Urothelial carcinoma is the most common type of bladder cancer. Recently, two clinical trials explored the use of immunotherapy to treat patients with urothelial carcinoma. Additional research is also underway. In this interview, ONCOLOGY spoke with Arjun V. Balar, MD, the director of the Genitourinary Medical Oncology Program at New York University Langone’s Perlmutter Cancer Center. Dr. Balar, who specializes in the treatment of patients with bladder, prostate, kidney, and testicular cancers, discussed the treatment landscape for urothelial carcinoma, as well as promising advances that have the potential to change practice.
Q: Several immunotherapies have now been approved by the US Food and Drug Administration (FDA) for the treatment of urothelial carcinoma, both for treatment-naive patients and those with relapsed/refractory disease. Can you provide a brief overview of these therapies?
DR. BALAR: The current landscape of available immunotherapies for advanced bladder cancer can be broken down into two disease states. The first group, the disease state that was tested during initial development, includes patients who are refractory to platinum-based chemotherapy—including cisplatin- or carboplatin-based treatments. In this setting, five different FDA-approved agents are available: two agents that target the programmed death 1 (PD-1) pathway, specifically the PD-1 receptor, and three agents that target programmed death ligand 1 (PD-L1), which is the ligand for PD-1 (Figure). Essentially, these drugs lead to a range of responses from 15% to 21%.
There are two trials involving two agents that have shown a benefit vs chemotherapy, which was the standard of care before immunotherapies were available: a study of pembrolizumab and an intent-to-treat analysis from an atezolizumab study. In the first-line setting, these two FDA-approved agents are available for patients who are cisplatin-ineligible. Both agents were tested in single-arm clinical trials focused on patients with advanced bladder cancer who were ineligible for cisplatin-containing chemotherapy. The data from these studies demonstrated a response rate in the range of 23% to 29% and a median survival as high as 15.9 months, which was observed with atezolizumab.
More recently, we found more evidence from two separate randomized trials informing us how best to use these agents in the cisplatin-ineligible patient population. Specifically, safety alerts from two randomized phase III trials, KEYNOTE-361 and IMvigor130, showed that patients with low levels of PD-L1 expression did better if they received platinum-based therapy rather than immunotherapy. As a result, in August 2018, the FDA amended the prescribing labels for both atezolizumab and pembrolizumab to limit their use to cisplatin-ineligible patients with advanced bladder cancer who have low PD-L1 expression or are ineligible for any platinum-containing chemotherapy. In addition, the prescribing information was updated to require the use of an FDA-approved test specific for each individual agent to better guide patient selection.
Q: Ongoing trials are now combining immunotherapy with either another immunotherapy agent or with another modality, such as a targeted agent or chemotherapy. In February of this year, the results of the PIVOT-02 trial were released. This trial focused on front-line treatment of advanced or metastatic urothelial carcinoma with a combination of NKTR-214 and nivolumab, which is approved on its own to treat bladder cancer. Can you tell us more about the design and results of PIVOT-02?
DR. BALAR: PIVOT-02 is a fairly large phase I study that served as the initial development platform for the agent NKTR-214. Specifically, this agent is essentially a reformulation of one of the oldest immunotherapy compounds to be tested in cancer, interleukin-2. Going back to the 1990s, interleukin-2 was administered as a high-dose intravenous bolus treatment for 5 consecutive days in a monitored intensive care treatment setting within the hospital because it causes an intense systemic immune response that causes patients to become quite sick; however, at the end of therapy, up to 10% of patients with advanced kidney cancer were essentially cured of their stage IV disease.
Now, fast forward to the 2010s, and this agent was reformulated by adding 6 polyethylene glycol (PEG) molecules to create a slow-release formulation. As the PEG molecules decrease from 6 PEGs down to 2, the active form of the cytokine is then present in the body, allowing immune stimulation, as well as preferential immune stimulation toward immune effector T cells, while minimizing stimulation of the suppressive T cells (regulatory T cells).
