First-Line Chemotherapy vs Immunotherapy in Urothelial Cancer: How Do We Choose?

Arjun V. Balar, MD

On May 18, 2018, the FDA released a safety alert concerning decreased survival observed in 2 separate ongoing first-line randomized clinical trials of checkpoint inhibitors in metastatic urothelial cancer (KEYNOTE-361 and IMVigor 130) for patients treated in the monotherapy arms with low PD-L1 expression compared with patients who received cisplatin- or carboplatin-based chemotherapy. The FDA also cautioned that the populations enrolled in these studies were eligible for platinum-containing chemotherapy, which differed from those enrolled in the single-arm studies that led to the accelerated approvals of these agents as first-line therapy in cisplatin-ineligible patients with metastatic urothelial carcinoma. This safety alert raises several issues relevant to the treatment of patients with urothelial cancer and, more broadly, the clinical challenges that recent approaches by the FDA to accelerate access to novel cancer therapies to the public can pose.

The single-arm studies referenced in the FDA statement that led to accelerated approval for atezolizumab (Tecentriq) and pembrolizumab (Keytruda) were cohort 1 of IMVigor 210 and KEYNOTE-052, respectively.^1,2These studies tested immunotherapy as first-line treatment in cisplatin-ineligible patients—a poorly defined, heterogeneous and often frail and elderly population historically treated with carboplatin-based therapy, the accepted community standard, but just as often treated with single-agent chemotherapy or best supportive care alone out of concerns of excessive toxicity. Importantly, the absence of randomization increased the likelihood of chemotherapy-ineligible patients to be enrolled, which was reflected in the baseline demographics of the patients in both studies.

Urothelial cancer is a disease of older individuals, with a median age of 70, and comprises a population burdened with significant medical comorbidities. For those ineligible for cisplatin, the outcomes are undeniably poor, even with carboplatin. The advent of immunotherapy provided a very-well-tolerated option that could lead to durable remissions and, most importantly, expanded the treatable population with this disease. Thus, the approval of immunotherapy for this population was hailed, and deservedly so, as a pivotal moment in urothelial cancer treatment.

However, in the absence of randomization, questions lingered as to whether there was a population of patients who were still best served with chemotherapy, in particular since response rates with immunotherapy were in the range of 24% to 29%,1,2 which did not compare favorably with the 40% to 45% response rate historically observed with carboplatin.³There is also the issue of disease biology. Patients with high-volume and symptomatic disease, rapid kinetics, and/ or visceral metastases respond poorly to immunotherapy and are likely best served with chemotherapy as their first treatment. These issues and more are not addressed in nonrandomized studies and can lead to significant controversy when subgroup analyses from subsequent randomized trials show differential outcomes for certain populations.

For now, we must wait for more granular data from these 2 critical randomized trials. Until then, we are left to interpret the FDA’s statement on our own to then translate to our patients in discussions regarding treatment. My interpretation is that patients with low PD-L1 expression should probably receive platinum-containing chemotherapy as long as they are medically fit for it. For those who are chemotherapy ineligible, immunotherapy remains the most viable treatment option.

Nonetheless, we are likely destined to face similar challenges in the future as more drugs gain approval in the context of single arm phase I and II trials. The pace of discovery leading to a direct impact on patient care in cancer currently is unprecedented, which is of course a good thing. I just hope we can hang on for the ride.

References:

1. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line therapy in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.Lancet.2017;389(10064):67-76. doi: 10.1016/S0140-6736(16)32455-2.
2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin- ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study.Lancet Oncol.2017;18(11):1483-1492. doi: 10.1016/S1470-2045(17)30616-2.
3. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986.J Clin Oncol.2012;30(2):191-199. doi: 10.1200/ JCO.2011.37.3571.