PD-L1 Therapy for High-Risk Superficial Urothelial Carcinoma

EP: 1.73-Year-Old Man With Locally Advanced Urothelial Carcinoma

EP: 2.Prognosis at Diagnosis of Urothelial Carcinoma

EP: 3.Results of the JAVELIN Bladder 100 Trial

EP: 4.Managing Patients on Avelumab for Urothelial Carcinoma

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EP: 5.PD-L1 Therapy for High-Risk Superficial Urothelial Carcinoma

EP: 6.Future Directions for Treating Urothelial Carcinoma

Neeraj Agarwal, MD: Let’s switch gears and look at what is exciting in the context of treatment of patients with high-risk superficial urothelial carcinoma, or superficial bladder cancer. Before I move into that discussion, let’s look at what high risk is. For medical oncologists who are increasingly treating these patients with PD-1 axis inhibitors, looking at the definition of high-risk urothelial carcinoma, it basically includes patients who have carcinoma in situ, or T1 disease, or high-grade disease. When looking at the low-grade T1, Ta disease, if they have recurrence or the tumor is large in size—more than 3 cm in size—or there are multiple sites, we can categorize them in the high-risk disease category.

Ultimately, there are multiple ways we can define these patients to have high-risk superficial bladder cancer even though there is no muscle invasion. Until recently, these patients received BCG [bacillus Calmette-Guerin] vaccination, BCG therapy, and then BCG maintenance therapy; or they were rechallenged with BCG. After that, if they had recurrence, the only option these patients had was surgical treatment with cystectomy or other definitive treatment. Obviously, this was the work of a multidisciplinary team led by surgeons, in my view. But overall, the treatment landscape for these patients has changed with the studies just reported on. One of these studies was with pembrolizumab, known as the KEYNOTE-057 study. Hopefully more PD-1 axis inhibitors will show benefit in this setting, but other trials will be reported on very soon.

With pembrolizumab, we saw close to 40% responses that were durable, which was exciting news for our patients. Based on the results of these responses, pembrolizumab was approved as therapy for patients who have high-risk recurrent non-muscle-invasive superficial bladder cancer. I expect more PD-1 axis inhibitors to be approved in this setting in the near future. We saw approximately 40% complete responses that were durable, of high degree.

There’s also a subset of patients who don’t want to go for a cystectomy. No matter how much evidence we show them, they just cannot accept the idea of removing the bladder, and we respect their decisions. For those patients, this is a great option—using pembrolizumab therapy after recurrence is established.

As I said, the field is rapidly evolving. There are ongoing trials, and hopefully we’ll have better options for these patients. One trial is avelumab with BCG in patients who have had BCG in the past and have recurrence of bladder cancer, or superficial bladder cancer. Avelumab is combined with BCG. The other trial is looking at atezolizumab with intravesical BCG therapy in high-risk invasive bladder cancer. It’s being led by Dr Daniel Castellano in Spain. The trial was presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2020.

With these trials, in my view, PD-1 axis inhibitors are going to be moving upstream. Right now, we have PD-1 axis inhibitors approved for second-line metastatic urothelial carcinoma. We have avelumab with a category 1 indication for frontline maintenance therapy. We have pembrolizumab approved for patients who have recurrence after BCG therapy in high-risk superficial bladder cancer. We’ll be seeing the movement of PD-1 axis inhibitors like avelumab or atezolizumab continue to evolve further upstream in combination with BCG therapy in patients who have recurrence, or maybe up-front BCG therapy in combination with atezolizumab in those patients who have high-risk superficial bladder cancer.

It will be fascinating to see how these trials pan out. It will be fascinating to see how things evolve and how these immune checkpoint inhibitors move upstream. We are really looking forward to data from these trials that are going on and are really hoping that none of our patients develops metastatic or locally advanced urothelial carcinoma with early intervention.

Transcript edited for clarity.

Case Overview: A 73-Year-Old Male With Urothelial Carcinoma

Initial presentation

• A 73-year-old man presents with LUTS with intermittent hematuria
• PMH: HTN, well-controlled on an ARB; mild hepatic and renal impairment
• PE: distension of bladder; slow flow on voiding
  
  

Clinical workup

• Labs: Hb 11.4 g/dl, WBC 3.5 x 109/L, AST and ALT: ~4x ULN, CrCl: 35 mL/min; others WNL
• Cystoscopy: showed a 2.6 cm mass around the neck of the bladder
• TURBT was performed; transition cell carcinoma of the urothelium, with tumor invading the perivesical tissue
• Chest/abdomen/pelvic CT scan: large bladder mass, evidence of multiple regional lymph nodes involved (perivesical and sacral), and a 2.3 cm mass in the left upper lobe
• Stage IIIB; ECOG PS 1

Treatment

• Patient received 6 cycles of carboplatin + gemcitabine; achieved partial response
• CT abdomen/pelvis showed decrease size in bladder mass, nodal findings mildly improved, no evidence of new disease
• Initiated avelumab 10 mg/kg IV q2W as maintenance therapy