Immune-checkpoint inhibitors changing the landscape of bladder cancer management
Since the approval of immune checkpoint inhibitors (ICIs) as standard of care in the second-line setting for metastatic urothelial carcinoma, new approaches on how clinicians manage this condition are emerging.
“For cisplatin-eligible patients, chemotherapy remains the standard of care in the first-line setting. However, ICIs may play an important role among cisplatin-ineligible patients or patients who did not respond to chemotherapy,” said Dr Darren Poon from the Department of Clinical Oncology, Chinese University of Hong Kong (CUHK).
“There are currently five US FDA-approved ICIs for the management of metastatic urothelial carcinoma in the second-line setting, namely, atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab,” Poon noted.
“Among cisplatin-ineligible urothelial cancer patients, the overall response rate is higher among patients who received gemcitabine plus carboplatin [36 percent; EORTC 30986 trial; n=238] compared with pembrolizumab [29 percent; KEYNOTE-052 trial; n=370] or atezolizumab [24 percent; IMvigor 210 cohort 1; n=119],” said Poon. [Vuky J, et al, ASCO 2018, abstract 4524; Balar AV, et al, ASCO 2018, abstract 4523; J Clin Oncol 2012;30:191-199]
The use of ICIs as neoadjuvant therapy was demonstrated by pembrolizumab in the PURE-01 study among cisplatin-eligible patients (n=50), which showed a high pathologic complete response rate (pCR; 40 percent) and an even more prominent response among PD-L1–positive patients (pCR, 54.3 percent). [J Clin Oncol 2018, doi: 10.1200/JCO.18.01148]
Similar results were reported with atezolizumab in the ABACUS study, which focused on cisplatin-ineligible patients (n=68). The study showed a pCR of 29 percent among patients treated with atezolizumab, and a pCR reaching 40 percent among those who tested PD-L1 positive. [J Clin Oncol 2018;36(suppl15): 4506-4506]
“There are currently three ongoing phase III clinical trials evaluating atezolizumab, nivolumab and pembrolizumab in the adjuvant setting. A meta-analysis has shown that chemotherapy is not very effective in the adjuvant setting for bladder cancer,” said Poon. [ClinicalTrials.gov NCT02450331; ClinicalTrials.gov NCT02632409; ClinicalTrials.gov NCT03244384; Lancet Oncol 2015:16;76-86]
In the single-arm, open-label, phase II KEYNOTE-057 study, treatment with pembrolizumab for 3 months showed a complete response rate of 38.8 percent among high-risk non–muscle invasive bladder cancer patients (NMIBC; n=103) unresponsive to Bacille Calmette-Guerin (BCG) therapy.
“It is important to note that there is very high PD-L1 expression in carcinoma-in-situ, and the expression increases 15–20 times among patients with recurrence after BCG therapy,” Poon added. [Cancer 2007;109:1499-1505]
In an ongoing phase II open-label study, investigators are assessing the efficacy and safety of nivolumab ± BMS-986205 ± intravesical BCG in patients with BCG-unresponsive NMIBC. Endpoints include complete response rate, duration of complete response, and event-free survival. The study is expected to be completed in 2023. [ClinicalTrials.gov NCT03519256]
BMS-986205 is an indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor which has demonstrated clinical activity in combination with nivolumab in patients with immunotherapy-naÏve advanced bladder cancer who have received ≥1 prior line of therapy. IDO-1 is an enzyme that facilitates tumour immune escape through activation of regulatory T cells and suppression of effector T cell proliferation.[https://www.urotoday.com/conference-highlights/asco-gu-2019/asco-gu-2019-bladder-cancer/]