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Checkpoint inhibitors targeting the PD-1 receptor and its ligand, PD-L1, are showing efficacy in early-phase clinical trials in urothelial bladder cancer, generating the promise of new therapies for a disease that has not had a significant treatment advance in 30 years.
Daniel P. Petrylak, MD
Checkpoint inhibitors targeting the programmed death-1 (PD-1) receptor and its ligand, PD-L1, are showing efficacy in early-phase clinical trials in urothelial bladder cancer (UBC), generating the promise of new therapies for a disease that has not had a significant treatment advance in 30 years.
Daniel P. Petrylak, MD, is among the leading researchers exploring MPDL3280A, an anti-PD-L1 monoclonal antibody that disrupts the ligand’s binding to its receptors, PD-1 and B7.1. The FDA has designated the agent as a breakthrough therapy in bladder cancer.
MPDL3280A demonstrated a 52% response rate among 30 patients with metastatic UBC whose tumors tested positive for PD-L1 with immunohistochemistry (IHC) 2/3 scores, according to phase I results presented at the ESMO 2014 Congress in Madrid, Spain, in September.1 Some responses lasted more than 30 weeks; the median duration of response had not yet been reached.2 The findings initially were detailed at the 2014 American Society of Clinical Oncology Annual Meeting in June.3
Petrylak, who is director of Prostate and Genitourinary Medical Oncology at Yale Cancer Center, discussed this agent in the context of the difficult-to-treat malignancy in an interview with OncologyLive.
OncologyLive: Bacillus Calmette-Guérin (BCG) therapy for superficial UBC, the first FDA-approved immunotherapy, was introduced nearly 40 years ago. Why has immunotherapy for bladder cancer remained static for so long, and why has it become a hot topic once again in 2014?
Petrylak: Immunotherapy is in the spotlight now because some of the targets for the newer checkpoint inhibitors have been identified in locally advanced and metastatic disease, and we really didn’t have any treatments that targeted those particular agents in the past. So we know that PD-1 and PD ligand are expressed both in bladder cancer cells as well as on the infiltrating immune cells, and we just simply didn’t have drugs that targeted those particular immune checkpoints.
Are checkpoint inhibitors particularly suited to bladder cancer?
Checkpoint inhibitors are not just specific to this cancer. Bladder cancer was selected for study based on identification of immune targets, as well as on the fact that there has been no major advance in this cancer in 30 years. We knew from experience with superficial disease that BCG therapy had activity, so it made a lot of sense.
Does BCG therapy work through a mechanism related to immune checkpoint molecules such as PD-1 and PD-L1?
That’s a good question, and nobody knows the answer yet. The response to BCG is multifactorial, but it may be through a similar mechanism to checkpoint inhibitors. It’s hard to determine.
You were an investigator in a phase I trial of MPDL3280A. What are the advantages of this immunotherapeutic agent over the present standard of care?
This study was conducted with patients with metastatic UBC who had failed prior chemotherapy, and there is no standard therapy for these patients now. This is certainly a group that needs new treatment options. Response rates are 10% to 20% with cytotoxic agents among this population, whereas they are much higher in this trial. In contrast to cytotoxic therapy, the side effects with the anti-PD-L1 antibody are significantly less.
Are there any plans to investigate MPDL3280A as a first-line therapy?
There is now no standard of care for metastatic platinum-ineligible urothelial cancer. Although there are no supporting phase III data, gemcitabine and carboplatin are commonly used to treat patients with metastatic UBC who are ineligible to receive cisplatin. The phase II trial of MDPL3280A is looking at two groups of patients: those who are platinum-ineligible with no prior chemotherapy, and those who are platinum-refractory.4 Thus, these platinum ineligible-patients will be treated upfront with immunotherapy.
The trial results showed that 11% of patients with tumors identified as PD-L1 negative responded to MPDL3280A. What are the hypotheses for why those patients achieved a response?
Several different factors may be involved. One is that the biomarker testing in this trial, for the most part, was done on archival tissue. Thus, if the primary specimen was obtained two or three treatments removed from the patient’s current status, those samples may not be indicative of the current interaction between the tumor and the patient’s immune system. That may be part of the explanation. The other explanation is that resistance to these drugs is probably multifactorial, and PD ligand expression may be part of the story but not the whole story.
Are there any other promising immunotherapeutic agents being developed for use in bladder cancer?
Evaluations are under way for anti-PD-1 antibodies, the anticytotoxic T-lymphocyte antigen—4 (CTLA-4) antibodies, and there are some novel combination trials that are going on with checkpoint inhibitors. I think that this is a very fruitful area of investigation. It’s a totally new area of investigation. The ultimate question is how these agents will be sequenced with chemotherapy.
Are there any new immunotherapeutic agents with the potential to treat muscle-invasive bladder cancer?
The current standard for muscle-invasive UBC is cytotoxic chemotherapy. We need to understand more about how and why patients progress. I think that there is a potential for it. Certainly, these agents need to be evaluated both as adjuvants and neoadjuvants in high-risk patients.
Where do you think that immunotherapy is going, and what role will it play in the treatment of bladder cancer 10 years from now?
I think that it plays a significant role. There are always going to be several different treatments that you’ll need to effectively treat cancer, whether a combination of chemotherapy and immune therapy, or some other combination. The optimal sequences of these agents with surgery, chemotherapy, and immunotherapy will be defined through clinical trials.
Dr Petrylak is co-chair of the 8th Annual Interdisciplinary Prostate Cancer Congress, which Physicians’ Education Resource (PER) will sponsor March 14, 2015, in New York City. www.gotoper.com