Highlights from ASCO 2019

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Published: 3 Jun 2019
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Asst. Prof Bishal Gyawali and Monique Biryiana

Asst. Prof Bishal Gyawali and Monique Biryiana speak at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the highlights from this year's conference.

Asst. Prof Gyawali discusses several presentations that address topics ranging from racial disparities, accelerated drug approvals and the importance of assessing overall survival in clinical trials.

The presentations that he referred to are:

Affordable Care Act (ACA): Medicaid expansion impact on racial disparities in time to cancer treatment.
Phase III ANNOUNCE trial: A randomised, placebo-controlled, double-blind trial of doxorubicin olaratumab versus doxorubicin and placebo in patients with advanced soft tissue sarcomas.
Phase III MONALEESA-7 trial: In which Sara A. Hurvitz spoke with ecancer about the effect of endocrine therapy with or without ribociclib on overall survival in premenopausal patients.
Phase III POLO trial: In which Dr Hedy Kindler spoke with ecancer about the role of olaparib as a maintenance treatment following first-line, platinum-based chemotherapy in patients with a BRCA mutation and metastatic pancreatic cancer.
Phase III ENZAMET trial: In which Dr Christopher Sweeney spoke with ecancer about the effect of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer on overall survival.
Phase III TITAN trial: A double-blind, randomised study of apalutamide versus placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy.
Phase III KEYNOTE-062 trial: In which Dr Josep Tabernero spoke with ecancer about pembrolizumab with or without chemotherapy, compared to chemotherapy alone for gastric or gastroesophageal junction adenocarcinoma.

All opinions expressed in this video are the speakers own and do not reflect that of any institution.

 

MB: Hi, and welcome to our highlights video from ASCO 2019. I’m here with Assistant Professor Bishal Gyawali, thank you for being here.
BG: Thank you very much for having me.
MB: So what’s your overall impression of this year’s meeting?
BG: I’m actually pretty impressed with this year’s ASCO. There are a lot of positives to take away from this ASCO. The thing that impressed me the most was the selection of plenary abstracts, especially the selection of the abstract which showed that the use of medical expense and help to diminish the racial disparities between white and black cancer patients with regards to the time to receipt of treatment. This is not the typical abstract that you are used to seeing in ASCO plenaries. ASCO plenaries has always been about phase III trials, positive phase III trials, changing practice, so this is not the typical abstract that you see in ASCO plenaries, this is health service research using a real world database and this is actually a policy paper. This is policy research, this is not a drug or an intervention research. This research is looking at how the use of a policy initiative can help improve cancer outcomes for patients and help erase racial gaps. So this is very exciting, this means your research does not have to be a phase III trial for you to get an ASCO plenary so this is a very big deal in oncology, getting an ASCO plenary. So until now policy researchers, researchers doing other kinds of research like method research, health service research, economics research, they always had the feeling of being a little rejected from ASCO because no matter how good quality research they produce they are never going to get the ASCO plenary. But now they are confident that if the research is good then you can get to that stage. So this is a very bold statement from ASCO.
Of course I’ll talk about the implications of that particular research but overall I’m impressed with the selection of this abstract as the plenary, a, and b, the selection of the olaratumab trial as the plenary also impressed me a lot because this is a negative phase III trial and typically negative phase III trials are either not published at all or they get published in very low tier journals and definitely not at ASCO plenary. So the selection of olaratumab as the ASCO plenary also gives a very strong and important message to the oncology community that negative trials are as important to inform practice and treatment decisions as the positive trials are.
And there are another couple of things that I noticed at ASCO that impressed me. So first I want to talk about all the positive things. For example, they gave an important venue for the discussion of cancer drug approval bars and the value of cancer drugs, financial toxicity of cancer drugs, so these are issues that usually are ignored at such main conferences. So now giving an important place for this type of issue at ASCO is a very important step from ASCO. It also signifies that the oncologic community now cannot just turn a blind eye to these issues. We have always been doing that, like an ostrich, but we no longer can become an ostrich. These are real problems in front of us. We may have better treatments, we may have a new phase III trial showing improved survival but there is no point in having new drugs that the patients cannot have, the patients cannot have access to or afford. So in one of my papers I have written that the discovery of these new molecules for most of the patients in the world, it’s like the discovery of a black hole – someone says, ‘There is a black hole,’ it’s exciting from the scientific point of view but from the practical utility point of view if 80-85% of the patients can’t use that drug then what’s the point in having that drug? So, yes, these are the positives that I drew from this ASCO conference and I’m very happy about it.
