Immunotherapy shows robust potential for metastatic urothelial cancer
Chemotherapy has shown dismal results in treatment of metastatic urothelial cancer (UC). The advent of immunotherapy in UC has improved responses and overall survival (OS) in both chemotherapy-pretreated and treatment-naïve patients, according to data presented at the recent 15th Urological Association of Asia Congress held in Hong Kong.
Results of the phase III KEYNOTE-045 trial in 542 UC patients previously treated with platinum-based chemotherapy showed a longer duration of OS among those randomized to receive the anti-PD1 therapy pembrolizumab vs standard chemotherapy (median, 10.3 vs 7.4 months; hazard ratio [HR], 0.73; p=0.002). [N Engl J Med 2017;376:1015-1026]
“The progression-free survival [PFS] curves did not separate until later [after 8 months of treatment], which is a typical characteristic of immunotherapy due to a phenomenon called ‘pseudo-progression’,” explained Dr Tsun-Wen Chong of the Singapore General Hospital, Singapore.
In the phase II IMvigor210 trial composed of 119 platinum-ineligible and 316 platinum- pretreated metastatic UC patients, overall response rate (ORR) was higher with the anti-PD-L1 therapy atezolizumab vs historical controls (15 vs 10 percent; p=0.0058). [Lancet 2016;387:1909-1920]
“However, the phase III IMvigor211 trial showed no difference in OS between atezolizumab and chemotherapy. We are awaiting the details,” added Chong. [https://www.gene.com/media/press-releases/14665/2017-05-09/genentech-provides-update-on-phase-iii-s]
“Patients usually respond better to anti-PD1/PD-L1 therapy if they have high PD-L1 expression. However, low PD-L1 expression did not preclude response when anti-PD1/PD-L1 therapy was used in first-line or second-line treatment of metastatic UC,” commented Chong. [Lancet 2017;389:67-76; Lancet 2016;387:1909-1920; ASCO 2017, abstract 4528; Lancet Oncol 2017;18:312-322; N Engl J Med 2017;376:1015-1026]
In another study, ORR of patients with the luminal subtype II of muscle-invasive bladder cancer was found to be significantly higher than that of patients with other luminal (luminal I) or basal (basal III and basal IV) subtypes (p=0.0072). [Nat Rev Urol 2014;11:400-410]
In a multicentre, phase II study of 123 patients, higher mutational loads in the tumour was associated with significantly better OS with atezolizumab in both platinum-pretreated (p=0.0012) and platinum-ineligible (p=0.0079) patients. [Lancet 2017;389:67-76]
“To further improve response, novel approaches under investigation include the use of oncolytic viruses and indoleamine 2,3-dioxygenase [IDO] inhibitors, which both enhance cellular immune responses,” explained Chong. [J Immunother Cancer 2015;3:51]
“The treatment landscape for UC is evolving rapidly with the recent US FDA approval of checkpoint inhibitor therapy as a new standard of care in platinum-pretreated patients. These checkpoint inhibitors also prove to hold significant promise in treatment-naïve patients unfit for cisplatin. Future research will be driven by molecular mechanisms of immunotherapy resistance,” Chong concluded.
Upregulation of the PD1/PD-L1 pathway limits immune activation. Cancer cells highjack this pathway to dampen the immune response. PD1/PD-L1 pathway inhibitors reverse these effects, resulting in enhanced cancer cell recognition by T cells and immune activation.