The PIVOT-02 study tested nivolumab in combination with NKTR-214, which was administered once every 3 weeks in the outpatient setting, so that the toxicities were much milder compared with patients receiving high-dose interleukin-2. In this particular study update, a cohort of 41 patients with advanced bladder cancer who were treatment-naive received first-line nivolumab and NKTR-214. The data were presented at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium and included the 27 efficacy-evaluable patients, defined as those who had at least one response-evaluable imaging after starting protocol therapy. Essentially, the researchers found that up to 48% of patients achieved an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and 52% of patients had an immune-related RECIST response. Additionally, of the 15 patients with visceral metastases, 8 had responses to therapy. So, this agent seems to be quite active, even in patients with visceral metastases.
Interestingly, 6 patients achieved a complete response, suggesting that NKTR-214 is quite active and may actually deepen responses in combination with nivolumab. A subgroup correlative analysis of this study found that, among patients who underwent an on-treatment biopsy vs a baseline biopsy, an influx of CD8+ T cells were present within tumors; in addition, the level of PD-L1 expression increased among patients who received combination therapy, suggesting that NKTR-214 can actually induce a more vigorous local immune response. While these data are promising, they involve only the 27 efficacy-evaluable patients; the study is ongoing and will enroll more patients. Ultimately, randomized trials will be necessary to really understand what NKTR-214 truly adds to nivolumab monotherapy for patients with advanced bladder cancer.
Q: Pembrolizumab is now being tested in earlier stages of disease. The results of the phase II PURE-01 clinical trial of pembrolizumab as a neoadjuvant therapy before cystectomy in patients with muscle-invasive bladder cancer were reported last year. Can you tell us about the results of this trial and their potential significance for early-stage disease?
DR. BALAR: PURE-01 was a very interesting study in that it tested neoadjuvant immunotherapy in patients with muscle-invasive bladder cancer who then underwent radical cystectomy. The historical standard of care for muscle-invasive bladder cancer is cisplatin-based chemotherapy for up to 4 cycles followed by a radical cystectomy. We use neoadjuvant therapy followed by cystectomy because we have level I evidence that the addition of chemotherapy in this setting improves survival and the rate of cure.
In the PURE-01 study, all patients were eligible for cisplatin-based chemotherapy but opted to participate in this trial; therefore, they received 3 doses of pembrolizumab immunotherapy administered every 3 weeks (6 to 9 weeks of treatment total) followed by a radical cystectomy, the standard-of-care surgical procedure with a curative intent. Essentially, the data showed that approximately 40% of patients achieved a complete pathologic response, suggesting that the addition of pembrolizumab elicited a significant local tumor immune response such that in 40% of patients, all cancer present in the bladder at the time of surgery was eradicated.
These data are provocative because we have historically used the response rate to cisplatin chemotherapy as a surrogate for long-term survival. That is because data from the Southwest Oncology Group (SWOG) 8710 trial, one of the pivotal studies that established cisplatin-based therapy as the neoadjuvant standard of care, showed that patients who achieved pT0 had a long-term cure rate of roughly 85% to 90%. The rate with which we see pT0 with cisplatin is estimated to be between 30% and 40%. So, to see a similar rate of pathologic complete response with neoadjuvant immunotherapy suggests that we may be able to see similar efficacy in the bladder.
These are promising data because more patients can tolerate pembrolizumab or immunotherapy in general compared with cisplatin. The challenge with this particular study is that it is a single-arm trial, so we don’t have any comparisons to other active treatments; furthermore, we don’t know whether the complete response in the bladder to pembrolizumab means the same thing as a complete response to cisplatin therapy. This is where long-term follow-up via randomized trials is absolutely necessary.
All of that being said, these data are very important and certainly lend a lot of background and evidence to support conducting larger randomized trials in which patients receive neoadjuvant immunotherapy followed by cystectomy and then are followed to see whether the rates of cure are improved compared with radical cystectomy alone. Not surprisingly, a subgroup analysis of the PURE-01 study showed that patients with high levels of PD-L1 expression in their baseline tumor sample were far more likely to achieve a pathologic complete response to immunotherapy, which is in line with what we typically see in the metastatic setting. Additional data and analyses will be necessary to test if other biomarkers, such as tumor mutational burden or specific genetic mutations, might predict which patients will do best with neoadjuvant immunotherapy.
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