MB: Has it been different to other ASCO conferences, bringing up issues like that in the plenary sessions?
BG: Yes, it has been different from many other conferences because, as I mentioned, the usual conferences always give top priority to phase III trials, new drugs are hyped irrespective of their margin of benefit, no matter whether they improve surrogate or real endpoints, no matter what the cost is. So nobody wants to talk about these issues, everybody wants to say, ‘Wow, we got a new drug in this cancer. We never had a drug for this cancer so this is a big deal,’ even though that drug is improving a surrogate measure by only two months, three months. Yes, everybody wants to jump on the bandwagon and everybody wants to celebrate something because everybody is here for celebration. But on the flipside of the coin we have to be aware of the fact that these drugs may not be helpful for all the patients, even for those patients in whom they help that help may only be in a surrogate measure that may not translate to real clinical benefit in terms of improved survival or improved quality of life. And patients may have to pay a huge amount of money for that gain and the trade-off may not be as optimistic as we are painting it to be. So I am glad that, at least at this ASCO, I have found that the other side of the coin is also being discussed equally, if not more importantly, than the usual meetings.
MB: Just moving on to endpoints and assessing overall survival, how important is that to these trials?
BG: It is very important and I think we have a couple of very good examples from this ASCO meeting. First, I want to use the example of olaratumab and I also want to highlight the issue of accelerated approval in this regard. Olaratumab is a drug for soft tissue sarcoma, it was tested in a phase I/phase II trial and the primary endpoint was progression free survival. The drug did not improve progression free survival but surprisingly it improved overall survival. The difference in overall survival was huge, it was like a year. We have never seen that in sarcoma, an overall survival benefit of more than a year. But that was not the primary endpoint, the primary endpoint was progression free survival and it was not a phase III trial, it was a phase I/phase II trial. It received accelerated approval on the basis of those results, improved overall survival in a phase I/phase II trial. Accelerated approval means it is a conditional approval, it’s not a full approval. The purpose of giving accelerated approval is faster access to the patients so, of course, cancer patients can’t wait for drugs forever. So accelerated approval, I’m a big fan of accelerated approval, it’s a very nice social compromise in which the FDA gives faster approvals so that the patients can have the drug sooner but there is a condition, there is a mandate for the industry to conduct a post-approval confirmatory trial using a real endpoint – overall survival or quality of life. Based on the results of that confirmatory trial they can either revoke the previous accelerated approval or they can turn the accelerated approval into a full approval.
So the confirmatory trial results were published, were presented yesterday in the ASCO plenary which was a negative trial, as I previously mentioned. So unfortunately there was no benefit in overall survival in the phase III trial and there are a couple of lessons that we need to learn from this. A, we should always be careful about interpreting phase I/phase II results. There was more than one year of benefit in the pre-approval trial, that’s why it got accelerated approval. That one year of benefit is gone, when we did a randomised phase III trial actually there was no benefit at all. Today we are in the world where we are celebrating response rates, progression free survival from phase I/phase II. This trial shows that even overall survival from phase I/phase II is not predictive of overall survival in phase III. So this is a very important cautionary tale, a, and b, the discussant of this trial made a very strong point that we have already spent more than a billion dollars on this particular drug because it was approved as an accelerated approval and we saw overall survival benefit and every sarcoma patient wanted to use the drug. All the guidelines said you have to use the drug so all the sarcoma doctors were using the drug and it is not a cheap drug, it is a very expensive drug and it comes with its own list of side effects. Now we see that actually the drug was not helping at all. So now we are in the process of withdrawing the drug. Now most of the countries are trying to revoke the approval but between these two, three years we have already used this drug for so many patients and we have spent more than a billion dollars on this drug that was not helping anybody at all.
