Expert Discusses Promising Data With Pembrolizumab for Unmet Need in NMIBC

Arjun V. Balar, MD, highlights the KEYNOTE-057 study findings and provides insight into the role of immunotherapy in bladder cancer.

Arjun V. Balar, MD

Arjun V. Balar, MD

Arjun V. Balar, MD

Early data indicate that pembrolizumab (Keytruda) is a feasible option for patients with high-risk nonmuscle—invasive bladder cancer (NMIBC) who are unresponsive to Bacillus Calmette-Guérin (BCG), explained Arjun V. Balar, MD.

Data for cohort A of the phase II KEYNOTE-057 study, which were presented at the 2019 Genitourinary Cancers Symposium, showed that pembrolizumab induced a 3-month complete response (CR) rate of 38.8%. Among the 40 patients who achieved a CR at 3 months, 72.5% maintained a CR at a median follow-up of 14 months; median CR duration had not been reached at the time of presentation. However, 80.2% of patients had a CR lasting ≥6 months.

Cohort A was comprised of 102 patients with NMIBC who had carcinoma in situ with or without papillary disease, said Balar, who is lead author of the trial. Patients received pembrolizumab at 200 mg every 3 weeks for up to 24 months. Grade 3/4 treatment-related adverse events were observed in 12.6% of patients; 1 death was considered to be related to treatment.

In an interview withTargeted Oncology, Balar, director of the Genitourinary Medical Oncology Program, and assistant professor in the Department of Medicine, at NYU Langone’s Perlmutter Cancer Center, highlighted the KEYNOTE-057 study findings and provided insight into the role of immunotherapy in bladder cancer.

TARGETED ONCOLOGY:What was the rationale for the KEYNOTE-057 study?

Balar:KEYNOTE-057 aimed to test pembrolizumab, a PD-1 antibody, in a specific population of patients with NMIBC. These are patients with high-risk disease who have received BCG, an intravesical immunotherapy, in the past. These patients did not respond to BCG therapy. Historically, this population is treated with radical cystectomy, meaning surgical removal of the bladder. The reason we do this is because BCG-unresponsive disease has a natural history of progressing to muscle-invasive and eventually metastatic disease. Historically, radical cystectomy has been the only curative therapy available for these patients. In this context, pembrolizumab was tested as a means to achieve responses in the bladder and to help patients preserve their bladders.

TARGETED ONCOLOGY:What findings were presented at the 2019 Genitourinary Cancers Symposium?

Balar:I presented the preliminary analysis of 102 patients enrolled in cohort A of the study. Overall, this trial focused on 2 cohorts: cohort A focused on patients with carcinoma in situ with or without papillary disease, and cohort B focused on patients with papillary disease alone without carcinoma in situ. At a median follow-up of about 14 months, results for 102 patients in cohort A showed CR rates of about 40% with pembrolizumab. Additionally, the median duration of response at this point for CR is about 12.5 months. About 53% of patients will have CRs lasting 9 months or longer, which is quite encouraging. Of course, these are early data, and longer-term follow-up will be necessary.

TARGETED ONCOLOGY:What are the next steps for this research?

Balar:The next steps for this trial are to follow up on these patients who have achieved a CR and truly see how long and durable these responses are. It is also worth noting that this needs to be tested in a randomized setting, and that's what the KEYNOTE-676 trial is addressing. While this study has the potential for registration implications for pembrolizumab in this population, the randomized phase III study is also important. That will focus on patients with BCG-refractory disease after induction BCG and will be randomizing patients to receive either BCG reinduction alone or BCG reinduction plus pembrolizumab.

TARGETED ONCOLOGY:Is it likely that BCG will retain its role in this space?

Balar:BCG has a longstanding history in NMIBC treatment, and I believe it will have a firm role for decades to come; this is largely because it is still very active. In fact, about 70% of patients with carcinoma in situ will achieve a CR with BCG; it is very effective. What I envision in the future is not that BCG will get replaced, but that it will be augmented by the addition of other synergistic agents, like PD-1 antibodies.

TARGETED ONCOLOGY:Where do we stand in terms of predictive biomarkers of immunotherapy response in bladder cancer?

Balar:Certainly, in metastatic disease, some advancements have been made in terms of biomarkers to help us select who should and should not receive immunotherapy. For instance, PD-L1 expression certainly has value in the first-line metastatic setting. In high-risk NMIBC, I also presented data on the role of PD-L1 expression [at the 2019 Genitourinary Cancers Symposium]. Interestingly, we found that PD-L1 expression does not really predict the rates of CR in the bladder in this space. However, other biomarkers certainly need to be tested. For example, in the metastatic setting, we are also looking at tumor mutational burden.

​​​​​​​TARGETED ONCOLOGY:Is immunotherapy the path forward in the treatment of patients with bladder cancer?

Balar:Immunotherapy is here to stay in bladder cancer, and it will be firmly established, even as frontline therapy. KEYNOTE-361 and IMvigor130 are 2 randomized trials comparing platinum chemotherapy alone with immunotherapy alone as well as platinum-based chemotherapy plus immunotherapy. Many of us in the field anticipate that platinum-based chemotherapy plus immunotherapy will be a new standard of care for patients in the frontline setting. However, even for patients who are not eligible for any chemotherapy, immunotherapy will still have a role, because we know the majority of patients who can't tolerate chemotherapy can feasibly receive immunotherapy.

​​​​​​​TARGETED ONCOLOGY:Were there any other bladder cancer updates presented at that conference that you were excited about?

Balar:I was particularly excited about the data that Scott T. Tagawa, MD, MS, of Weill Cornell Medicine, presented from the phase I study of sacituzumab govitecan. This is an antibody-drug conjugate (ADC) that is particularly important for patients who are not responsive to PD-1 antibodies. We know that about 20% of patients will respond in the second-line setting to immunotherapy, meaning that we need treatment options for the remaining majority of patients. It seems that ADCs are quite attractive in terms of inducing responses and achieving disease control.

TARGETED ONCOLOGY:What does the outlook for patients with bladder cancer look like today versus 5 years ago?

Balar:The conversations I used to have with patients with metastatic bladder cancer were quite somber. We were talking about platinum-based chemotherapy and then single-agent chemotherapy or best supportive care upon progression. Many times, in the second-line setting, patients would opt for best supportive care because the treatments we had did not lead to meaningful responses and certainly not an improvement in survival.

Fast forward to 2019, we have 5 different agents targeting the PD-1 pathway available in the second-line setting and 2 of these agents are indicated for use in the frontline space. Several studies are also testing novel compounds that could potentially have significant impact in the clinic in the near future. These [approaches] include ADCs, targeted therapies that hitFGFR3, as well as other experimental immunotherapy compounds.


Balar AV, Kulkarni GS, Uchio EM, et al. KEYNOTE 057: phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG).J Clin Oncol. 2019;37(suppl 7, abstr 350). doi: 10.1200/JCO.2019.37.7_suppl.350.

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