Yu then highlighted the strict criteria for what makes a patient “unfit” for cisplatin, based on the criteria as previously stated by Galsky et al. :
- WHO or ECOG performance status of 2 or Karnofsky performance status of 60-70%
- Creatinine clearance <60 mL/min
- CTCAE v4 grade ≥2 audiometric hearing loss
- CTCAE v4 grade ≥2 peripheral neuropathy
- NYHA class III heart failure
Yu’s opinion, there is no role for carboplatin for patients that are unfit for cisplatin-based chemotherapy. As he points out, in oncology, platinum in the curative setting is universally cisplatin, not carboplatin (e.g. germ cell tumors, lung cancer, etc). Standard of care would be to proceed with cystectomy, but these patients have a high-risk of systemic relapse. Indeed, clinical trials for this patient population are needed.
In 2018, we now have five PD-1/PD-L1 antibody FDA approved therapies for urothelial cancer: pembrolizumab, atezolizumab, nivolumab, durvalumab, and avelumab. The publication last year of KEYNOTE 045 showed a 27% reduction in mortality favoring pembrolizumab vs chemotherapy in the second-line setting (HR 0.73, 0.59-0.91), sparking great interest for immunotherapy in the bladder cancer population .
There are several points regarding why we need neoadjuvant clinical trials that Dr. Yu highlights:
- There is an unmet need as there have been no new advancements in this disease state since cisplatin, and patients have a high risk of relapse
- Low toxicity yet efficacious options now for more advanced disease with logical rationale to test in this earlier setting
- Tissue acquisition for translational biomarker studies to better understand the biology
- There is a decent endpoint with complete response
- The patient is treatment naïve and generally in good health
- Neoadjuvant atezolizumab for localized bladder cancer: non-metastatic BCG refractory NMIBC or non-metastatic MIBC who are ineligible or refusing cisplatin-based chemotherapy (n=40). Primary endpoint: T cell infiltration; secondary endpoint: pT0 at cystectomy
- Neoadjuvant durvalumab + tremelimumab: MIBC patients not eligible for cisplatin based chemotherapy (n=68). Primary endpoint: objective response rate by RECIST v1.1 criteria
- Neoadjuvant nivolumab +/- urelumab: cisplatin ineligible MIBC (n=22 per arm). Primary endpoint: CD8+ T cell density; secondary endpoints: safety profile, <pT2N0 rate, pCR rate
- Neoadjuvant nivolumab +/- lirilumab: MIBC patients not eligible for cisplatin based chemotherapy (n=40). Endpoint: pT0
1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
2. Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long term results of the BA06 30894 trial. J Clin Oncol 2011;29(16):2171-2177.
3. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol 2011;29(17): 2432-2438.
4. 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.
Presented by: Evan Y. Yu, MD, University of Washington, Seattle, WA
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
Read the Original Presentation: Treatment for MIBC for Cis-Platinum Ineligible Patients: Immediate Cystectomy