Adjuvant Nivolumab for High-Risk Muscle-Invasive Bladder Cancer

EP: 1.Case Overview: A 75-Year-Old Woman with High-Risk Muscle Invasive Bladder Cancer

EP: 2.Standard of Care for Muscle-Invasive Bladder Cancer

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EP: 3.Adjuvant Nivolumab for High-Risk Muscle-Invasive Bladder Cancer

EP: 4.Ongoing Clinical Trials in Muscle-Invasive Bladder Cancer

EP: 5.The Future of Treatments for Muscle Invasive Bladder Cancer

Karim Chamie, MD: In the adjuvant setting we do have an FDA-approved drug: nivolumab. Nivolumab is an anti-PD-1 inhibitor which has been shown in the CheckMate 274 study to demonstrate a recurrence-free survival benefit. Patients who've mostly have either undergone neoadjuvant chemotherapy or not, I believe that 40% of them had neoadjuvant chemotherapy and 60% didn't, underwent a radical cystectomy. Then depending upon the stage of disease, namely if they were T3, T4, or node-positive disease in the setting of non-neoadjuvant chemotherapy or T2 disease or higher or node-positive disease in the setting or prior neoadjuvant chemotherapy, those patients were included in the study. They were randomized 1-1 to either receive 1 years’ worth of nivolumab, or placebo. The patients were found to have a statistically significant recurrence-free survival benefit if they were randomized to the nivolumab arm. The median recurrence-free survival in the nivolumab arm was about 20-21 months, versus 11 months for patients who had placebo. They then looked at factors such as PD-L1 status or not, and again patients who had nivolumab and were PD-L1-positive still significantly better. They looked at non-urothelial-tract recurrence-free survival and again found that patients who had nivolumab statistically did significantly better. The data demonstrates that the drug was well-tolerated with the most common side effects being fatigue, rash, and pruritis.

In the sub-analysis, nivolumab was found to be more beneficial in patients who were PD-L1-positive. It's also found to be more beneficial when we're talking about non-urothelial-tract recurrence-free survival. It was found to be less beneficial in patients with upper-tract urothelial carcinoma. Part of the reason with the upper-tract urothelial carcinoma may be related to the fact that they're measuring recurrence-free survival. About 21% of their cohort were patients who were included in the study for upper-tract urothelial carcinoma and underwent nephroureterectomy. It's entirely possible that patients underwent nephroureterectomy and had non-muscle-invasive disease recurrences in the bladder; that was deemed to be a recurrence. It's entirely possible that there may be some noise in patients who have received placebo versus nivolumab and had recurrences in the bladder that were not clinically significant, but were defined as a recurrence.

Coming back to our case with the 75-year-old woman with clinical T3N1 disease who underwent neoadjuvant chemotherapy and radical cystectomy, the decision to pursue adjuvant therapy would be based on what we find in pathology. If the patient was found to have a positive margin in the pelvis, she's someone that I probably would offer radiation therapy. If the patient was found to have muscle-invasive disease or higher or node-positive disease, I would probably offer her adjuvant nivolumab therapy. I wouldn't offer her a chemotherapy because she's already received 4 cycles, and it's unlikely that she had a clinically meaningful response if she requires adjuvant setting. If she had a complete response, then I wouldn't offer her anything. However, if she didn't have a complete response, meaning she had T2 disease or higher or node-positive disease, I probably would move on to nivolumab.

In my experience, patients who would be good candidates for adjuvant nivolumab would be the ones that have muscle-invasive disease in the setting of prior neoadjuvant chemotherapy or nodal disease, or patients who were unable to tolerate chemotherapy. Those are the patients that I see the most benefit. I often find that these patients report very little adverse effects; they tend to have fewer complaints compared to adjuvant chemotherapy. The reason that is important is because we know that adjuvant chemotherapy is much less tolerated than neoadjuvant chemotherapy. We've looked at this and we know that 90% + of patients who've ever enrolled in a clinical trial for neoadjuvant chemotherapy can complete all 3 or 4 cycles. Whereas only about 2/3 of patients who were enrolled in clinical trials were ever able to complete their adjuvant component. In this study the vast majority, over 80% of patients, were able to tolerate a year's worth of nivolumab, let alone 4-6 cycles, which is 4-6 months.

At UCLA [University of California, Los Angeles], all patients who undergo radical cystectomy have their tissue examined for PD-L1 status; for every patient that gets a radical cystectomy, we know whether they're high-PD-L1 versus not. Now, that doesn't necessarily affect our decision-making because in the CheckMate 274 study, everybody had a significant benefit whether patients were PD-L1-positive or not. Patients who were PD-L1-positive had an even greater benefit than those who were PD-L1 negative, but everybody had a benefit from nivolumab.

Transcript edited for clarity.

Case: A 75-Year-Old Woman with High-Risk Muscle Invasive Bladder Cancer

Initial presentation

• A 75-year-old woman with gross painless hematuria in August 2020

Patient history

• Diabetes and hypertension, both of which are managed with medications
• Current smoker 10 pack/year
• ECOG PS 0
• No family history of bladder cancer

Clinical workup and imaging

• eGFR 56 mL/min
• Patient undergoes TURBT and is found to have muscle invasive bladder cancer (MIBC)
• Patient undergoes chest, abdominal and pelvic imaging and a 1 cm external iliac lymph node is identified
• Clinical stage T3N1M0 urothelial carcinoma

Treatment

• Patient undergoes neoadjuvant treatment with gemcitabine + cisplatin for 4 cycles, followed by radical cystectomy in Jan. 2021.
• Patient undergoes imaging and lab work to monitor for disease progression.