Two-drug combination a potential new standard in advanced urothelial cancer
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Key takeaways:
- First-line treatment with pembrolizumab and enfortumab vedotin nearly doubled OS and PFS.
- The combination is a potential new standard for first-line treatment of this population, researchers concluded.
MADRID — A two-drug combination improved outcomes compared with first-line chemotherapy for adults with locally advanced or metastatic urothelial carcinoma, according to findings presented at ESMO Congress.
The randomized phase 3 KEYNOTE-A39/EV-302 trial met its dual primary endpoints, showing the combination of pembrolizumab (Keytruda, Merck) and enfortumab vedotin (Padcev; Seagen, Astellas Pharma) nearly doubled OS and PFS among patients with previously untreated disease who were eligible for cisplatin- or carboplatin-containing chemotherapy.
The findings support the combination as a potential new standard of care for first-line treatment of this population, according to Thomas Powles, MBBS, MRCP, MD, professor of genitourinary oncology and director of Barts Cancer Centre at St. Bartholomew’s Hospital in England.
“This is the first time we have managed to beat chemotherapy in the first-line setting for overall survival, despite multiple previous attempts,” Powles said.
Platinum-based chemotherapy has been standard first-line treatment for locally advanced or metastatic urothelial carcinoma for decades.
“There is a very high unmet need,” Powles said. “Median survival has been stuck at about 12 to 14 months for a generation, and long-term survival is really poor.”
The FDA previously granted accelerated approval to the combination of pembrolizumab — a PD-1 inhibitor — and the antibody-drug conjugate enfortumab vedotin-ejfv as first-line treatment for cisplatin-ineligible adults with locally advanced or metastatic urothelial carcinoma.
The global, open-label KEYNOTE-A39/EV-302 trial served as the confirmatory trial to support the accelerated approval.
The trial included 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma regardless of PD-L1 expression.
Researchers randomly assigned 442 patients to 3-week cycles of enfortumab vedotin 1.25 mg/kg via IV on days 1 and 8, with pembrolizumab dosed at 200 mg IV on day 1. Protocol specified a maximum 35 cycles for pembrolizumab but no maximum for enfortumab vedotin. The other 444 patients received gemcitabine with cisplatin or carboplatin for up to six cycles.
Treatment continued until disease progression, clinical progression, unacceptable toxicity or maximum cycles.
PFS per blinded independent central review and OS served as dual primary endpoints. Secondary endpoints included overall response rate and safety.
The combination and chemotherapy groups appeared balanced for demographics and baseline characteristics, including sex (male, 77.8% vs. 75.7%), age (median, 69 years each), race (white, 69.7% vs. 65.3%), geographic region and ECOG performance status (0 or 1, 96.7% vs. 97%).
At data cutoff, one-third (33%) of patients assigned the combination remained on treatment.
Median follow-up was 17.2 months.
Results showed the enfortumab vedotin-pembrolizumab combination significantly prolonged PFS, reducing risk for progression or death by 55% (median, 12.5 months vs. 6.3 months; HR = 0.45; 95% CI, 0.38-0.54). The PFS benefit appeared consistent in select prespecified subgroups, including those based on age, sex, ECOG performance status, primary disease site, liver metastases or PD-L1 expression.
Patients assigned the combination also achieved significantly longer OS, with the combination reducing the risk for death by 53% (median, 31.5 months vs. 16.1 months; HR = 0.47; 95% CI, 0.38-0.58).
The OS benefit appeared consistent regardless of cisplatin eligibility (eligible, HR = 0.53; 95% CI, 0.39-0.72; ineligible, HR = 0.43; 95% CI, 0.31-0.59), PD-L1 expression (high, HR = 0.49; 95% CI, 0.37-0.66; low, HR = 0.44; 95% CI, 0.31-0.61) and other prespecified factors.
Researchers also reported a higher confirmed ORR (67.7% vs. 44.4%; P < .00001) and a higher complete response rate 29.1% vs. 12.5%) in the combination group.
“This complete response rate is not something we’ve seen before,” Powles said. “The median duration has not been reached, so it’s the durability as well as the high response rate that is translated into the overall survival signal.”
The combination exhibited a generally manageable safety profile, Powles said.
Four treatment-related adverse events occurred in each treatment group. In the combination group, the deaths were due to asthenia, diarrhea, immune-mediated lung disease and multiple organ dysfunction syndrome. In the chemotherapy group, the deaths were due to febrile neutropenia, myocardial infarction, neutropenic sepsis and sepsis.
Grade 3 or higher treatment-related adverse events occurred among 55.9% of patients assigned the combination and 69.5% of those assigned chemotherapy. The most common such events in the combination arm included maculopapular rash (7.7%), hyperglycemia (5%), and neutropenia (4.8%), whereas the most common such events in the chemotherapy arm included anemia (31.4%), neutropenia (30%), and thrombocytopenia (19.4%).
The most common grade 3 or higher treatment-related adverse events of special interest with enfortumab vedotin included skin reactions (15.5%), peripheral neuropathy (6.8%) and hyperglycemia (6.1%); whereas the most common such events of special interest with pembrolizumab were severe skin reactions (11.8%).
Perspective
Back to TopAndrea B. Apolo, MD
This is monumental for our field. We welcome a new standard of care in the management of advanced/metastatic urothelial carcinoma. But with new standards of care come questions and challenges.
What would be the best second-line therapy? Does cis-platinum move to the second line? What about third and fourth lines? Is there a role for immune checkpoint inhibition after enfortumab vedotin-pembrolizumab? We need to conduct clinical trials to answer these questions, and to assess the efficacy and toxicity after enfortumab vedotin-pembrolizumab.
How can we reduce the toxicity of enfortumab vedotin-pembrolizumab? Enfortumab vedotin has a unique toxicity profile, including peripheral neuropathy — which can be treatment limiting — skin reactions, ocular toxicity and hyperglycemia. Can we give enfortumab vedotin maybe for 6 months in combination and then continue pembrolizumab as maintenance? Can we dose de-escalate enfortumab vedotin for responders? It will be crucial to assess the efficacy of dose de-escalation studies. A better understanding of the complementary mechanisms of enfortumab vedotin plus pembrolizumab will help us build on its therapeutic effect and target mechanisms of resistance.
What is the efficacy of enfortumab vedotin-pembrolizumab in earlier states of disease, such as muscle invasive and non-muscle invasive.
And we must discuss the cost. Enfortumab vedotin-pembrolizumab is expensive. Will patients, insurance and public systems be able to afford this treatment?
The future looks bright for our patients. Enfortumab vedotin-pembrolizumab has raised the bar for OS in metastatic urothelial carcinoma.
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Powles TB, et al. Abstract LBA6. Presented at: European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid.
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