Joaquim Bellmunt MD, PhD
Checkpoint inhibitors have been rapidly approved by the FDA for the treatment of patients with metastatic bladder cancer, leaving a challenge of how to determine an optimal sequence. For guidance, community oncologists should refer to 2 pivotal trials, according to Joaquim Bellmunt, MD, PhD.
Two-year follow-up data from the KEYNOTE-045 trial showed sustained improvements in overall survival (OS) in patients with metastatic bladder cancer who received pembrolizumab (Keytruda) versus standard chemotherapy in the frontline setting.
Results showed that the median OS was significantly longer in those who received pembrolizumab compared with those who received chemotherapy at 10.3 versus 7.3 months, respectively (HR, 0.70; P
Progression-free survival (PFS) did not significantly differ between the 2 arms at 2.1 months versus 3.3 months, respectively (HR, 0.96; P
Based on the initial data from this trial, the FDA approved pembrolizumab in May 2017 as a frontline therapy for patients with locally advanced or metastatic urothelial carcinoma (mUC) who are ineligible for cisplatin-containing chemotherapy. Pembrolizumab also received an indication for patients with locally advanced or mUC with disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Atezolizumab (Tecentriq) is also approved as a frontline treatment for cisplatin-ineligible patients with locally advanced or mUC. In a cohort of the phase II IMvigor210 trial, results showed that the overall response rate with the PD-L1 inhibitor was 23.5% (95% CI, 16.2-32.2), including a complete response rate of 6.7%.2 The frontline approval followed its indication as a treatment for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy, or <12 months of receiving platinum-containing chemotherapy, either before or after surgery.
However, in May 2018, the FDA issued a drug safety notification warning against the use of frontline single-agent immune checkpoint inhibition for patients with urothelial carcinoma who are considered biomarker-negative; these are patients with PD-L1–low expressing platinum-eligible disease. A similar warning was issued by the European Medicines Agency, both following data demonstrating lower OS with pembrolizumab and atezolizumab versus platinum-based chemotherapy in these patients.
Despite that there have not been any head-to-head trials, Bellmunt, who is the director of the Bladder Cancer Center at Dana-Farber Cancer Institute and a professor of Medicine at Harvard Medical School, said pembrolizumab should be the frontline option followed by atezolizumab in the second-line setting for patients with metastatic bladder cancer.
In an interview with OncLive
, Bellmunt provided insight on how to navigate the complex treatment paradigm of metastatic bladder cancer.
OncLive: What are the latest advances in the treatment of patients with metastatic bladder cancer?
: We have a wealth of new opportunities for patients. In fact, we have seen that in the span of just 1 year, there have been 7 FDA approvals for immunotherapy agents in this space. Five drugs were approved for second-line treatment for patients who progress on platinum-based chemotherapy; two of these drugs were approved for the frontline treatment of patients who are ineligible for chemotherapy.
Which checkpoint inhibitor should be the first choice for treatment?
We have no head-to-head comparisons. The approvals were based mainly on phase I and II clinical trials where we saw the responses were highly durable. The survival benefit also made it worth it to use these agents. We need to move on to the era of phase III trials, and we currently have 2 of these ongoing. We can say the only one that has demonstrated a clear survival advantage is the KEYNOTE-045 trial, which compared pembrolizumab with standard chemotherapy for second-line treatment. This trial showed superiority for the checkpoint inhibitor versus chemotherapy. The quality of life was also much better for the patients who received immunotherapy.
The other trial was the [phase II] IMvigor210 study, which tested the use of atezolizumab against chemotherapy in a similar design. Atezolizumab did a great job, matching what we saw in [other] phase II studies. However, in the phase III [IMvigor211] trial, there was no statistically significant difference.