Conclusion. Avelumab maintenance significantly improved OS compared with BSC in patients with advanced/metastatic urothelial carcinoma whose disease did not progress after first-line platinum-based chemotherapy.
Commentary
In summary, the JAVELIN Bladder 100 trial showed significantly longer OS with the use of maintenance avelumab following first-line platinum-based chemotherapy. This survival benefit was seen in all subgroups, including those who received cisplatin or carboplatin therapy, as well as those with stable disease, partial response, or complete response to initial chemotherapy. Furthermore, the survival benefit was seen in both the overall population as well as in the PD-L1–positive population. There did not appear to be any new safety concerns noted in this trial. Based on these findings, avelumab maintenance in those who do not progress on first-line platinum-based therapy certainly represents a potentially new standard of care in this patient population. While the results of this study are promising and potentially practice changing, whether this “switch maintenance” approach is superior to treatment at progression (ie, use of checkpoint inhibition in the second-line setting) remains debatable. Nevertheless, for most patients, this appears to be the preferred approach given the notable longer OS and improved PFS, which is meaningful, particularly if the progression event is symptomatic. Furthermore, a portion of patients will not proceed to second-line therapy for a variety of reasons, and thus will not be exposed to checkpoint inhibitors if one takes a treatment break approach.
In the previous KEYNOTE-45 study evaluating pembrolizumab versus chemotherapy in the second-line setting after progression on previous platinum therapy, the median OS was just 10 months in the pembrolizumab arm.1 This is markedly different from the 21.4-month median OS noted in the current study. While there are many limitations to this comparison, it does appear that switch maintenance leads to meaningful improvements in patient outcomes. It should be noted, however, that a portion of patients will have a durable response to platinum-based therapy, and thus there may be a portion of patients who would be “overtreated” with such an approach.
A similar approach has been explored in a randomized phase 2 trial looking at maintenance pembrolizumab after first-line chemotherapy (HCRN GU14-182).2 This trial similarly showed improvement in PFS; however, OS was not yet mature at the time of data analysis. It should be noted that crossover was permitted in the HCRN study, while this was not allowed in the current Javelin 100 study. Certainly, this crossover effect influenced OS data in that trial. Thus, the current study is the first and only to show an OS benefit with such an approach in this population. Numerous ongoing studies are seeking to evaluate the efficacy of immune checkpoint inhibitors in the first-line setting for advanced urothelial carcinoma, and the results of these studies will help shed additional light regarding the efficacy of this approach.
Applications for Clinical Practice
First-line maintenance avelumab in patients who do not progress on platinum-based chemotherapy improves both progression-free and overall survival. This approach is certainly practice-changing and represents a new standard of care in this patient population. Careful discussion with each patient about the benefits and risks of a switch maintenance approach is warranted.
Daniel Isaac, DO, MS