Enfortumab vedotin confers benefit ‘across the spectrum’ of advanced urothelial carcinoma
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Results of two studies presented at Genitourinary Cancers Symposium showed treatment with enfortumab vedotin-ejfv benefited patients with locally advanced or metastatic urothelial carcinoma previously treated with a PD-1 or PD-L1 inhibitor.
In the open-label phase 3 EV-301 trial, simultaneously published in The New England Journal of Medicine, enfortumab vedotin-ejfv (Padcev; Astellas, Seagen) — an antibody-drug conjugate directed against nectin-4 — significantly prolonged OS and PFS compared with standard chemotherapy among patients who previously had received platinum-based treatment. These results — intended to support conversion of FDA’s accelerated approval of the agent to a regular approval — showed a 30% reduction in the risk for death with enfortumab vedotin, supporting its use as a standard of care in this setting.
In cohort 2 of the single-arm phase 2 EV-201 study, enfortumab vedotin conferred durable responses with encouraging rates of PFS and OS among patients ineligible for treatment with cisplatin. The results suggest enfortumab vedotin may serve as an alternative to platinum therapy after progression on PD-1 or PD-L1 inhibitors, according to the researchers.
“The activity demonstrated in EV-201 cohort 2 builds upon the OS benefit shown in PD-1/PD-L1-inhibitor- and platinum-treated patients in EV-301,” Arjun V. Balar, MD, director of the genitourinary medical oncology program at NYU Langone’s Perlmutter Cancer Center, said during his presentation. “Overall, what we’ve observed is that enfortumab vedotin has activity in advanced urothelial carcinoma across the spectrum of the disease.”
EV-301
The EV-301 trial included 608 patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had progressed during or after treatment with a PD-1 or PD-L1 inhibitor.
“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging,” Thomas Powles, MBBS, MRCP, MD, professor of genitourinary oncology and director of Barts Cancer Centre of Cancer Research UK, said during his presentation. “OS is short, and therapeutic options are limited. Chemotherapy has been used as the global standard of care, but randomized trials supporting these treatment choices are actually lacking. In this setting, new therapeutic agents supported by randomized trials are needed.”
Researchers randomly assigned patients 1:1 to receive 1.25 mg/kg enfortumab vedotin on days 1, 8 and 15 of a 28-day cycle (n = 301; median age, 68 years; 79.1% men) or investigator-chosen chemotherapy — which included standard docetaxel, paclitaxel or vinflunine — on day 1 of a 21-day cycle (n = 307; median age, 68 years; 75.6% men).
OS served as the study’s primary endpoint. Secondary endpoints included investigator-assessed PFS, safety, objective response rate and disease control rate per RECIST version 1.1.
Median follow-up was 11.1 months.
Researchers reported significantly prolonged median OS (12.88 months vs. 8.97 months; HR = 0.7; 95% CI, 0.56-0.89) and PFS (5.55 months vs. 3.71 months; HR = 0.62; 95% CI, 0.51-0.75) in the enfortumab vedotin group.
“You can see that the curves go apart and stay apart, and the data look incredible in my opinion,” Powles said.
Subgroup analyses for OS broadly favored enfortumab vedotin, although some subgroups were too small to draw definitive conclusions, he added.
ORR (40.6% vs. 17.9%) and disease control rate (71.9% vs. 53.4%) also were higher in the enfortumab vedotin group (P < .001 for both).
A comparable proportion of patients in the enfortumab vedotin and chemotherapy groups experienced treatment-related adverse events (93.9% vs. 91.8%) and grade 3 or worse adverse events (51.4% vs. 49.8%).
More patients assigned chemotherapy experienced grade 3 or worse decreased neutrophil count (13.4% vs. 6.1%) and decreased white blood cell count (6.9% vs. 1.4%), whereas more patients assigned enfortumab vedotin experienced grade 3 or worse maculopapular rash (7.4% vs. 0%).
Adverse events that led to treatment withdrawal occurred among 14% of the enfortumab vedotin group and 11% of the chemotherapy group. Also, more adverse events leading to death occurred in the enfortumab vedotin group (2.4% vs. 1%).
“Enfortumab vedotin is the first drug, beyond chemotherapy and immunotherapy, to show a significant survival advantage in previously treated advanced urothelial cancer,” Powles said. “This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited.”