The other important lesson to take away from this trial is actually I want to commend the trialists. I really appreciate the trialists who did this trial because they did it in such a timely fashion. It’s not easy to run a big trial of sarcoma, it’s not a very common cancer like breast cancer, lung cancer, but they did it and they gave us the results within three years. Now I have recently published a paper on accelerated approval of cancer drugs in JAMA Internal Medicine. It came out a week ago and even in that paper we saw that most of the drugs that have received accelerated approval actually the confirmatory trial is not completed in time. There are so many trials that are delayed and a lot of trials that take more than five years. Now, imagine if this particular trial of olaratumab, if it had taken ten years for completion, if they had published the results after ten years or after five years, then we’d be talking about tens of billions of dollars. Now we are talking about one billion dollars that we spent but if it had taken longer then it would be more and more money spent and exposing more and more patients to a drug that was not helping them.
So that’s why at the heart of accelerated approval we have two points. One is that there will be a confirmatory trial, the confirmatory trial will be completed in time and the confirmatory trial will use a real endpoint, all things that happened with olaratumab. That’s why I’m very happy with the researchers presenting this in a timely fashion. Actually, that’s how accelerated approval should function and that’s why I say I’m a fan of accelerated approval. That’s how it is supposed to happen – you get accelerated approval based on preliminary data and then you run a confirmatory trial. In the confirmatory trial you use the real endpoint of overall survival and if the overall survival does not improve in the confirmatory trial you quickly withdraw the drug and that’s what happened with olaratumab so that’s how it should function.
The other point of the compromise of accelerated approval is why do we give accelerated approval in the first place? Because we want cancer patients to have the drug quickly without waiting for the real endpoint results. But if these drugs cost so high then that whole social compromise is lost. So if the drug cost is so prohibitive that patients cannot afford the drug then what’s the point in having early approval to the drug? So we have actually highlighted these issues in our last year Nature Reviews Clinical Oncology paper called ‘The social compromise of accelerated approval’. So olaratumab gives a very poignant example of how that social compromise can be distorted and actually how the accelerated approval process is supposed to function. So this was a very important lesson. So this plenary presentation was not only a presentation of olaratumab’s efficacy in sarcoma, and I think that’s not why it got into plenary, but it is also a lesson on how cancer policy affects the trial decisions and how that ultimately affects patients. It also shows how the accelerated approval pathway is a nice compromise between speed and the demand for efficacy but the main point remains that for the accelerated approval pathway to function well we have to mandate that the confirmatory trial should be running at the time of accelerated approval. That’s what happened with olaratumab. Otherwise it would not happen, getting these results within just three years, it would have taken longer. But when olaratumab got accelerated approval its phase III was already underway. So we should mandate for all accelerated approvals that the phase III should already be underway at the time of approval so that this duration of uncertainty is limited and we can come to reliably certain evidence at a quicker time. It is very common for cancer drugs to received accelerated approval from the US FDA, it’s not as common for the drug to be withdrawn later. The other example of a drug that was withdrawn is bevacizumab in breast cancer which happened many years ago. So olaratumab is a recent example.
Now if we talk about accelerated approval there are so many issues that I can talk about it and I have pointed out all of those issues in my recent JAMA Internal Medicine paper. In most of the cases what happens is even in the confirmatory trial they don’t use the overall survival endpoint, they use the same surrogate endpoint. So even after the confirmatory trial is over we don’t know whether survival is improved or not. Or sometimes the survival is not improved but still the drug goes and gets full approval. So that’s why I’m saying that olaratumab is the perfect example of how accelerated approval pathways should function. Because in most other cases the confirmatory trial does not use an overall survival endpoint and even if the confirmatory trial shows that the results are negative sometimes it receives full approval anyway.
MB: Just moving on to the MONALEESA-7 trial, that’s received quite a lot of attention at this year’s meeting.
BG: Yes it did.
