Arjun V. Balar, MD
After a series of rapid approvals, checkpoint blockade immunotherapy has emerged as a key component of an increasingly complex treatment landscape in advanced and metastatic urothelial carcinoma (mUC). Researchers now are turning their attention toward earlier disease settings involving patients who are refractory to standard therapies in nonmuscle-invasive bladder cancer (NMIBC) or who are poor candidates for surgery in muscle-invasive bladder cancer (MIBC).
Those were the trends that Arjun V. Balar, MD, described during a presentation at this year’s American Urological Association (AUA) Annual Meeting. Balar, a leading immunotherapy investigator, said extended follow-up has confirmed noteworthy benefits for patients with advanced disease who are cisplatin-ineligible or who progress on a platinum-based regimen.
Balar said he is encouraged about the future. “Immunotherapy is a viable treatment option for the majority of our patients,” said Balar, who is the director of the Genitourinary Medical Oncology Program at NYU Langone Medical Center in New York. “Although the pace of progress of drug development in bladder cancer is unprecedented, there remain unmet needs, including the need for reliable biomarkers and more studies exploring combination therapies.”
To date, 5 agents that target the PD-1/PD-L1 pathway have received FDA approval for the treatment of UC, the most common type of bladder cancer. These include the anti–PD-1 antibodies nivolumab (Opdivo) and pembrolizumab (Keytruda) and the anti–PD-L1 antibodies atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio). All of the drugs are approved for patients with locally advanced or metastatic UC whose disease progresses during or after platinum- containing chemotherapy. Pembrolizumab and atezolizumab also are approved for patients in this disease state who are not eligible for cisplatin- containing regimens (Figure1
However, the FDA announced on June 20 that the use of the drugs in cisplatin-ineligible patients should depend upon PD-L1 expression level based upon observed results in ongoing clinical trials.2
For cisplatin-ineligible patients, pembrolizumab is now indicated for those with a PD-L1 expression combined positive score (CPS) ≥10%. Atezolizumab is now approved for cisplatin-ineligible patients whose PD-L1 expression is ≥5% on tumor-infiltrating immune cells (ICs). Both drugs also are indicated for patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
Figure. Current Therapeutic Paradigm in Bladder Cancer1
Atezolizumab became the first approved immunotherapy for UC in May 2016 based on results from IMvigor210, a 2-cohort phase II study in patients with inoperable locally advanced or metastatic UC, said Balar. Cohort 1 consisted of 119 cisplatin- ineligible, and cohort 2 comprised 310 patients with platinum-treated metastatic disease.
Among patients who had been previously treated with platinum therapy, the median time to first response was 2.1 months, with a range of 1.6 to 8.3 months. Additional complete responses (CRs) and partial responses (PRs) were observed with longer follow-up, including conversions of 5 PRs to CRs and 2 with stable disease to PRs. Median follow-up was reported as 17.5 months (range, 0.2-21.1+).3
“The continuous treatment is feasible with immunotherapy, but not really feasible with chemotherapy, largely because of toxicity,” said Balar. “Ongoing responses in this trial are important, about 20 months or more. You typically never see this in second-line bladder cancer, which we consider a uniformly fatal malignancy.” Responses were ongoing in 37 of 46 (80%) patients per RECIST criteria and 46 of 60 (77%) patients per modified RECIST criteria. Dreicer and colleagues reported that the median duration of response was not reached in any group when results were stratified for PD-L1 status scored on tumor-infiltrating ICs.3
Extended follow-up results have also been reported for pembrolizumab in the pivotal KEYNOTE-045 trial. Updated overall survival (OS) rates presented at the European Society for Medical Oncology meeting and the Genitourinary Cancers Symposium 2018 meeting demonstrated HRs of 0.73 (P
= .0022) at 14.1 months’ median follow-up and 0.70 (P
= .00017) at 28 months follow-up, said Balar.