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PARIS -- Nearly two-thirds of patients with untreated cisplatin-ineligible advanced urothelial cancer responded to an antibody-drug conjugate (ADC) and immunotherapy, a small randomized study showed.

Overall, 49 of 76 patients responded to frontline enfortumab vedotin (EV; Padcev) and pembrolizumab (Keytruda), including eight complete responses. An additional 17 patients had stable disease, resulting in a clinical benefit rate of 86.9%. That compared with responses in 33 of 73 treated with single-agent EV.

Almost all patients had some degree of tumor shrinkage, which occurred irrespective of tumor PD-L1 status, reported Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York City, during the European Society for Medical Oncology (ESMO) annual congress.

"In this patient population with a high unmet need, EV and pembrolizumab showed encouraging activity in first-line cisplatin-ineligible patients with locally advanced/metastatic urothelial cancer," said Rosenberg. "The results were consistent with those previously reported in a . EV monotherapy results were generally consistent with previous results in the second-line setting. EV and pembrolizumab is being further investigated in three ongoing phase III trials."

"EV plus pembrolizumab has the potential to become a first-line therapeutic option for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer," he added.

Although cisplatin chemotherapy remains the standard therapeutic option for untreated advanced urothelial cancer, a substantial proportion of patients do not qualify for the therapy. Those patients currently have limited treatment options.

Individually, EV and pembrolizumab have demonstrated a survival benefit in urothelial cancer in the second line. Absent the constraints of cisplatin eligibility, a rationale existed for investigating the combination in the first-line setting.

Rosenberg reported findings from EV-103 Cohort K, a component of an ongoing clinical investigation platform evaluating EV in various combination strategies for urothelial cancer. Cohort K compared the EV-pembrolizumab combination with single-agent EV in cisplatin-ineligible patients.

Data analysis included 149 patients. The primary reasons for cisplatin ineligibility were inadequate kidney function (~60%), hearing loss (~15%), and poor functional status (~10%). Additional patients had more than one disqualifying condition.

Rosenberg emphasized that the trial was not designed for statistical comparison between the treatment groups. Nonetheless, the results showed a clear difference, as the combination arm had an overall response rate of 64.5% versus 45.2% for the monotherapy group. Clinical benefit rates were 86.9% with the combination and 79.4% with the ADC alone.

Responses to the combination were observed across all prespecified subgroups, including seven of 13 (53.8%) patients with liver metastases. Overall, 97.1% of patients in the combination arm had some degree of tumor shrinkage.

Rosenberg said the activity of single-agent EV was consistent with results observed in the second-line setting.

Median duration of response (DOR) had yet to be reached in the combination arm, and two-thirds of the 49 responses were ongoing at 12 months. Median DOR with EV was 13.2 months.

After a median follow-up of 15 months, median progression-free survival had yet to be reached with the combination versus 8.0 months with monotherapy. By blinded independent review, the 12-month PFS rate was 55.1% with the combination and 35.8% with single-agent EV.

Median overall survival (OS) was 22.3 months with the combination and 21.7 months with single-agent ADC. Independent review showed a 12-month OS rate of 80.7% with the combination and 70.7% with monotherapy.

Grade ≥3 treatment-related adverse events (TRAEs) occurred in 63.2% of the combination arm and 47.9% of the monotherapy group. The most common grade ≥3 TRAEs in the combination arm were maculopapular rash (17.1%), fatigue (9.2%), and diarrhea (6.6%). Serious TRAEs occurred in 23.7% of the combination arm versus 15.1% of patients who received single-agent EV. Three fatal TRAEs occurred in the combination group versus two in the monotherapy group.

The results are consistent with the initial assessment of the combination, which showed an overall response rate of 73%, albeit in a smaller group of patients, acknowledged ESMO invited discussant Laurence Albiges, MD, PhD, of Gustave Roussy Institute in Villejuif, France. The absolute difference from single-agent EV in Cohort K was almost 20%, and the 73% response rate from the earlier cohort exceeds historical results with chemotherapy or PD-1 inhibition.

The higher rate of high-grade toxicity with the combination should not be ignored, she added. However, the incidence in the EV monotherapy arm appeared lower as compared with the phase III EV-301 trial, which compared EV and chemotherapy in previously treated advanced urothelial cancer.

Displaying a slide showing a long list of trials of new strategies that failed to unseat chemotherapy as the first-line standard, Albiges said, "The response rate [with EV-pembrolizumab] gives us quite an optimistic point of view. We need to address one major issue: We need to have early [disease] control, and will EV-pembro provide this early control?"

"It is an evolving field," she added. "We've seen neoadjuvant data as well as adjuvant data. There are other drugs being developed in the same setting that we should be looking at carefully."

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