Avelumab first-line maintenance for advanced or metastatic urothelial carcinoma: analysis from JAVELIN Bladder 100 trial

Since the phase 3 JAVELIN Bladder 100 trial, patients with advanced urothelial carcinoma (UC) were found to have significantly longer progression free survival (PFS) with avelumab first-line maintenance plus best supportive care (BSC) compared to BSC alone (1,2). Prior to JAVELIN trial, patients with locally advanced or metastatic UC underwent chemotherapy with studies only recommended up to six cycles but no further information on timing, or amount or duration based on individual factors (3,4). In addition, the optimal number of chemotherapy cycles preceding maintenance avelumab and its ideal timing of avelumab is not well known. A significant portion of patients are unable to tolerate that amount. No prior publications have focused on these subsets of patients with advanced UC without progression after 4–6 weeks of chemotherapy.

We applaud the contribution of Sridhar et al., in their study: “Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance” (5). This article further breaks down outcomes based on duration, number of chemotherapy cycles, and interval between chemotherapy and starting maintenance avelumab to provide a better clinical guidance and individualized treatment approach.

There was a good long-term follow-up with median ≥38 months. Group stratifications also benefited from being separated by complete or partial response and location of metastasis which could confound overall survival. Conversely, there are some considerations to interpreting the study. The study did not consider dose density or intensity for chemotherapy. There were some discrepancies with cycle timing which was <17 days being the same cycle and >17 days being a new cycle. The number of cycles was extrapolated from data records so the actual number may be different. There is limited information on how this 17-day timeline was decided on, however, this could model troubleshooting timing in real life as mentioned, such as patient or provider preference, room capacity, logistics etc. The study does mention that they did not include patients with intervals shorter than 4 weeks or longer than 10 weeks. While their decision regarding greater than 10 weeks unlikely to provide potential survival benefit, it could have been beneficial to include those with less than 4 weeks for resolution of chemotherapy related toxicity and what their baseline characteristic stratification was.

Some other important factors to consider when interpreting the study findings. There also was no formal statistical analysis of baseline characteristics which may have elucidated why certain individuals tolerated BSC better than others or why some had longer interval times to reach symptom free status after chemotherapy. However, baseline characteristics were at least well broken down and it was even noted that the 4- to less than 6-week interval between chemotherapy and start of maintenance subgroup included higher proportions of patients with Eastern Cooperative Oncology Group (ECOG) performance status 1 and visceral metastases which could enriched the study population with reduced length of survival. While this trial did not study those who received chemotherapy less than four cycles or greater than six cycles, there have already been previous reports showing no significant difference in overall survival with more (3). Lastly while quality of life (QoL) assessment was not within the primary outcome of this trial and is being studied in the DISCUS phase 2 trial, it will be interesting to see the impact of three versus six cycles of chemotherapy on QoL in these subgroups.

In conclusion, this well-formulated post hoc analysis substantiates utilization of avelumab first-line maintenance plus BSC compared to BSC alone and better elucidates duration, number of chemotherapy cycles and interval between chemotherapy and start of maintenance immunotherapy. As such, both first-line chemotherapy and first-line avelumab can be tailored according to individual patient factors. Further attention should be focused on assessing secondary outcomes such as QoL and analyzing baselines patient characteristics and how to interpret those to make decisions on duration or timing of treatments.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-16/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-16/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020;383:1218-30. [Crossref] [PubMed]
2. Grivas P, Park SH, Voog E, et al. Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial. Eur Urol 2023;84:95-108. [Crossref] [PubMed]
3. Sonpavde GP, Mariani L, Lo Vullo S, et al. Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma. J Urol 2018;200:1207-14. [Crossref] [PubMed]
4. Grivas P, Agarwal N, Pal S, et al. Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice. Cancer Treat Rev 2021;97:102187. [Crossref] [PubMed]
5. Sridhar SS, Powles T, Climent Durán MÁ, et al. Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance. Eur Urol 2024;85:154-63. [Crossref] [PubMed]