Joaquim Bellmunt MD, PhD
The therapeutic landscape is rapidly being altered by clinical trials of immunotherapy for patients with metastatic urothelial carcinoma (mUC), but simply changing the way quality of life (QoL) is monitored could provide dramatic improvements in overall survival (OS), according to findings presented at the 2017 Global Congress on Bladder Cancer.
Immunotherapy concerns regarding atypical responses and immune-related adverse events (AEs) must also be taken into account, experts added.
“The current standard of care in metastatic urothelial cancer is cisplatin-based chemotherapy, which provides a high initial response rate; however, these responses are rarely durable and the median OS is approximately 12 to 15 months,” said Joaquim Bellmunt MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center at Dana-Farber Cancer Institute.
“The 5-year OS rate with cisplatin regimens is only around 13%, indicating a high unmet need for new treatments,” he continued. “Furthermore, there is little consensus on how to treat metastatic urothelial cancer that has relapsed or is refractory to first-line platinum-based chemotherapy.”
Bellmunt added that taxanes are currently used in the United States, while vinflunine is commonly used in Europe. However, neither shows a statistically significant improvement in OS over best supportive care.
Bellmunt discussed the promising treatment of inhibiting the pathway regulated by PD-L1 and PD-L2, which are expressed on tumor cells and allow immune escape by binding to activated T cells. “Targeting PD-1 and PD-L1 has shown clinically meaningful antitumor activity,” said Bellmunt, adding that immunotherapeutic agents pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq) are approved in the European Union for treatment of patients with mUC. During the congress, he provided an overview of second-line immunotherapy clinical trials, referencing the IMvigor210 trial of atezolizumab and the CheckMate-032 and CheckMate-275 trials of nivolumab, which have demonstrated objective response rates (ORR) of 15%, 25%, and 19.6%, respectively.1,2,3
The issue of prognostic markers of response remained a major issue, citing IMvigor211 where an OS advantage was demonstrated for atezolizumab over chemotherapy in the overall population. However, this primary endpoint was not met in the subgroup of patients with higher PD-L1 expression on immune cells (IC2/3) as expected.
He explained that PD-L1 expression may be an unreliable marker for immunotherapeutic response and advised using the more traditional markers of ECOG performance scores of 0 to 1 versus 2, hemoglobin levels <10 versus ≥10, the presence of liver metastasis, and the time from last chemotherapy dose of <3 versus ≥3 months as better indicators of response. A combined positive score (CPS) of these factors that is indicative of poorer response was developed by his group. Regarding efficacy with pembrolizumab, mature results of the KEYNOTE-045 trial demonstrated an OS benefit with the PD-1 inhibitor over chemotherapy at a median follow-up of 22.5 months in both arms. The median OS was 10.3 versus 7.4 months with pembrolizumab and chemotherapy, respectively (HR, 0.70; P
Additionally, significantly improved OS was observed regardless of the level of PD-L1 expression, as measured by CPS, with patients having CPS ≥10% demonstrating a median OS of 8.9 with pembrolizumab versus 5.2 months with chemotherapy (HR, 0.58; P
KEYNOTE-045 also demonstrated a superior safety profile for pembrolizumab over chemotherapy, with 62.0% versus 90.6% of patients experiencing a treatment-related AE (TRAE), and 16.5% versus 50.2% of patients experiencing grade ≥3 AEs, respectively. Pembrolizumab was associated with a low rate of immune-related AEs, with hypothyroidism being the most often reported any grade (<10%) and colitis grades 3 to 5 being reported by <3% of patients.
In discussing trials of immunotherapy as first-line therapy in cisplatin-ineligible patients, Bellmunt noted that atezolizumab demonstrated median OS of 15.9 months overall in the IMvigor210 trial, but 12.3 versus 19.1 months, respectively, in the IC2/3 versus IC0/1 subgroups. He noted that the tumor mutation load (TML) was higher in responders versus non-responders across all subgroups, and patients with high TML also showed prolonged OS.5
“Data from studies of immunotherapy in the first- and second-line [setting] for treatment of patients with mUC are available and support immunotherapy as a promising new treatment for these patients,” Bellmunt concluded.