Targeting PD-L1 blocks signaling between the tumor cell and both PD-1 and B7.1, and may prevent down-regulation of T cell activity. The PD-L2/PD-1 interaction is preserved, and may potentially minimize effects on immune homeostasis. Targeting PD-1 blocks signaling between the tumor cell and PD-1, possibly sparing the interaction between the tumor cell and B7.1. PD-L2/PD-1 interaction is blocked and may potentially increase the chance of autoimmunity.
Fradet then discussed the KEYNOTE-045 phase III RCT, testing pembrolizumab in the second-line setting2. This study compared pembrolizumab and investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine), and found a median OS of 10.3 months (95%CI 8.0-11.8) in the pembrolizumab group, compared with 7.4 months (95%CI 6.1-8.3) in the chemotherapy group (HR 0.73, 95%CI 0.59-0.91). Furthermore, the median OS among patients who had a tumor PD-L1 combined positive score (CPS) of ≥10% was 8.0 months (95%CI 5.0-12.3) in the pembrolizumab group, as compared with 5.2 months (95%CI 4.0-7.4) in the chemotherapy group (HR 0.57, 95%CI 0.37-0.88). Based on these results, pembrolizumab was FDA approved for the treatment of locally advanced or metastatic urothelial carcinoma in the second line.
The KEYNOTE-052 phase II trial of first-line pembrolizumab in cisplatin-ineligible patients reported that among 370 patients receiving at least one dose of pembrolizumab, 89 (24%, 95%CI 20-29) patients had a centrally assessed objective response, and 74 (83%) of 89 patients had ongoing responses over a median follow-up of 5 months (IQR 3.0-8.6)3. Additionally, a PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab: 42 (38%, 95%CI 29-48) of 110 patients had an objective response. Based on these results, pembrolizumab was granted FDA approval for the treatment of cisplatin-ineligible patients with advanced urothelial carcinoma. In an updated analysis of KEYNOTE-052 reported last month at ASCO, pembrolizumab appears to have clinically meaningful and durable results (follow-up time more than twice as long as reported in the initial analysis) in a heavily treated and comorbid population of which ~50% of patients were ≥75 years of age 4.
In the neoadjuvant setting for urothelial carcinoma, Fradet highlights the PURE-01 study, a phase II open-label, single-arm trial evaluating the effects of pembrolizumab administered prior to radical cystectomy 5. The first stage of enrollment included 43 patients, among which there were 35 males/7 females, with 37.2% of patients with cT2N0 disease, 58.1% with cT3N0, and 4.7% of patients with T2-3N1. At the time of this analysis, there were 17/43 patients that were pT0 (39.5%, 95%CI: 26.3-54.4) and 5 <pT2 (total <pT2 rate: 51.2%). Similarly, the ABACUS study is a single arm, phase II trial investigating two cycles of atezolizumab (1200mg every three weeks) prior to radical cystectomy 6. Among 68 evaluable patients, the baseline pT2 rate was 71%, pT3 was 22%, and pT4 was 7%. The pathologic complete response rates were 29% for all patients, 40% for PD-L1 positive patients, 16% for PD-L1 negative patients, 35% for cT2 patients, and 15% for cT3-T4 patients.
Fradet concluded by highlighting several trials that will be reporting results over the next few years. Currently, there are several phase III first-line treatment trials of PD-1/PD-L1 inhibitors vs chemotherapy in advanced urothelial carcinoma. These include:
- KEYNOTE-361 (n=990): pembrolizumab + cisplatin + gemcitabine vs pembrolizumab vs standard of care chemotherapy. Estimated primary completion June 1, 2019.
- IMvigor 130 (n=1,200): atezolizumab + cisplatin + gemcitabine vs atezolizumab vs standard of care chemotherapy. Estimated primary completion December 31, 2018.
- DANUBE (n=1,200): durvalumab + tremelimumab vs durvalumab vs standard of care chemotherapy. Estimated primary completion September 23, 2019.
- CheckMate 901 (n=897): nivolumab + ipilimumab nivolumab vs nivolumab + cisplatin + gemcitabine nivolumab vs standard of care chemotherapy. Estimated primary completion April 26, 2020.
1. Gleave ME, Elhilali M, Fradet Y, et al. Interferon-gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med 1998;338(18):1265-1271.
2. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.
3. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
4. Vuky J, Balar AV, Castellano DE, et al. Updated efficacy and safety of KEYNOTE-052: A single-arm phase 2 study investigating first-line pembrolizumab in cisplatin ineligible advanced urothelial cancer. ASCO 2018 abstr 4524.
5. Necchi A, Briganti A, Bianchi M, et al. Preoperative pembrolizumab before radical cystectomy for muscle-invasive urothelial bladder carcinoma: Interim clinical and biomarker findings from the phase 2 PURE-01 study. ASCO 2018 abstr 4507.
6. Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle-invasive bladder cancer (ABACUS). ASCO 2018 abstr 4506.
Presented by: Yves Fradet, MD, CHU de Quebec – Universite Laval – L’Hotel-Dieu de Quebec, Quebec, Canada
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia
Further Related Content:
Watch: Long-term Efficacy with Atezolizumab an IO Update- Arjun Balar