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), respectively, translating to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95%, 0.38-0.54; P < .00001). The PFS benefit was sustained across all prespecified subgroups, such as those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.

Additional results showed that the confirmed objective response rate (ORR) was 67.7% (95% CI, 63.1%-72.1%) in the EVP arm compared with 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P <.00001). The ORR in the EVP group consisted of a complete response (CR) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%. The median duration of response was NR (95% CI, 20.2-NR) with the combination vs 7.0 months (95% CI, 6.2-10.2) with chemotherapy.

The median number of cycles received was 12 (range, 1-46) for EVP and 6 (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Adverse effect (AE)–related discontinuations occurred in 21.9% and 14.0% of patients in the 2 arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/L1 inhibitor and 30% of patients received maintenance avelumab.

In terms of safety, 56% of patients receiving EVP and 70% of patients who received chemotherapy experienced grade 3 or greater treatment-related AEs (TRAEs). Serious TRAEs occurred in 27.7% vs 19.6% of patients in the combination and chemotherapy arms, respectively.

EV-103 Data Deliver an Accelerated Approval

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.² The approval was based on data from the earlier EV-103/KEYNOTE-869 trial (NCT03288545). The multi-cohort study evaluated enfortumab vedotin plus pembrolizumab in dose escalation and in cohort A, and patients in cohort K were randomly assigned to receive the combination or enfortumab vedotin alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy.

Efficacy was determined by objective response rate (ORR) and duration of response (DOR) according to blinded independent central review using RECIST v1.1 criteria. The confirmed ORR in the 121 patients who received the combination was 68% (95% CI, 59%-76%), including 12% with complete responses. The median DOR for the dose-escalation cohort and cohort A was 22 months (range, 1+ to 46+) and for cohort K was NR (range, 1 to 24+).

In an interview with OncologyLive, Powles discussed the magnitude of benefit seen with the combination, both in efficacy and safety, and forecasts the potential role of the combination, both in terms of clinical practice and future benchmarks for clinical research.

OncologyLive: Please provide the rationale for evaluating enfortumab vedotin plus pembrolizumab in locally advanced or metastatic urothelial cancer.

Powles: Enfortumab vedotin is an antibody-drug conjugate [ADC] that targets Nectin-4 and has MMAE as the payload. Pembrolizumab is a PD-1 inhibitor. Both agents are widely used in urothelial cancer, particularly in platinum-refractory disease in the second- or third-line setting. In urothelial cancer, chemotherapy, either gemcitabine and cisplatin or gemcitabine and carboplatin has been the standard of care for a generation. There’s been a desire to try and supersede that with non-chemotherapy or platinum chemotherapy regimens.

The rationale was to combine these two active drugs together, enfortumab vedotin very good at getting control of disease and [pembrolizumab], which is associated with durable responses. By combining those two drugs together, we had hoped to show high response rates. [Previously], we did a phase 2 trial, and in that study, we showed that the combination was associated with a 68% response rate, about 12-month PFS about 2-year OS, and that looked higher in indirect comparisons than chemotherapy. For that reason, we embarked on a large, randomized phase 3 study comparing enfortumab vedotin and pembrolizumab with standard chemotherapy in previously untreated patients with metastatic urothelial cancer.

How was the trial designed and what were the eligibility criteria?

The EV-302 study focused on patients with first-line urothelial cancer. They had to have not had systemic therapy for advanced disease, they had to have measurable cancer, they had to have adequate organ function including adequate kidney function, and they had to be eligible for gemcitabine/cisplatin or gemcitabine/carboplatin, standard chemotherapy, and they couldn’t have contraindications to enfortumab vedotin or pembrolizumab. The trial was a one-to-one randomization, open-label trial, with PFS and OS, as primary endpoint. [Patients received] 6 cycles of chemotherapy, and pembrolizumab was given with enfortumab vedotin until progression. The trial had a statistical analysis plan that was followed, and we're presenting the interim analysis, the final analysis [for] PFS, and an interim analysis, which turned out to be the final analysis also for OS, because that [turned out to be] positive.

How do you see the results shaping the treatment armamentarium?

Approximately 850 patients were randomized to 1:1 in this trial. The population was characteristic of urothelial cancer. About 70% of patients had visceral metastasis, about 55% received cisplatin-based therapy. Most patients had performance status of 0 or 1, and the population was nicely balanced between the two arms. The median follow-up of the trial was 17 months. The results showed a dramatic increase in PFS. In fact, there was a hazard ratio of 0.45, a 55% reduction in the risk of progression compared with chemotherapy, which is somewhat unprecedented. But more importantly, we also showed an over 50% reduction in the risk of death with a hazard ratio of 0.47, and we’ve not previously managed to beat first-line chemotherapy in any trial in unselected first-line urothelial cancer. This is a big step in that direction. It’s important to recognize that there was a high response rate, 68%, a CR rate of 29%, which is impressive, and the durability of response has not yet been reached. This is a very comprehensive efficacy suite of end points, all of which have been hit.

The second component is the AE profile, and grade 3 or 4 AEs occurred with chemotherapy in 70% and with enfortumab vedotin and pembrolizumab in 56% of patients. AEs of special interest with enfortumab vedotin include skin toxicity, peripheral neuropathy, and hyperglycemia, all of which appeared manageable and in line with data we’ve seen in previous trials. Treatment-related deaths, there were only four in both arms, and those were not related to skin, peripheral neuropathy, or hyperglycemia in the enfortumab vedotin arm. It’s fair to say that these results are striking and transformative for urothelial cancer patients. An over 50% reduction in the risk of death is important. We’ve never seen anything like that before in urothelial cancer.

The control arm was platinum-based chemotherapy, six cycles, and 31% of those patients received maintenance avelumab [Bavencio] as well, which became the standard of care during the conduct of the trial. Real-world data suggest that under 50% of patients get maintenance avelumab. That is at least in part a contemporary control arm, and indeed, you can see the control arm performed well in the OS component in the trial. It’s also important to recognize the benefits were seen irrespective of platinum-based chemotherapy, PD-L1 status, and sites and metastasis. In summary, the trial is very positive. The combination is tolerable and in line with expectations. The drug works across all subgroups of patients, the control arm performed as expected. These data will be important for doctors and patients moving forward.

How do these data affect the clinical landscape and future research avenues for patients with this disease?

The future of urothelial cancer is very bright. These data will change the way we treat patients but also prompt a series of new trials. In fact, some of those trials are ongoing. We're looking at enfortumab vedotin and pembrolizumab, and enfortumab vedotin, durvalumab [Imfinzi], and tremelimumab-actl [Imjudo] in the neoadjuvant space. We have a spectrum of enfortumab vedotin and enfortumab vedotin plus immune checkpoint inhibition, particularly pembrolizumab and durvalumab/tremelimumab trials moving forward in this muscle-invasive space. I also think these data are the first combination of immune checkpoint inhibition and ADC therapy, and it’s my feeling that we need to explore this combination because it’s been so active in urothelial cancer in other cancers that have high expression of Nectin-4. It’s a very exciting time.

References

1. Powles TB, Perez Valderrama B, Gupta S, et al. 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
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. News release. FDA. April 3, 2023. Accessed October 22, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic