Voluntary Withdrawal In The US of Durvalumab and of Atezolizumab in Metastatic Urothelial Carcinoma - Petros Grivas
April 22, 2021
In February 2021 AstraZeneca announced the voluntary withdrawal of the Imfinzi (durvalumab) indication in the US for previously treated adult patients with locally advanced or metastatic bladder cancer. In March 2021, Genentech announced the voluntary withdrawals of Tecentriq® (atezolizumab) for the treatment of prior-platinum treated metastatic urothelial carcinoma.
Petros Grivas and Alicia Morgans discuss these two voluntary withdrawals and review the rationale for them. Petros reviews that Imfinzi was granted accelerated approval in the US based on promising tumor response rates and duration of response data from Study 1108, a Phase I/II trial that evaluated the safety and efficacy of Imfinzi in advanced solid tumors, including previously treated bladder cancer. Continued approval was contingent on results from the DANUBE Phase III trial in the 1st-line metastatic bladder cancer setting, which did not meet its primary endpoints in 2020. The withdrawal is aligned with FDA guidance for evaluating indications with accelerated approvals that did not meet post-marketing requirements, as part of a broader industry-wide evaluation. This withdrawal does not impact the indication outside the US and does not impact other approved Imfinzi indications within or outside the US. Clinical trials are continuing in the US too.
Petros also describes that the FDA granted accelerated approval to Tecentriq, for prior-platinum treated metastatic urothelial carcinoma based on tumor response rate and duration of response data in the phase 2 IMvigor210 study (NCT02108652). According to the Agency’s accelerated approval program, a drug may be approved earlier if it is intended to treat a serious condition or fills an unmet need; the approval is based on a surrogate end point that is thought to predict clinical benefit. However, results from a subsequent confirmatory phase 3 trial (IMvigor211; NCT02302807) showed that treatment with Tecentriq did not meet the primary end point of overall survival in the PD-L1 high patient population. Continued approval for this indication was contingent upon the results of IMvigor211, the original post-marketing requirement (PMR) to confirm clinical benefit. The IMvigor130 study (ClinicalTrials.gov: NCT02807636), which was subsequently designated as the PMR, will still continue until the final analysis.
Biographies:
Petros Grivas, MD, PhD, Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.
Alicia Morgans, MD, MPH Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts.
Read the Full Video Transcript
Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago in the United States. I'm so happy to have here with me today a friend and colleague, Dr. Petros Grivas, who is also an associate professor of medicine and a GU medical oncologist at the University of Washington in Seattle. Thank you so much for being here with me today, Petros.
Petros Grivas: Thank you so much for having me, Alicia. It's always a pleasure.
Alicia Morgans: Always wonderful to talk to you too. And today I wanted to really pick your brain about some recent FDA label changes for durvalumab and atezolizumab in the urothelial carcinoma space. These came out at the end of February and then in early March, and I think are important for us to consider as we continue to treat patients with urothelial carcinoma. Are you able to tell us a little bit about the label change, starting maybe with durvalumab?
Petros Grivas: Absolutely. Thank you, Alicia, for the question. There has been a recent withdrawal of durvalumab specifically for patients with metastatic urothelial cancer, either from bladder, urethra, or upper tract disease in patients, specifically when they had prior chemotherapy, platinum-based chemotherapy, and had progression in these, what we call salvage settings, second line and beyond. Durvalumab had an indication with an FDA accelerated approval based on a Phase 2 trial, if I recall, it was the 1108 trial published by Professor Thomas Powles and colleagues a few years ago. This was a single-arm Phase 2 study demonstrating, I would say, a promising overall response rate with durvalumab, I think it was in the order of 17% or so. Because this was corroborated by some durable responses in a few patients in a favorable toxicity profile compared to cytotoxic chemotherapy in the salvage setting, it received accelerated approval by the FDA.
This was back in the day. I think it was about May 2017 or so when this happened. Around that time, there was a total of five immune checkpoint inhibitors approved in that setting. The only one that met the primary endpoint of overall survival in the clinical trial was pembrolizumab. So over the years, the utilization of durvalumab probably was on the low side based on some market research data in that setting. More recently, the FDA has been looking closer into those accelerated approvals. More recently we had the presentation of the DANUBE trial, a Phase 3 trial, in the frontline setting, which I want to make the point here the DANUBE trial that was presented by Professor Powles at ESMO was in the frontline, so different indication from the platinum-refractory approval of durvalumab. The DANUBE trial did not meet the primary endpoints. Professor Powles saw the data at ESMO 2020, and just very quickly [inaudible] DANUBE trial, asked two questions, does durvalumab alone by itself prolong overall survival compared to platinum-based chemotherapy in the frontline setting in PD-L1 high patients.
