JAVELIN Bladder 100 Trial Impresses, Ensures Patients Have Access to Second-Line Immunotherapy at Disease Progression

Arjun V. Balar, MD

The plenary session of this year’s American Society of Clinical Oncology Virtual Scientific Program featured an important and highly anticipated trial in metastatic bladder cancer that evaluated the role for maintenance immunotherapy after platinum-based chemotherapy. Results from the study, JAVELIN Bladder 100 (NCT02603432), demonstrated that in patients who have achieved stable disease or better after first-line platinum-based chemotherapy, maintenance avelumab (Bavencio) significantly improved both progression-free survival and overall survival compared with best supportive care (BSC) alone.

Undoubtedly, the data from this trial significantly advance our understanding of how best to manage this disease and further shed light on how best we can use immunotherapy in metastatic bladder cancer. However, there are important limitations of this trial that should be considered, beginning by understanding the current standard of care.

Immunotherapy with PD-1/L1 blockade is the standard of care as second-line treatment after progression on prior platinum-based chemotherapy and improves survival over the previous standard of single-agent chemotherapy.¹ Thus, any trial that tests maintenance immunotherapy (ie, earlier use of second-line treatment) should ensure that all of the patients in the BSC arm at least have access to second-line immunotherapy at the time of progression. Essentially, a maintenance trial in this context, to be truly valid, should test treatment now versus treatment later, not treatment now versus treatment never. We measure the quality of this important metric by assessing the rate of “crossover” in the BSC arm, which for this trial was 41% of patients receiving immunotherapy at the time of progression.

The next point is how much crossover should reasonably be expected in this setting. In routine practice, even for patients who have achieved an excellent response to first-line chemotherapy, a nontrivial percentage of patients will either subsequently progress too quickly or will be unable or ineligible to receive second-line immunotherapy for a variety of reasons.

A similarly conducted study led by my colleague Matthew Galsky, MD, at The Mount Sinai Hospital in New York, New York, sheds light on this important issue.² This trial investigated maintenance pembrolizumab (Keytruda) versus placebo in 100 patients and enrollment occurred at selected academic sites in the United States. Although it was not designed to detect a difference in overall survival given its size, the study’s survival outcomes were virtually identical: approximately 60% to 70% of patients in the control arm were able to receive immunotherapy at the time of progression. This raises some questions about the true value of maintenance immunotherapy versus treatment at the time of progression. Regardless, as we know that some patients will progress quickly after first-line chemotherapy, why take the chance? Perhaps the safe thing to do to ensure all patients have at least a chance with immunotherapy is to take the maintenance approach. If I’m a patient facing this deadly disease, I think that’s what I’d want.

_References:

_{1. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683}

_{2. Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797- 1806. doi:10.1200/JCO.19.03091}