Dr. Guru Sonpavde on Nivolumab, Gem-Cis FDA Approval and Role in Treating Metastatic Bladder Cancer

Guru Sonpavde, MD, of AdventHealth Cancer Institute, provides an overview of the trial data that led to the FDA approving nivolumab in combination with cisplatin and gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma, as well as the potential of this treatment option for patients who are ineligible for enfortumab vedotin plus pembrolizumab.

—

Dr. Sonpavde: The approval of gemcitabine-cisplatin in combination with nivolumab was based on the CheckMate 901 trial. This trial compared gemcitabine-cisplatin for up to 6 cycles versus gemcitabine-cisplatin combined with nivolumab for up to 6 cycles. Patients who were not progressing on the combination continued with nivolumab for a total of 24 months.

In this study, the co-primary endpoints for progression-free survival (PFS) and overall survival (OS) were extended. The PFS extension had a hazard ratio of 0.72, and the OS extension had a hazard ratio of 0.78. The median OS improved to 21.7 months compared with 18.9 months, respectively.

The objective response rate also improved, rising from 43.1% to 57.6% for gem-cis nivo, with the complete response rate increasing from 11.8% to 21.7%. Responses were achieved early, with a median time of 2.1 months in both arms. Notably, the duration of complete remission was significantly longer for gem-cis/nivolumab at 37.1 months compared to 13.2 months for gem-cis alone, which was the most impressive feature of this trial and contributed to its approval.

The toxicities observed were as expected for gem-cis/nivolumab, with nothing unexpected seen in the combination group. Essentially, the combination had the expected toxicities of gem-cis/nivolumab, while maintaining quality of life. These data led to the approval of gem-cis/nivolumab by the FDA for first-line treatment of unresectable or metastatic urothelial carcinoma.

These data need to be considered alongside the EV/pembrolizumab approval, which was based on the EV-302 trial, including both cisplatin-eligible and ineligible patients. In that trial, the median survival with EV pembro was 31.5 months, doubling compared to the standard arm. The complete remission rate was 29.1% versus 12.5%, and PFS was also extended, with benefits seen across all subsets, leading to FDA approval in December 2023 for advanced urothelial carcinoma.

Historically, gemcitabine platinum followed by avelumab was approved in 2020 for patients with stable or responding disease following platinum-based chemotherapy. These options provide different avenues for treatment. While the EV/pembrolizumab data are impressive with a median survival of 31.5 months, gem-cis/nivolumab might play a role in select patients, particularly those who are cisplatin-eligible due to the long duration of complete remission.

Identifying predictive biomarkers is crucial, and further research is needed in this area. For instance, lymph node-only disease might be a subgroup that could benefit. Patients with poorly controlled diabetes or significant liver dysfunction might not be suitable for enfortumab vedotin. It is worth noting that all trials required controlled comorbidities at baseline. Additionally, the JAVELIN paradigm might be suitable for patients who are unfit for aggressive combinations.

Patients with neuropathy grade 2 might find it challenging to receive both enfortumab vedotin and cisplatin, especially those with poor performance or severe comorbidities. In such cases, the JAVELIN paradigm or pembrolizumab alone might be more feasible.

Overall, while these trials provide significant advancements in first-line treatment, the majority of patients are still not cured. Therefore, participating in clinical trials remains crucial for most patients with this disease.