And it is not based on statistical [inaudible] analysis. And the second question, did durvalumab plus tremelimumab anti-PD-L1 plus anti-CTLA-4, did the combo prolong overall survival versus platinum-based chemotherapy in the frontline setting chemotherapy-naive basis. And this did not meet statistical significance in the intent to treat all-comer populations. And because of that, the phase three trial, again, the different setting from where the approval has been, did not meet the endpoint. There was no phase three data suggesting overall survival benefit with durvalumab. So very recently the company decided to withdraw the indication of durvalumab in patients with platinum-refractory, metastatic urothelial cancer in the single [inaudible].
Alicia Morgans: Yes, I think it is really important to emphasize a few things. One, that the initial approval was an accelerated approval. And so the FDA really was leaving it to our community of course, to the company as well, to ensure that this was an indication that was appropriately administered. And so with the DANUBE trial really not meeting its endpoint though, of course, in a different population, it does make some sense that the company would then say "we are going to voluntary withdrawal at this time." One thing that I would also want to emphasize is that there are ongoing studies with durvalumab in some different settings. And so the benefit of durvalumab in urothelial carcinoma overall remains to be seen as these studies will eventually report out and we will find out whether or not there is a benefit or true benefit perhaps in other settings. So really important to make sure that that is clear as well.
There was another accelerated approval in urothelial carcinoma for atezolizumab. This was actually one of the first drugs actually approved in this setting, was a big, made a big splash. I know I was really excited when this approval was made. But Genentech Roche then has now made a voluntary withdrawal of atezolizumab for one particular part of the indication of atezolizumab in urothelial carcinoma. Can you tell us a little bit about that?
Petros Grivas: Absolutely. And before I do that, I want to echo your point that there are multiple ongoing clinical trials with all those drugs, both the durvalumab and atezolizumab in other disease settings that are separate from where the indication was and was withdrawn. And I think these trials are very important and we need to accrue those trials to answer separate questions about earlier disease settings and spaces. Now, going back to your great question, atezolizumab has two separate indications, at least until recently, had two separate indications in metastatic urothelial cancer patients in the frontline setting who are not fit, not eligible for cisplatin, and the tumor that has high PD-L1 expression could receive atezolizumab based on the single-arm phase two data of the IMvigor 210 cohort 1 trial that was reported a few years ago. And we published that in Lancet about three years ago, and as a separate indication was also in the patients who have platinum-refractory, advanced urothelial cancer.
So similar to where the durvalumab indication was in the same kind of second-line and beyond platinum-refractory setting. The particular indication that was withdrawn was the second one: platinum-refractory disease. The trial that led to that accelerated approval of atezo, I think it was back in 2016, actually May 2016 or so, and this was based on the IMvigor 210 cohort 2. Again, in patients with platinum-refractory disease, single-arm atezolizumab because of some durable responses and a favorable toxicity profile. Atezolizumab was the first checkpoint inhibitor in that setting to receive accelerated approval by the FDA and was the first one to be used in that setting. So there is some important, I would say the head of a new era of immunotherapy in advanced urothelial cancer with this drug, and the contingency was to do a phase three trial in that same platinum-refractory setting.
And Professor Powles also led this trial of the IMvigor211. This trial was interesting because the primary endpoint of overall survival between atezo and salvage chemotherapy, vinflunine in Europe, or taxane in the US, was not in all comers. It was in the biomarker selected population based on the PD-L1 positive high expression, based on the VENTANA SP142 assay. And in this subset of patients with PD-L1 high tumors, atezolizumab did not significantly prolong overall survival in this subset of patients. So the primary endpoint of the IMvigor211 was not met. Now, if you go back to the exploratory endpoint of all comers intention to treat, the atezolizumab was superior to chemotherapy, statistically significant, small numerical difference, but still significant, but because it was a hierarchical design, the primary endpoint was not met. So pretty much the trial was deemed negative.
So because of this negative phase three trial, again and the kind of extra discussions with the FDA, the company decided to voluntarily withdraw atezolizumab for this platinum-refractory second line and beyond setting. However, the indication in the frontline setting for cisplatin unfit, ineligible patients with PD-L1 high tumor still holds true. And by the way, in the United States, the FDA allows the use of atezo in this frontline setting chemotherapy patients in those who cannot get any chemotherapy, except not platinum eligible, I would have to be more precise, those patients who are not eligible for cisplatin and carboplatin so platinum [inaudible], they can get atezo or pembrolizumab in the front line without PD-L1 testing. That is only in the US by the FDA.
Alicia Morgans: Yes. So just to emphasize, there are remaining indications for atezolizumab in urothelial carcinoma. So in patients who are not cisplatin eligible, who do have high PD-L1 staining, as well as patients who are going to be platinum ineligible, regardless of their PD-L1 staining. So this indication remains. It is that post-platinum progression indication that has been voluntarily withdrawn and of course, there are ongoing trials. The IMvigor130 trial, I think is, we are still waiting for survival data to come out on that. And then there are other trials that are ongoing. So we will have a better understanding of whether atezolizumab may have a role in additional sites of or additional states of urothelial carcinoma over time. Just this one indication has been voluntarily withdrawn. So thank you so much for reviewing the specifics. I think that this has been a little bit confusing for all of us in the field, just to try to sort out what is still recommended and on the label by the FDA and what is now voluntarily changed for these two drugs: durvalumab and atezolizumab. I really appreciate your time.
Petros Grivas: Thank you, Alicia. Great discussion. I appreciate it.
Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago in the United States. I'm so happy to have here with me today a friend and colleague, Dr. Petros Grivas, who is also an associate professor of medicine and a GU medical oncologist at the University of Washington in Seattle. Thank you so much for being here with me today, Petros.
Petros Grivas: Thank you so much for having me, Alicia. It's always a pleasure.
Alicia Morgans: Always wonderful to talk to you too. And today I wanted to really pick your brain about some recent FDA label changes for durvalumab and atezolizumab in the urothelial carcinoma space. These came out at the end of February and then in early March, and I think are important for us to consider as we continue to treat patients with urothelial carcinoma. Are you able to tell us a little bit about the label change, starting maybe with durvalumab?
Petros Grivas: Absolutely. Thank you, Alicia, for the question. There has been a recent withdrawal of durvalumab specifically for patients with metastatic urothelial cancer, either from bladder, urethra, or upper tract disease in patients, specifically when they had prior chemotherapy, platinum-based chemotherapy, and had progression in these, what we call salvage settings, second line and beyond. Durvalumab had an indication with an FDA accelerated approval based on a Phase 2 trial, if I recall, it was the 1108 trial published by Professor Thomas Powles and colleagues a few years ago. This was a single-arm Phase 2 study demonstrating, I would say, a promising overall response rate with durvalumab, I think it was in the order of 17% or so. Because this was corroborated by some durable responses in a few patients in a favorable toxicity profile compared to cytotoxic chemotherapy in the salvage setting, it received accelerated approval by the FDA.
This was back in the day. I think it was about May 2017 or so when this happened. Around that time, there was a total of five immune checkpoint inhibitors approved in that setting. The only one that met the primary endpoint of overall survival in the clinical trial was pembrolizumab. So over the years, the utilization of durvalumab probably was on the low side based on some market research data in that setting. More recently, the FDA has been looking closer into those accelerated approvals. More recently we had the presentation of the DANUBE trial, a Phase 3 trial, in the frontline setting, which I want to make the point here the DANUBE trial that was presented by Professor Powles at ESMO was in the frontline, so different indication from the platinum-refractory approval of durvalumab. The DANUBE trial did not meet the primary endpoints. Professor Powles saw the data at ESMO 2020, and just very quickly [inaudible] DANUBE trial, asked two questions, does durvalumab alone by itself prolong overall survival compared to platinum-based chemotherapy in the frontline setting in PD-L1 high patients.
And it is not based on statistical [inaudible] analysis. And the second question, did durvalumab plus tremelimumab anti-PD-L1 plus anti-CTLA-4, did the combo prolong overall survival versus platinum-based chemotherapy in the frontline setting chemotherapy-naive basis. And this did not meet statistical significance in the intent to treat all-comer populations. And because of that, the phase three trial, again, the different setting from where the approval has been, did not meet the endpoint. There was no phase three data suggesting overall survival benefit with durvalumab. So very recently the company decided to withdraw the indication of durvalumab in patients with platinum-refractory, metastatic urothelial cancer in the single [inaudible].
Alicia Morgans: Yes, I think it is really important to emphasize a few things. One, that the initial approval was an accelerated approval. And so the FDA really was leaving it to our community of course, to the company as well, to ensure that this was an indication that was appropriately administered. And so with the DANUBE trial really not meeting its endpoint though, of course, in a different population, it does make some sense that the company would then say "we are going to voluntary withdrawal at this time." One thing that I would also want to emphasize is that there are ongoing studies with durvalumab in some different settings. And so the benefit of durvalumab in urothelial carcinoma overall remains to be seen as these studies will eventually report out and we will find out whether or not there is a benefit or true benefit perhaps in other settings. So really important to make sure that that is clear as well.
