CUA 2018: The Revolution of Immunotherapy in Genitourinary Cancers: The Tip of the Iceberg

Halifax, Nova Scotia ( Yves Fradet, MD, provided the keynote CUOG lecture at the CUA 2018 annual meeting, discussing the revolution of immunotherapy in genitourinary cancers. Fradet started by noting that CUOG will celebrate its 30th anniversary next year at the CUA and that one of the first trials to come from the cooperative group was the New England Journal of Medicine clinical trial testing interferon gamma-1b compared to placebo for patients with metastatic RCC1. Among 197 patients from 17 Canadian centers, the overall response rate for patients treated with interferon gamma-1b was 4.4% (3.3% complete response) and 6.6% (3.3% complete response) in the placebo group (p=0.54). Fradet also highlighted that BCG immunotherapy for bladder cancer was discovered in Canada (Queen’s University – Dr. Alvaro Morales) in 1976, with nearly 40 years of clinical success in Canada and subsequent FDA approval in the US in 1990.  The new era of cancer treatment is the anti-immune checkpoint therapies according to Fradet. The immune checkpoint inhibitors currently for genitourinary cancers include:

• Anti-CTLA-4:
  - Ipilimumab
  - Tremelimumab
• Anti-PD-L1:
  - Atezolizumab
  - Durvalumab
• Anti-PD-1:
  - Pembrolizumab
  - Nivolumab

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.
Similarly, there are several phase III first-line trials of PD-1/PD-L1 inhibitors with or without anti-CTLA4 vs chemotherapy in advanced urothelial carcinoma:

  • 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

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