MB: Do you have any comments or thoughts on it?
BG: Yes, yes I do. In fact, we are talking about overall survival and ribociclib in the MONALEESA-7 trial, it improved overall survival in premenopausal women with hormone positive HER2 negative breast cancer. This is a CDK4/6 inhibitor drug and we have other CDK4/6 inhibitor drugs as well in breast cancer – we have palbociclib, we have abemaciclib. In breast cancer especially whenever we talk about the efficacy of a cancer drug, everybody assumes that we can never achieve overall survival improvement so we should be happy with progression free survival .That’s what everybody thinks. Palbociclib and abemaciclib, they have already been approved based on PFS, progression free survival. Whenever someone brought a point that it does not have OS data then everybody would say, ‘You should not be expecting OS in breast cancer. This is hormone positive breast cancer, there can never be OS improvement.’ But now in MONALEESA-7 we see that actually OS is improved. So if you have a really good drug then OS improves.
I’m surprised that now when ribociclib improved OS in MONALEESA-7 everybody is saying this is a wonderful drug, see now we have a survival advantage, it actually improves survival. So my question is, if that’s true, then shall we go back and look at everolimus, for example, which improved PFS but did not improve OS in breast cancer. And the other drugs that have improved PFS and not improved OS, then are we ready to say that these were really bad approvals and should we re-think about them? Because we saw that drug has actively improved overall survival so what is our explanation for the other drugs not improving overall survival? At that time, when these drugs don’t improve overall survival we say that we can never improve overall survival so we should be happy with PFS. And now we have a drug that actually improves OS and how can we reconcile these two different logics. So, yes, I’m happy that ribociclib improved overall survival and that’s great news for breast cancer patients but my point is can we be consistent and can we say that, yes, OS is the benchmark to improve for our breast cancer patients? Our breast cancer patients really need to live longer if we are exposing them with such an expensive and toxic drug. They deserve that, don’t they? They deserve to live longer. And we are also approving so many other drugs that don’t do that, that don’t improve overall survival.
So MONALEESA-7 is a great trial in the sense that it shows that even in 2019, because people say that in 2019 you have ten drugs, twenty drugs, and even after progression the patient will receive all of the drugs so there will be no overall survival gain. MONALEESA-7 proves that wrong. So if you have a really good drug you can improve overall survival. We have seen that time and again in breast cancer – pertuzumab improved overall survival and TD1 improved overall survival – but for some reason we always want to be happy with progression free survival without knowing that the patient is living longer, living a better life. We don’t know this data but we still want to celebrate PFS alone.
Speaking of which, I want to talk about the POLO trial. BRCA germline mutation pancreatic cancer patients. Again this is a drug in the POLO trial which we saw that this drug improves PFS, does not improve OS. Now we are talking about pancreatic cancer. Pancreatic cancer, metastatic pancreatic cancer, is a lethal cancer. So for lethal cancers like metastatic pancreatic cancer or gall bladder cancer or small cell lung cancer, PFS can never be the primary endpoint because these people have a median survival of less than a year. So what’s the point of improving the duration until which your tumour does not grow by more than 30% or more than 20%? So what’s the point in doing that? So I have a patient with pancreatic cancer, will it matter to him that his tumour size was 3cm for five months or his tumour size was 3cm for eight months but he died at eleven months anyway? So if he is going to die at eleven months anyway will it matter to him what the centimetre size of his tumour was while he lived? It won’t matter to him unless if the tumour was big enough and it was causing him symptoms that deteriorated his quality of life. That’s why I keep saying that overall survival and quality of life should be the primary endpoint of all trials but specifically for diseases, for cancers, where the survival is so low. Because someone can argue that for cancers where the median survival is five years how can we wait for five years to get overall survival data? But in this case these are cancers, very lethal cancers, with median survival of a year or less than a year. So there is no argument about speed of trial completion using surrogate endpoints.
When these POLO trial results were announced and presented yesterday a lot of us were just happy and I know the reason for that happiness because, a, it is pancreatic cancer which is a lethal cancer and we are happy that we have now a new drug for such a lethal cancer. So having a new drug, that’s great news. We were also happy because this was a targeted therapy for a particular mutation, a BRCA mutation targeting therapy, and we thought, ‘Wow, so targeted therapy works in pancreatic cancer for the first time.’ We never had any targeted therapy in pancreatic cancer. But I look at the data and I don’t feel as happy as other colleagues have been because, yes, I get those points, I get the point that pancreatic cancer is lethal, we never had a drug, we never had a targeted drug, but does that mean we are ready to accept any drug, then? We don’t have a targeted drug for ten years, we never had a new drug approval for fifteen years, does that mean that we can approve any drug now? No, because if we look at the overall survival curves and overall survival data from this trial, the overall survival, they run parallel. They run parallel, there is absolutely no change in overall survival. And actually they did a very good thing, the researchers did a good thing because they collected quality of life data as well and quality of life also did not improve. There is no improvement in quality of life, there is no improvement in overall survival. We want to assume that progression free survival predicts quality of life but it did not. Quality of life was not improved.
It’s a little surprising trial design, too, in the sense that for metastatic pancreatic cancer patients we are never comfortable keeping them off chemotherapy because, as I said, it’s a lethal cancer so we want to give them chemotherapy as long as possible. But in this trial the patients received chemotherapy for a duration of 16 weeks, at least 16 weeks and then they were randomised. If they had a response they were randomised to receiving olaparib or placebo. Now, I can’t understand how can we put patients on a placebo arm because in the real world we would never put anybody on nothing, on placebos, we would want to continue chemo until the patient tolerates the chemo, until the disease progresses or until the patient dies. So that trial design surprised me very much, a, and b, this is a trial of a maintenance therapy of olaparib versus placebo so this means for one group of patients you are not giving anything at all. For pancreatic cancer patients usually if they were not in trial they would have received chemotherapy so you are not giving anything at all for this group of patients. For the other group of patients you are giving olaparib and still there is no change in OS and there is no change in quality of life. So if one group of patients does not get anything and the other group of patients get a drug you would obviously expect the progression free survival to be longer because these patients are not getting anything. It may not be that olaparib is working well, it may be that these patients are not getting anything.
Of course I have heard anecdotes of one patient having a response of two years, the other patient having a response of three years but we should not fall into those traps. That’s why we think case reports are not good quality studies, that’s why we do trials. So we should not fall into that. We can have anecdotes for anything, we can have anecdotes of any drug can have one or two very nice responses in any cancer type but we do randomised controlled trials because we don’t want to fall in to those traps.
I have written this in the Nature Reviews paper, I think in 2016 or 2017, I forget, but if we are doing a trial of maintenance therapy then for maintenance therapy PFS can never be an adequate endpoint. For pancreatic cancer PFS can never be an adequate endpoint. For pancreatic cancer the placebo arm can never be a control arm. For pancreatic cancer, despite all these issues, if still OS is not improved and there is no change in quality of life but there is increase in toxicities with the use of the drug, so what exactly did our patients get? Or what exactly will our patients get by receiving this drug? So if we are honest and if this drug gets approved, which I think it will because the bar is so low these days, then we have to be honest with our patients and we have to tell them that you take this drug, you are not going to live longer, you are not going to feel better, but, yes, take this drug, it costs you $15,000 a month.
MB: So, in your opinion, for the placebo arm how would you redesign that or make it a bit better?
BG: Okay. If I were designing the trial I would not have kept the placebo control arm, I would have asked for at least six months of chemotherapy at first and after six months of course we can randomise to olaparib versus continuing chemotherapy and I’d use overall survival as the primary endpoint and, of course, measure quality of life. So after six months of chemo randomised to olaparib versus active control arm, not placebo, and measure OS and quality of life.
MB: Moving on to prostate cancer, the TITAN and ENZAMET trials, what are your thoughts about them?
