Studying the Efficacy of Durvalumab and Radiation Therapy in Bladder Cancer

We spoke with Dr. Monika Joshi on the use of radiation therapy and durvalumab in patients with locally advanced bladder cancer.

Today, we are speaking about a novel and still investigational immunotherapy approach for bladder cancer with Dr. Monika Joshi, an oncologist at the Penn State Cancer Institute in Hershey, Pennsylvania who specializes in genitourinary cancers. Dr. Joshi is the lead principle investigator of a recently initiated phase I/II clinical trial that is testing the potential efficacy of the anti-PD-L1 antibody, durvalumab plus radiation therapy followed by adjuvant durvalumab for patients with locally advanced bladder cancer. The trial is fully being supported by United Kingdom-based AstraZeneca, the manufacturer of durvalumab, as part a research grant.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: First, could you tell us about the rationale of the trial design? What do we know about how bladder tumors may or may not respond to this type of immunotherapy and why combine it with radiation therapy?

Dr. Joshi: This is a very exciting trial as it is testing a novel immunotherapy with radiation therapy in locally advanced bladder cancer. So, to answer your question, first, we know that despite in advances in

immunotherapeutic options for cancer patients, only a select group of patients actually respond to immunotherapy alone; hence, there is a need to do clinical research with combinational approaches that can actually enhance the efficacy of these agents. And radiation therapy is a potential therapy for these combinations. Radiation therapy induces immunogenic cell death that comprises three main steps, which includes the cell surface transfer of calreticulin, then extracellular release of high mobility group protein B1 and release of ATP. We also know that immunogenic cell death causes production of neoantigens that could cause activation of tumor-specific T-cells and in addition, radiation causes upregulation of various pro-inflammatory signals such as CXCL9, interferon, and interleukin-1 beta that play key roles in immunmodulating pathways which can lead to better antitumor immunity.

We know from previous trials that radiation therapy is efficacious in locally advanced bladder cancer and it can have efficacy on its own or in combination with chemotherapy. We also know that immunotherapy such as PD-L1 agents show efficacy in bladder cancer. In our trial, we are using duravalumab, which is an anti-PD-L1 agent that we are combining with radiation therapy. This agent has been fast-tracked by the FDA for use in metastic bladder cancer patients. The recent data presented at ASCO [American Society of Clinical Oncology] annual meeting 2016 had shown promising efficacy of this agent in metastatic bladder cancer patients with an overall response rate of 31%. Our focus for this trial is mainly locally advanced patients who were unresectable or cisplatin ineligible because we know the options are very limited for this group of patients. So, we are trying to combine radiation therapy with immunotherapy to improve the efficacy in bladder cancer.

We have some preliminary data from animal studies that showed that combining radiation with PD-L1 directed agents can actually enhance the release of tumor antigens, improving the antitumor immunity. We also have retrospective results from our institution that was done by Dr. [Joseph] Drabick and his colleagues and was presented at ASCO 2016, wherein he showed that when patients with melanoma got ipilimumab along with radiation therapy, their overall survival was almost double, from 10 months to 21 months compared to ipilimumab alone. So, there is enough preliminary evidence to design a trial combining radiation therapy with immunotherapy in this disease type.

OncoTherapy Network: What is the general standard of care for locally advanced bladder cancer and who are the patients who are intended to be enrolled on this immunotherapy trial?

Dr. Joshi: The current general standard of care for locally advanced, muscle-invasive bladder cancer is neoadjuvant platinum-based chemotherapy followed by a radical cystectomy. And when we talk about this current standard of care, we basically talk about patients who are T2 to T4 and N0 to N1 and M0 patients. However, there are a significant number of patients that are unresectable because the disease is so locally advanced that the surgeons don’t feel comfortable to say that they could render them disease free upon surgery even after chemotherapy. And in addition, there are a significant number of patients who cannot get cisplatin-based chemotherapy; hence, this is an area of unmet need which is where our trial is going to focus.

So, the trial is a phase IB and phase II and we are enrolling patients for the phase IB part, those who are locally advanced with T3, T4, N0 to N2, M0 patients or if they are TX, N1 to N2 or treatment naïve or who are unresectable or unfit for surgery, we are also including patients in this trial who are T3 to T4, N0 to N2 and who are M0 and postneoadjuvant chemotherapy who are unfortunately become unresectable or for some reason are unfit for surgery. So that is a group that we are enrolling for the phase IB part. This group of patients will get radiation therapy along with two doses of durvalumab followed by adjuvant durvalumab for a year.

The phase II part will enroll a similar group of patients, but in addition, we are also enrolling patients who are T2 to T3 who are N0 and who are cisplatin ineligible. So we are really focusing on this locally advanced group of patients who are unresectable and who have poor prognosis when compared to patients who could actually undergo surgery or receive cisplatin.

OncoTherapy Network: Another similar immunotherapy that also targets the PD-L1 ligand, atezolizumab, was recently approved by the Food and Drug Administration for treatment of locally advanced or metastatic bladder cancer after progression on a platinum-based chemotherapy regimen. Is it thought that giving an immunotherapy antibody earlier in the course of disease could potentially result in more frequent and potentially more durable responses for more patients? Is that the rationale for the trial?

Dr. Joshi: That is a very interesting question. Immunotherapy has shown promising results in both first- and second-line setting in metastatic bladder cancer. We recently heard about the results of the phase II/III Keynote-052 study that evaluated the efficacy of PD-1 blockade agent pembrolizumab in first-line in cisplatin ineligible patients and the overall response rate was 24%. Similarly, atezolizumab has also shown comparable efficacy in cisplatin-ineligible patients and as you pointed out, atezolizumab has FDA approval as of May 2016 for treatment of patients with metastatic or locally advanced bladder cancer patients who progressed during or after treatment with a platinum-containing regimen or within 12 months of treatment of a platinum-containing regimen in the neoadjuvant or adjuvant setting.

So, in both first- or second-line, these drugs have shown efficacy. However, it is still an open question of whether they would work best in first-line or second-line and I think the future trial results will show us some data to this question to guide us. However, I think the most important question should be to develop a biomarker panel that could identify the select group of patients that could benefit from immunotherapy early or other targeted agents such as the EGFR inhibitors. It is also prudent to continue to research of how to turn nonresponders to immunotherapy into responders by using either combination approaches such as radiation therapy, chemotherapy, or addition of other therapeutic agents.

So, similar to this combination approach, I think, are trials, hopefully will help us further the advancement of immunotherapy in locally advanced bladder cancer patients who are unresectable or cisplatin-ineligible. 

Oncotherapy Network: Thank you so much for joining us today, Dr. Joshi.

Dr. Joshi: Thank you for having me; it was a pleasure talking to you.