First-line combination demonstrates durable benefit in advanced urothelial carcinoma
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Key takeaways:
- Nearly three-quarters of patients responded to the combination of enfortumab vedotin-ejfv and pembrolizumab.
- Approximately 64% of responses lasted at least 12 months.
CHICAGO — First-line enfortumab vedotin-ejfv plus pembrolizumab conferred promising long-term outcomes for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, study results presented at ASCO Annual Meeting showed.
After median follow-up of nearly 4 years, researchers reported median response duration of more than 22 months and median OS of more than 26 months.
“Results for this patient population have never reached this magnitude,” researcher Shilpa Gupta, MD, director of genitourinary medical oncology at Taussig Cancer Institute and co-leader of the genitourinary oncology program at Cleveland Clinic, told Healio. “This is very encouraging because the tail of the curve is still holding. It’s not like we saw great responses and good survival outcomes at 2 years but then patients dropped off. The key is the durability of responses, which is very reassuring.”
Background
Multiple treatment options are available for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. These include carboplatin-based chemotherapy, PD-1/PD-L1 inhibitors and maintenance avelumab (Bavencio; EMD Serono, Pfizer), an anti-PD-L1 inhibitor.
Cisplatin-ineligible patients historically achieved median survival of 6 to 9 months with platinum-based therapy, and more recent trials that incorporated maintenance avelumab reported median OS of 13 to 14 months, Gupta said.
“Patients who just receive platinum-based chemotherapy typically experience poor outcomes,” Gupta said. “We have seen improvement in OS with avelumab maintenance; however, there is an unmet need, as not everyone who responds to chemotherapy gets avelumab maintenance. We want something patients can start as front-line chemotherapy and then continue, in hopes of improving outcomes and avoiding dropout.”
Enfortumab vedotin-ejfv (Padcev; Astellas, Seagen) is a first-in-class antibody-drug conjugate directed against nectin-4, a protein highly expressed in urothelial cancers. Pembrolizumab (Keytruda, Merck) is an anti-PD-1 therapy.
Both agents have prolonged survival as monotherapy for treatment-naive patients with locally advanced or metastatic urothelial carcinoma.
The phase 1B/phase 2 EV-103 study assessed enfortumab vedotin alone or with other therapies for urothelial cancer.
The FDA granted accelerated approval to the combination as first-line treatment for cisplatin-ineligible adults with locally advanced or metastatic disease based on efficacy and safety findings from two study cohorts.
Results
At ASCO, Gupta and colleagues presented updated efficacy and safety data from Study EV-103’s dose escalation/cohort A.
The analysis included 45 patients (median age, 69 years; range, 51-90) with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma.
All patients received enfortumab vedotin dosed at 1.25 mg/kg on days 1 and 8 in combination with pembrolizumab on day 1 of every 3-week cycle.
Safety and tolerability served as the primary endpoint. Key secondary endpoints included confirmed objective response rate, duration of response and PFS — all assessed by investigators and blinded independent central review — and OS.
Median follow-up was 47 months. All patients had discontinued treatment and 18 remained on study at data cutoff.
After a median nine treatment cycles, results showed a confirmed ORR by blinded independent central review of 73.3% (95% CI, 58.1-85.4), with a 15.6% complete response rate and an 84.4% (95% CI, 70.5-93.5) disease control rate.
Results showed a median response duration of 22.1 months (95% CI, 8.38 to not reached), with 63.9% (95% CI, 44.19-78.17) of responses lasting at least 12 months.
Investigators reported median PFS of 12.7 months (95% CI; 6.11 to not reached), a 12-month PFS rate of 55% (95% CI, 38.84, 68.58), median OS pf 26.1 months (95% CI, 15.51 to not reached) and a 12-month OS rate of 83.4% (95% CI, 68.25-91.72).
The most common treatment-related adverse events of special interest with enfortumab vedotin included skin reactions (66.7%), peripheral neuropathy (62.2%) and ocular disorders (40%).
The most common treatment-emergent adverse events of special interest with pembrolizumab included skin reactions (24.4%), pneumonitis (8.9%), colitis (6.7%) and hypothyroidism (6.7%).
More than half (60%) of patients received subsequent cancer therapies. These included systemic therapy (48.9%), surgery (8.9%) and palliative radiotherapy (8.9%). The most common second-line systemic therapies included pembrolizumab (17.8%), carboplatin-based therapy (11.1%) and enfortumab vedotin (6.7%).
Next steps
The efficacy of the combination observed in cohort A has been replicated in Study EV-103’s cohort K, Gupta said.
In that cohort, researchers randomly assigned patients to enfortumab vedotin with or without pembrolizumab. However, follow-up is shorter in cohort K than cohort A.
Consequently, the randomized phase 3 EV-302 trial — which completed enrollment late last year — can be viewed as confirmatory, Gupta said.
The two-arm trial is designed to compare enfortumab vedotin and pembrolizumab vs. chemotherapy alone — gemcitabine-cisplatin or carboplatin — for untreated locally advanced or metastatic urothelial cancer.
The trial includes patients who are cisplatin eligible and cisplatin ineligible.
“We certainly hope the results we have seen so far are maintained,” Gupta said. “Outside of the U.S., this combination will only get approved if there is an OS benefit, so all eyes are on EV-302 to see whether this combination can replace the current standard of care.”
Perspective
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Sarmad Sadeghi, MD
This presentation provided an update on results of Cohort A of the EV-103 trial, published last year in Journal of Clinical Oncology. Gupta and colleagues concluded that this combination continues to show efficacy with an acceptable toxicity profile.
In April, the FDA granted accelerated approval to the enfortumab vedotin-pembrolizumab combination based on results of Cohort K. This randomized cohort compared enfortumab vedotin plus pembrolizumab (n = 76) to enfortumab vedotin alone (n = 73). Researchers reported ORRs of 64.5% with the combination vs. 45.2% for enfortumab vedotin alone, demonstrating an ORR improvement of 20 percentage points by adding pembrolizumab. This is in line with expectations for ORR for pembrolizumab monotherapy in this disease. The toxicity profile was similar to that reported for Cohort A.
This combination has significant toxicities; however, given the high response rate and lack of equally effective standard-of-care options available to patients with advanced or metastatic urothelial carcinoma, this combination presents a reasonable option.
This combination is now available for cisplatin-ineligible patients in frontline setting and is a significant step forward in development of therapies for this aggressive and deadly cancer. This approval has significantly changed the treatment landscape of this disease. Whether this combination in frontline should be offered to cisplatin-eligible patients is a question that can’t be answered by this trial. Therefore, at this time, patients who are cisplatin-eligible should continue to be treated with cisplatin-based chemotherapy. This is appropriate because there is opportunity for most cisplatin-eligible patients to receive immunotherapy in maintenance or second line settings followed by enfortumab vedotin.
As immunotherapy and antibody-drug conjugates find a role in neoadjuvant and adjuvant settings, the optimal sequence of therapy — especially the use of platinum-based regimens in subsequent lines of therapy — will remain a research question. Finally, toxicity build-up — particularly neuropathy — may become a limiting factor on the option available for a subsequent line of therapy now that we have several drugs and regimens with overlapping toxicities.
References:
Rosenberg J, et al. Abstract LBA73. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
Yu EY, et al. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00094-2.
Perspective
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Gupta S, et al. Abstract 4505. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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