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Immunotherapy: Hope for cisplatin-ineligible advanced urothelial cancer patients?

Dr. Joseph Delano Fule Robles
29 Jan 2018

Findings of recently completed trials have shown that atezolizumab and pembrolizumab could be possible first-line therapy options for cisplatin-ineligible patients with advanced and metastatic urothelial carcinoma, according to a presentation at the Hong Kong Society of Uro-Oncology Annual Scientific Meeting 2018.

In the multicentre, phase II IMvigor210 study in 119 patients from 47 participating institutions, treatment with atezolizumab, a programmed death ligand-1 (PD-L1) inhibitor, showed an objective response rate (ORR) of 23 percent after 17.2 months of follow-up. [Lancet 2017;389:67-76]

“The ORR was better with chemotherapy, but atezolizumab fared better in terms of overall survival [OS] [median, 15.9 months vs 9.3 months],” said Dr Kala Sridhar of the Princess Margaret Hospital, Toronto, Ontario, Canada.

In the multicentre, phase II KEYNOTE-052 study in 370 cisplatin-ineligible patients with advanced urothelial cancer, treatment with pembrolizumab, a programmed death-1 (PD-1) inhibitor, showed an ORR of 29 percent after a median follow-up of 5 months. [Sridhar KS, et al, HKSUO 2018; Lancet Oncol 2017;18:1483-1492]

Some patients experienced complete response (CR) (7 percent) or partial response (PR) (22 percent), with a median OS of 11 months in the intention-to-treat population.

In a biomarker analysis, an 18-gene expression profile and PD–L1 combined positive score (CPS) were both positively associated with response. Patients with CPS ≥10 percent had higher ORR (51 percent), CR (18 percent) and PR (34 percent) than those in the total trial population. [ASCO 2017, abstract 4502]

“These drugs can be used as first-line agents and were well tolerated among cisplatin-ineligible patients, including the elderly and patients with poor performance status,” commented Sridhar.

“Other agents [nivolumab, durvalumab, avelumab] that have been tested either as second-line or first-line agents for cisplatin-ineligible metastatic urothelial carcinoma helped patients achieve an ORR of around 20–25 percent,” she added.

 “Compared with chemotherapeutic agents, treatment-related adverse events [AE] are not really an issue with anti–PD-1/PD-L1 agents, with fatigue, pruritus and rash being the most common AEs observed in clinical trials,” she continued. [Lancet Oncol 2017;18:1483-1492]

“Over the last few years, there has been a multitude of trials of anti–PD-1/PD-L1 agents used both as single agents or in combination for cisplatin-ineligible metastatic urothelial carcinoma. With these new treatment options, the focus has shifted towards developing novel biomarkers for treatment stratification,” Sridhar noted.

Ongoing phase III trials expected to be completed later this year involve comparison of outcomes in patients given atezolizumab vs atezolizumab plus chemotherapy vs chemotherapy alone (IMvigor130), and those given pembrolizumab vs pembrolizumab plus chemotherapy vs chemotherapy alone (KEYNOTE-361).

Metastatic urothelial carcinoma has a 5-year survival rate of around 5 percent. Standard first-line treatment is with cisplatin-based chemotherapy. For second-line therapy, patients are usually given taxanes or vinflunine. [J Clin Oncol 2000;18:3068-3077]

Around half of the patients with metastatic urothelial carcinoma are unfit to receive cisplatin. A drop in ORR, CR, progression-free survival and OS are experienced by cisplatin-ineligible patients who receive chemotherapy. [J Clin Oncol 2000;18:3068-3077; Eur J Cancer 2006;42:50-54; J Clin Oncol 2012;30:1107-1113; J Clin Oncol 2012;30:191-199] 

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