BG: Firstly I have to say that, this is my disclosure of interest, I am very good friends with the trial group of the ENZAMET trial – Professor Ian Davis, Professor Martin Stockler, they are very good friends of mine. So I always have a softspot of ENZAMET, a, and b, I like the ENZAMET trial because this is an academia sponsored trial and this reflects such a nice, huge collaboration effort across the continents, primarily led by Australia and New Zealand but Dana-Farber was also participating in it and Ireland was participating in it. And now I have to mention that I am working in Canada, the Canadian Clinical Trial Group was also a big part of the ENZAMET trial. So a, congratulations on pulling off such a big trial in prostate cancer as an academia led trial, which is not an easy thing to do, and b, yes, we saw that the use of enzalutamide improved overall survival in metastatic castration sensitive, hormone sensitive, prostate cancer.
So we have already seen a couple of other trials where we have seen positive outcomes in hormone sensitive prostate cancer, specifically the use of docetaxel up front also led to improved overall survival, the use of abiraterone also led to improved overall survival. And, as the TITAN trial showed, the use of apalutamide also improved overall survival. So now we have plenty of options but if I have to compare between the apalutamide and enzalutamide trials, the TITAN and the ENZAMET trials, of course TITAN was an industry sponsored trial and I guess that’s why there was not much flexibility with trial design, because when the docetaxel trial was published, when it was presented and we knew that using docetaxel up front improves overall survival, then it becomes unethical to continue to not give docetaxel to patients. Because the CHAARTED trial and later on the STAMPEDE trial showed that we should use docetaxel up front and that will improve OS so once we know that, for the control arm patients if we don’t give docetaxel then they are getting sub-standard treatment by getting enrolled onto the trial. They would have received better treatment if they were not a part of the trial. So that becomes an ethical issue with the trial. But unfortunately in the TITAN trial the control arm patients were not getting this but in the ENZAMET trial, the trial started a little earlier than when the docetaxel results were published, but when it was published they changed the trial design midway and they allowed patients to receive docetaxel. So that’s why I’m happy with the trial design of the ENZAMET.
The other difference was the control arm in the ENZAMET trial, it is an active control arm, but the control arm in the apalutamide trial is a placebo controlled arm. So I would favour the enzalutamide results to the results of apalutamide because of these two things – the control arm is an active control arm and the patients were allowed to receive docetaxel after the docetaxel results were published. Having said that, if we look at the subgroup analysis then patients who were getting docetaxel did not derive any benefit from enzalutamide but patients who were not getting docetaxel they had a substantial survival benefit from getting enzalutamide.
So we have four options now – docetaxel, abiraterone, apalutamide and enzalutamide – for the same disease setting and the choice of which drug to use will depend on the physician and the patient, of course. But, for the reasons I mentioned, I would not be very enthusiastic about apalutamide. The other factors that will come into consideration is a, docetaxel is an IV chemo whereas enzalutamide and abiraterone they are oral drugs so that might come into factor. But we have to balance that against the treatment duration – for docetaxel it’s a limited duration, you get six cycles of chemo, but with the oral drugs you receive them for three years or until the disease progresses. So it’s the patient’s choice, whether the patient wants to get IV chemo for a limited duration and then be happy with it and get over it, so no more chemo, no more drugs for me, or no, I hate IV, I would rather take pills for three years. And the side effect profiles are, of course, different. Docetaxel is a classic cytotoxic chemo, it has all the side effects of a classic cytotoxic chemo – neutropenia, hair loss, neuropathy, all of those things. But enzalutamide, for example, gives more fatigue, there is a slightly increased risk of seizure, so we have to balance those side effects and cost. Docetaxel is the cheapest of all the options. So having many options is a good thing and the patient and the physician have to reach to a shared decision making. But I don’t want to see any more trials in the same setting using a placebo control arm.
MB: There was also another presentation presented by Dr Joseph Tabernero, the KEYNOTE-062 trial. Do you have any other thoughts on that one?
BG: I do, I do in fact, because this is a trial of pembrolizumab in advanced gastric cancer and again we come back to the concept of accelerated approval. Pembrolizumab has already received accelerated approval for this indication and this is supposed to be a confirmatory trial. This trial shows that pembrolizumab was non-inferior to chemo. It was not superior and pembrolizumab plus chemo was also not superior so pembrolizumab plus chemo is out of the question.
