Prolonging Overall Survival in Patients with Muscle-Invasive Bladder Cancer - Petros Grivas

July 30, 2020

Petros Grivas, MD, PhD, joins Alicia Morgans, MD, MPH, to review updates from the virtual ASCO 2020 meeting in the muscle-invasive bladder cancer setting. Dr. Grivas first provides an overview of the IMvigor010 trial which showed that disease-free survival was not prolonged with the addition of atezolizumab after neoadjuvant therapy in patients with muscle-invasive disease. The JAVELIN 100 trial, however, which Dr. Grivas was a senior author of, did have a positive result. It found that treating patients with a platinum-based regiment and then switching to avelumab administered every two weeks could prolong overall survival. Both trials — one with a negative result and one with a positive outcome — provide important information for the future of clinical practice in this setting and for enhancing the quality and quantity of a patient’s life.

Biographies:

Petros Grivas, MD, Ph.D., Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans: Hi, this is Alicia Morgans, GU Medical Oncologist and Associate Professor of Medicine at Northwestern University, and I am so excited to have here with me today, a friend and colleague, Dr. Petros Grivas who is an Associate Professor of Medicine and a GU Medical Oncologist at the University of Washington. Thank you so much for being here today, Petros.

Petros Grivas:
 Thank you so much for having me, Alicia. Always a pleasure to discuss with you.

Alicia Morgans: 
Wonderful. Well, Petros, I wanted to speak with you today about your take on some of the highlights from ASCO, the virtual meeting that happened just a few weeks ago. Because I think that, as usual, there have been developments in urothelial oncology. One of the incredibly significant, but both really informative to our practice and I wanted to get your take. Let's talk first about IMvigor010 or IMvigor 10 as some people call it. What are your thoughts on this particular trial that looked at the adjuvant use of therapy after initial cystectomy?

Petros Grivas: 
Alicia, I do agree with you that IMvigor010 was a very important trial that was presented at the virtual ASCO meeting by Dr. Hussain and it's important for many reasons. Number one, we struggle with what to do with patients who either receive neoadjuvant cisplatin-based chemotherapy and they still have muscle-invasive residual disease either radical cystectomy or radical nephron [inaudible] upper tract disease. And also, what to do with patients who never received neoadjuvant chemotherapy, but they are not fit to receive cisplatin. And for bladder cancer specifically, there is no good evidence of using carboplatin in the neoadjuvant or adjuvant setting. So the important question is, in those patients where they receive neoadjuvant chemotherapy, but still have muscle-invasive disease residual after radical surgery, or are not fit for cisplatin whatsoever, or some patients even refuse to get cisplatin in the adjuvant setting if they never received it before.

What do you do with those patients? And to answer this question, the IMvigor010 trial was a randomized phase three trial comparing the Anti-PD-L1 agent atezolizumab to observation in a large study with a very high number of patients. I think it was about 800 patients randomized and the primary endpoint was disease-free survival with a secondary point of overall survival. And Dr. Hussain presented the data very nicely at the ASCO virtual meeting two months ago, showing that the atezolizumab did not prolong disease-free survival. The hazard ratio was not significantly different, which also was corroborated by data in overall survival in an interim, and I would say probably, a premature analysis, but there was no overall survival difference either. You would not expect that probably that early on. However, the practical point for the community and not academic oncologists is that in the adjuvant setting, immunotherapy has no proven role based on the IMvigor010 trial.

However, there are two other important adjuvant immunotherapy trials. One of them is called AMBASSADOR and is led by Dr. Andrea Apolo, our colleague who is working in the NCI. And the AMBASSADOR trial is randomizing patients to adjuvant pembrolizumab and the PD-1 versus observation, looking at disease-free survival and overall survival. And then we have the CheckMate 274 with adjuvant NIVO versus placebo.

This trial has not reported results either. And as far as I know, the AMBASSADOR trial with adjuvant pembrolizumab observation is still open and accruing patients at the University of Washington in Seattle Cancer Care Alliance where I practice. So my take-home point is despite the negative results of the IMvigor010, I still feel comfortable accruing to other adjuvant trials. And in that context, there is also an adjuvant trial with targeted therapy, with an FGF receptor inhibitor for patients who have FGF receptor three mutations for fusions. It's an adjuvant trial with adjuvant Infigratinib versus placebo. And this is led by Dr. Pal and Dr. Dennis Mount. And it's a different study because it's not immunotherapy but still in the adjuvant setting.

Alicia Morgans:
 So, thank you for that excellent recap. And just to clarify and really summarize for readers, the IMvigor010 trial, tried to use an adjuvant therapy with atezolizumab versus surveillance in patients who had muscle-invasive disease after neoadjuvant therapy if they were eligible and agreed or after just cystectomy. And all patients had had a cystectomy and they followed them and found that disease-free survival was not prolonged with this addition.

So, I think it's so important as you mentioned to really acknowledge other studies that are ongoing and to say that these other studies are somewhat different, using different agents using different approaches and that it is still completely reasonable that if we have residual disease or have a high-risk patient after initial neoadjuvant chemotherapy or not and cystectomy that it is still reasonable for us to think about an adjuvant treatment that could improve survival in this patient population, definitely a population in need.

