The combination of nivolumab plus gemcitabine/cisplatin chemotherapy achieved high response rates and durable responses and improved overall survival and progression-free survival compared with gemcitabine/cisplatin chemotherapy alone in patients with urothelial carcinoma and clinical evidence of lymph node–only metastases (ie, cN+ urothelial cancer), providing optimism that patients with this type of urothelial carcinoma may achieve long-term remission. These findings were based on a post hoc subset analysis of the phase III CheckMate 901 trial presented at the 2024 ASCO Annual Meeting.1
The findings of the post hoc analysis characterize patients with metastatic urothelial carcinoma who are more likely to achieve the best response to the immunotherapy/chemotherapy combination.
“We have long known that lymph node–only metastatic disease is a favorable prognostic factor in patients with metastatic urothelial carcinoma and that a subset of patients with lymph node–only metastatic urothelial carcinoma achieve durable disease control with cisplatin-based chemotherapy,” said lead author Matthew D. Galsky, MD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York. Patients with lymph node–only disease are also more likely to benefit from immunotherapy, he added.
Matthew D. Galsky, MD
Study Details
The international, phase III, double-blind, placebo-controlled CheckMate 901 trial was conducted at 135 sites. The combination of nivolumab plus gemcitabine/cisplatin is already approved by the U.S. Food and Drug Administration as first-line treatment for cisplatin-eligible patients with previously treated unresectable or metastatic urothelial carcinoma, based on the primary results of CheckMate 901.2 At baseline, the median age of patients with lymph node–only metastasis was about 65 in both arms. Slightly less than 70% of both arms had an Eastern Cooperative Oncology Group performance status of 0. The rate of PD-L1 expression ≥ 1% was higher in the combination arm: 48% vs 30% in the chemotherapy arm.
A total of 608 patients were randomly assigned; of them, 18% of both arms had lymph-node–only metastatic disease. Among all patients, the complete response rate was 21.7% with nivolumab plus chemotherapy vs 11.8% with chemotherapy alone. The complete response rate for those with lymph node–only disease was almost double with the nivolumab/chemotherapy combination: 63% vs 33.9%, respectively. The 12-month complete response rate in the lymph node–only subset was more than twice as high with the combination vs chemotherapy alone: 70% vs 32%, respectively. Slightly more than half of the patients in both arms who achieved a complete response had lymph node–only disease.
The median time to complete response in patients with lymph node–only metastasis was comparable between the two treatment arms: 2.1 months and 2 months, respectively. However, the median duration of response was not reached for the nivolumab/chemotherapy arm, whereas it was 8.7 months in patients treated with chemotherapy alone.
Interestingly, analysis of complete response rates according to the site of lymph node involvement suggested the nivolumab/chemotherapy combination was more effective in patients with pelvic or retroperitoneal lymph node involvement compared with those who had distant lymph node involvement. However, the numbers were small in the group with distal node involvement.
Nivolumab plus chemotherapy extended overall survival by 42% and progression-free survival by 62% compared with chemotherapy alone.
“These results may be particularly important for thinking about treatment of patients with clinical node-positive urothelial cancer. The objective response rates and complete response rates for the combination of nivolumab with gemcitabine/cisplatin make this an attractive option for such patients in hopes of facilitating curative-intent surgery,” Dr. Galsky told listeners.
Expert Point of View
Camillo Porta, MD
Invited discussant Camillo Porta, MD, of the University of Bari Aldo Moro, Italy, said that a similar trial, EV-302, was “the elephant in the room.”3
“A recent subanalysis of EV-302 showed that the combination of enfortumab vedotin-ejfv plus pembrolizumab is highly active in metastatic urothelial carcinoma…. The combination of nivolumab plus gemcitabine/cisplatin is one therapeutic option, not the main or preferred option,” Dr. Porta said. He noted that situations such as comorbidities or specific toxicity concerns “could prompt us to prescribe one combination over the other.”
Although these results could be considered practice-changing for patients with lymph node–only metastatic disease, they should be viewed with caution, commented Dr. Porta. The study reported by Dr. Galsky was an exploratory post hoc analysis in just 18% of the study population, and results should be considered in that context, he said.
DISCLOSURE: The study was funded by Bristol Myers Squibb. Dr. Galsky holds stock or other ownership interests in Rappta Therapeutics; has served as a consultant or advisor to AbbVie, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Curis, Daiichi Sankyo Europe GmbH, EMD Serono, Gilead Sciences, Janssen, Merck, Pfizer, and Seagen; has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech/Roche, Janssen Oncology, Merck, and Novartis; and holds patents or receives royalties related to methods and compositions for treating cancer and related methods. Dr. Porta has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Genenta Science, Ipsen, Merck Serono, and MSD; has served on speakers bureaus for Bristol Myers Squibb, Eisai, Ipsen, Lilly, and MSD; and has received compensation for travel, accommodations, or other expenses from Ipsen and MSD.
REFERENCES
1. Galsky MD, et al: Characterization of complete responders to nivolumab + gemcitabine-cisplatin versus gemcitabine-cisplatin alone in patients with lymph node–only metastatic urothelial carcinoma from the CheckMate 901 trial. 2024 ASCO Annual Meeting. Abstract 4509. Presented June 3, 2024.
2. Van der Heijden MS, et al: Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. N Engl J Med 389:1778-1789, 2023.
3. Van der Heijden MS, et al: Enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated locally advanced metastatic urothelial cancer. 2024 ASCO Genitourinary Cancers Symposium. Abstract LBA530. Presented January 26, 2024.