There was another accelerated approval in urothelial carcinoma for atezolizumab. This was actually one of the first drugs actually approved in this setting, was a big, made a big splash. I know I was really excited when this approval was made. But Genentech Roche then has now made a voluntary withdrawal of atezolizumab for one particular part of the indication of atezolizumab in urothelial carcinoma. Can you tell us a little bit about that?
Petros Grivas: Absolutely. And before I do that, I want to echo your point that there are multiple ongoing clinical trials with all those drugs, both the durvalumab and atezolizumab in other disease settings that are separate from where the indication was and was withdrawn. And I think these trials are very important and we need to accrue those trials to answer separate questions about earlier disease settings and spaces. Now, going back to your great question, atezolizumab has two separate indications, at least until recently, had two separate indications in metastatic urothelial cancer patients in the frontline setting who are not fit, not eligible for cisplatin, and the tumor that has high PD-L1 expression could receive atezolizumab based on the single-arm phase two data of the IMvigor 210 cohort 1 trial that was reported a few years ago. And we published that in Lancet about three years ago, and as a separate indication was also in the patients who have platinum-refractory, advanced urothelial cancer.
So similar to where the durvalumab indication was in the same kind of second-line and beyond platinum-refractory setting. The particular indication that was withdrawn was the second one: platinum-refractory disease. The trial that led to that accelerated approval of atezo, I think it was back in 2016, actually May 2016 or so, and this was based on the IMvigor 210 cohort 2. Again, in patients with platinum-refractory disease, single-arm atezolizumab because of some durable responses and a favorable toxicity profile. Atezolizumab was the first checkpoint inhibitor in that setting to receive accelerated approval by the FDA and was the first one to be used in that setting. So there is some important, I would say the head of a new era of immunotherapy in advanced urothelial cancer with this drug, and the contingency was to do a phase three trial in that same platinum-refractory setting.
And Professor Powles also led this trial of the IMvigor211. This trial was interesting because the primary endpoint of overall survival between atezo and salvage chemotherapy, vinflunine in Europe, or taxane in the US, was not in all comers. It was in the biomarker selected population based on the PD-L1 positive high expression, based on the VENTANA SP142 assay. And in this subset of patients with PD-L1 high tumors, atezolizumab did not significantly prolong overall survival in this subset of patients. So the primary endpoint of the IMvigor211 was not met. Now, if you go back to the exploratory endpoint of all comers intention to treat, the atezolizumab was superior to chemotherapy, statistically significant, small numerical difference, but still significant, but because it was a hierarchical design, the primary endpoint was not met. So pretty much the trial was deemed negative.
So because of this negative phase three trial, again and the kind of extra discussions with the FDA, the company decided to voluntarily withdraw atezolizumab for this platinum-refractory second line and beyond setting. However, the indication in the frontline setting for cisplatin unfit, ineligible patients with PD-L1 high tumor still holds true. And by the way, in the United States, the FDA allows the use of atezo in this frontline setting chemotherapy patients in those who cannot get any chemotherapy, except not platinum eligible, I would have to be more precise, those patients who are not eligible for cisplatin and carboplatin so platinum [inaudible], they can get atezo or pembrolizumab in the front line without PD-L1 testing. That is only in the US by the FDA.
Alicia Morgans: Yes. So just to emphasize, there are remaining indications for atezolizumab in urothelial carcinoma. So in patients who are not cisplatin eligible, who do have high PD-L1 staining, as well as patients who are going to be platinum ineligible, regardless of their PD-L1 staining. So this indication remains. It is that post-platinum progression indication that has been voluntarily withdrawn and of course, there are ongoing trials. The IMvigor130 trial, I think is, we are still waiting for survival data to come out on that. And then there are other trials that are ongoing. So we will have a better understanding of whether atezolizumab may have a role in additional sites of or additional states of urothelial carcinoma over time. Just this one indication has been voluntarily withdrawn. So thank you so much for reviewing the specifics. I think that this has been a little bit confusing for all of us in the field, just to try to sort out what is still recommended and on the label by the FDA and what is now voluntarily changed for these two drugs: durvalumab and atezolizumab. I really appreciate your time.
Petros Grivas: Thank you, Alicia. Great discussion. I appreciate it.