So I do look forward to hearing about other studies in hopefully relatively near future, where we might be able to move the needle in that adjuvant space for muscle-invasive bladder cancer. But as we think about the other main highlight from ASCO 2020, I think that we can all be encouraged that the JAVELIN study was actually a very positive study, was the first urothelial carcinoma plenary session for the overall ASCO meeting and was so exciting because this has been an issue for years for our patients, and is now recognized as something important for everyone to hear about. And of course, we're moving the needle. Can you tell us a little bit about the JAVELIN trial? And I should mention that you are the senior author on this study, so congratulations on your work.

Petros Grivas: 
Thank you so much, Alicia, for the kind words as everything that we do is a huge team effort and a great work by many, Tom Powells did a great job presenting the data at the ASCO plenary session, as you said, on May 31st. And definitely this one was one of the biggest highlights in the entire ASCO meeting this year. And definitely one of the biggest highlights in the history of metastatic urothelial cancer research. And we're all proud of these results that definitely changed the practice in how we deal with metastatic urothelial cancer is a paradigm-changing and practice-changing study. As you said, for context, and this particular trial is trying to answer the question, whether the immunotherapy role has as switch maintenance therapy in patients with metastatic or locally advanced unresectable urothelial cancer patients in the frontline setting, the majority of those patients get treated with cornerstone of therapy, which is platinum-based chemotherapy.

And when this chemotherapy is completed after four or five or six cycles, usually these patients so far before JAVELIN trial came about, they were observed until progression and they went on to second-line therapy. So JAVELIN Bladder 100 tried to answer the question, whether avelumab anti–PD-L1 agent could prolong overall survival compared to best supportive care alone in those patients who had response or stable disease, meaning did not progress after induction chemotherapy in the frontline setting.

The prominent point was a little survival in all cameras regardless of PD-L1 expression, as well as the subset of patients with PD-L1 positive tumors and patients were stratified based on visceral versus non visceral disease, as well as a response to stable resistant action, platinum-based chemotherapy. The JAVELIN Bladder 100 trial met the primary endpoint with overall survival being significantly longer in patients with avelumab versus best supportive care alone.

The median overall survival was more than seven months longer with Avelumab and the hazard ratio for all comers for overall survival was 0.69. And this magnitude degree of benefit was even more in patients with PD-L1 positive tumors, with a hazard ratio of 0.56, and significant p-value. Even if you look at the landmark data in 18 months, there was a significant difference with many more patients being alive at 12 and 18 months with Avelumab versus best supportive care, so clearly a significant benefit. Statistically speaking, and clinically speaking overall survival benefit, there was also significant benefit for progression-free survival, favoring avelumab over the best supportive care in this switch maintenance setting. And we also had significant differential response rate favoring avelumab, obviously response rate is very hard to measure in maintenance trials and the toxicity and safety of Avelumab was very consistent in line with what we expect with immunotherapy in this disease, that it was only a 7% of grade three immune-related adverse events.

And if I recall correctly, there was no grade four or five immune-related event, and about 12% of patients discontinued avelumab because of emergent adverse events. Again, the safety profile, very consistent with what we know. Overdramatic results, if I can use the term, the FDA approved avelumab as switch or stable disease after a platinum-based frontline chemotherapy in the frontline switch maintenance setting, and the guidelines change recently to reflect that use of avelumab in the switch maintenance setting, and we're waiting for the manuscript to be published in the very near future. And also we're working to present some more granular data in different subset of patients. So far, we think every subset benefited in different degrees, of course, but we also look at biomarkers in patient outcomes and quality of life data, which I know that this data can be very high interest also to you because you are an expert in [inaudible].

Alicia Morgans: 
Well thank you so much for going through that. And I do look forward to hearing more granular data to understand how does Avelumab treat older patients or patients who may be more on the cusp, have more comorbidities than others granted that all patients in a clinical trial need to have controlled comorbidities, but those with more may more appropriately sort of mirror those patients that we end up seeing in our clinics.

And certainly, we look forward to the patient-reported outcomes so that we understand how patients feel when the disease is controlled. So all of this is really exciting and I so appreciate you sharing these updates from ASCO. And just to recap for all who are listening, there is currently no data to suggest that atezolizumab should be used in an adjuvant setting after neoadjuvant therapy or without neoadjuvant therapy, after cystectomy, there is no clear indication that the use of avelumab prolongs disease-free survival as compared to a routine surveillance as we have done for some time.

However, in the metastatic urothelial cancer setting, when we treat patients with a platinum-based regimen and have at least stable disease, if not some sort of response if we switch then and use switch maintenance avelumab, given every two weeks, we can, according to the JAVELIN 100 trial, prolong overall survival in our patients. So this is really phenomenal information, wonderfully important advances in the field, positive or negative. This informs what we do in clinical practice, and I sincerely appreciate your time today.

Petros Grivas: Thank you, Alicia. I echo your enthusiasm. We're very excited about this teamwork and the very positive impacting a patient's quality and quantity of life was longer overall survival, which is a big deal, as you mentioned, and we're going to have more data, as you mentioned for quality of life, they're always in the near future great news for the patients and great teamwork.

Alicia Morgans: Thank you.
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