EV-201
In cohort 2 of the EV-201 trial, 89 patients (median age, 75 years; 74% men) with locally advanced or metastatic urothelial carcinoma who progressed on or after PD-1/PD-L1 inhibitors received 1.25 mg/kg enfortumab vedotin on days 1, 8 and 15 of each 28-day cycle. All patients were ineligible for cisplatin due to creatinine clearance less than 60 mL/min (66%), grade 2 or worse hearing loss (15%) or ECOG performance status of 2 (7%), with an additional 12% of patients meeting more than one of these criteria.
“Cisplatin-based chemotherapy is considered the standard of care in advanced disease and is associated with a survival benefit, but approximately half of all of our patients are ineligible for cisplatin-containing chemotherapy,” Balar said. “The most common reasons include poor performance status, renal dysfunction and other medical comorbidities. ... After progression on immunotherapy, these patients have limited treatment options.”
Seventy-nine percent of patients had visceral metastases, including 24% with liver metastases. Forty-three percent of patients had a primary tumor in the upper tract.
“This highlights the overall poor prognosis of patients enrolled in this trial,” Balar said, adding that the patient age skewed older (range, 49-90 years) than the typical population because this was a cisplatin-ineligible group.
Confirmed ORR per RECIST version 1.1 by blinded independent central review served as the study’s primary endpoint. Secondary endpoints included duration of response, PFS, OS and safety.
Median treatment duration was 6 months (range, 0.3-24.6).
The confirmed ORR was 52% (95% CI, 40.8-62.4), which included a 20% complete response rate. Median time to response was 1.8 months (interquartile range, 1.7-1.9), and median duration of response was 10.9 months (95% CI, 5.8-not reached), demonstrating durability of response, Balar said.
Nine percent of patients had progressive disease as their best response to treatment.
“This shows us the breadth of activity of this agent across the patients who were treated,” Balar said, adding that 88% of assessable patients had some decrease in their tumor diameters.
Researchers observed responses across all patient subgroups, including patients with primary tumors in the upper tract (ORR = 61%), with liver metastases (ORR = 48%) and who did not respond to PD-1/PD-L1 inhibitors (ORR = 48%).
Median PFS was 5.8 months (95% CI, 5-8.3) and median OS was 14.7 months (95% CI, 10.5-18.2).
The most common treatment-related adverse events included alopecia (51%), peripheral sensory neuropathy (47%) and fatigue (34%). Researchers also noted that 61% of patients experienced rash (grade 3, 17%), 54% experienced peripheral neuropathy (grade 3, 8%) and 10% experienced hyperglycemia (grade 3, 6%).
Four treatment-related deaths occurred — including cases of acute kidney injury, metabolic acidosis and multiple organ dysfunction syndrome within 30 days of the first dose, all among patients with BMI of 30 kg/m2 or greater, and one case of pneumonitis occurred 30 days after the first dose — all of which occurred among patients aged 75 years or older and with multiple comorbidities.
“The safety profile was quite tolerable, especially in a patient population that was generally elderly with many medical comorbidities,” Balar said.
“The response rates to enfortumab vedotin in this study are the highest numerically observed for any regimen in cisplatin-ineligible patients with advanced disease,” he added.
References:
Balar AV, et al. Abstract 394. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
Powles T, et al. Abstract 393. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
Powles T, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2035807.
Perspective
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Pooja Ghatalia, MD
In both the randomized, phase 3 EV-301 study and cohort 2 of the single-arm, phase 2 EV-201 study, enfortumab vedotin — an antibody drug conjugated against the nectin-4 protein — induced responses even in patients with liver and visceral metastases.
Adverse effects of special interest, including skin reactions, peripheral neuropathy and hyperglycemia, were manageable and consistent with those seen in prior phase 1/phase 2 studies of enfortumab vedotin. These adverse effects were more prominent in the EV-201 trial, but that may be related to inclusion of more frail patients in the study.
Overall, enfortumab vedotin is a good option for patients with metastatic urothelial carcinoma who have limited treatment options beyond platinum-based chemotherapy and immunotherapy.
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Powles T, et al. Abstract 393. Presented at: Genitourinary Cancers Symposium (virtual meeting); Feb. 11-13, 2021.
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