Pembrolizumab was non-inferior to chemo so I have two big concerns here – a, why was a non-inferiority design acceptable? And I saw that the actual non-inferiority margin was considered to be a 1.2 upper limit of 95% confidence interval of hazard ratio.  So that means we were ready to accept up to a 20% increase in the risk of mortality as non-inferior. We have never asked our patients up to what percent increase in mortality is acceptable to you. How do we know that up to a 20% increase in mortality is acceptable? If we tell our patients that here is a drug, we are going to test if it increases your risk of mortality by less than 20% or more than 20% why would anyone want to get such a drug? Because this is not testing whether it reduces the risk of mortality or not, this is testing whether it increases your risk of mortality by a certain margin, 20% margin, or not. Any patient who would want to get such a drug if there were any other benefit from the drug, for example currently you are getting chemo but if you get this drug this drug will cost you much less than what chemo costs. Okay, then if it is costing me 50% less then, okay, a 20% increased risk of mortality I may accept that negotiation. But no, pembrolizumab costs quite a lot compared to chemo, it’s not a cheaper drug. Pembrolizumab is also an IV drug, it’s not an oral drug, so I can understand that chemotherapy may be a little more toxic and people assume immunotherapy to be less toxic, although immunotherapy has its own list of side effects which does not look like cytotoxic chemo drug side effects but the side effects are still important and dangerous nonetheless, that can lead to hypophysitis which can kill patients. So the side effects are different and they are not as visible as the chemo side effects but still immunotherapy, nobody considers it to be a totally safe drug.
So I can’t understand the trial design of non-inferiority. We are not trying to improve survival in gastric cancer, we are trying to see if this is not worse than 20% increased risk. So how is that okay for our gastric cancer patients? Our gastric cancer patients want to live longer, they don’t want to live shorter than the non-inferiority margin of 1.2 hazard ratio. The trial concluded non-inferiority. The trial concluded that the hazard ratio, I don’t remember exactly what it was, 0.9 or something, and the upper bound of the confidence interval was 1.18. If it had been 1.21 it would be considered inferior. It was 1.18 and now we are saying it is non-inferior.
So that is one of my concerns about the design itself and the other concern is this was supposed to be a confirmatory trial for the accelerated approval that it has already received. So how can a confirmatory trial be a non-inferiority design trial? I recently published a paper in JAMA Oncology, a viewpoint about non-inferiority trials in oncology and, in fact, we propose that all non-inferiority trials should receive conditional approvals, accelerated approvals, they should never receive full approvals. But here this is a non-inferiority design trial done as a part of a confirmatory trial of the previous accelerated approval it has already received so the actual definition of accelerated approval, if you see, the mandate for confirmatory trial, then what it says is accelerated approval are based on surrogate measures that are reasonably likely to predict clinical benefit and confirmatory trials should be conducted to duly confirm that there is actual clinical benefit. So how can a non-inferiority trial be a confirmatory trial because it cannot confirm clinical benefit, it can only say that the drug is not worse than the drug we already have by a certain margin. This can never be a confirmation of benefit, this can only be a confirmation of the drug not being worse. It’s not a benefit. How is it a benefit?
And b, I’m worried because I read about this trial in the media from many colleagues and many people have said that pembrolizumab was comparable to chemotherapy. No, it is not comparable, you cannot use the word comparable to describe non-inferiority. To say comparable you have to use an equivalence trial which is a totally different category of trial. This was not an equivalence trial, this was a non-inferiority trial. So what we proved was pembrolizumab is non-inferior, we did not prove pembrolizumab was comparable. We did not prove pembrolizumab was equal. No, we cannot say that. That is statistics 101. So it is important in ASCO meetings to also have some session on bio statistics and how to... Because you assume that the top people, the very best of the best who are describing the trials would know that non-inferior does not mean comparable. But everyone is saying that this is comparable.
MB: Thank you so much for offering your thoughts and for participating today and hopefully we’ll see you next year.
BG: Thank you very much.