It’s my big pleasure today to be back with you all again for a roundup of important abstracts presented at ASCO 2022. This was a very nostalgic and important meeting; post-pandemic first in-person meeting and there was huge enthusiasm and ASCO didn’t disappoint. Meeting friends was an important part of this event but let’s get to the trials that make ASCO what it is.
GI cancers
First I would like to start with the GI trials that were presented at this ASCO. Let’s just start with the PARADIGM study which was presented at the plenary session from the Japanese group. I might have a conflict of interest here – the senior author is my mentor from Japan, Dr Muro. Anyway, the PARADIGM trial was conducted to test the efficacy of panitumumab, which is an EGFR monoclonal antibody, versus bevacizumab, which is a VEGF inhibitor, in left-sided colon cancer. When this trial started there was no evidence for a difference in efficacy of treatment or even prognosis based on right- versus left-sided colon cancer but as the trial was starting there was evidence coming up showing right- and left-sided colon cancers behave differently so we need to treat them differently. Based on that information, they changed the primary endpoint to overall survival in left-sided colon cancer only and then if that is positive then they will look after the entire colon cancer.
We had seen data from the CALGB 80405 trial in the past but that was a retrospective look at the data before knowing about the sidedness effect. That trial actually showed that bevacizumab and panitumumab or cetuximab might be similar. However, if it is left-sided then an EGFR antibody is effective whereas if it is right-sided then an EGFR antibody might not have any beneficial effect. That is something that we knew from the CALGB trial but in this PARADIGM, the Japanese trial, for left-sided colon cancer only they were trying to look at panitumumab plus FOLFOX versus bevacizumab plus FOLFOX and the primary endpoint, as I mentioned, is overall survival in left-sided colon cancer. They found that actually panitumumab improves median overall survival by almost four months – 38 months versus 34 months – with a hazard ratio of 0.82. The hazard ratio does not sound too impressive but these drugs have always provided incremental benefit to begin with. These are not big game changers but the incremental benefit is there and there is an absolute difference of four months of survival here and which is statistically significant.
But there are a couple of things that are very intriguing, for me, in this trial. One is why would there be a crossover of the curves at the 28 month point? Which is intriguing. If we had taken a look at the data before that time probably we would have concluded just the opposite. The other thing is that PFS actually is negative here – there is no difference in progression free survival. This is not an immunotherapy so I would not expect why PFS would be negative but OS would go on to be positive. This also shows that PFS is actually not a good surrogate endpoint but for the opposite reason in this case because usually you see PFS positive, OS negative. Here PFS is negative but OS is positive and fortunately the primary endpoint is OS so we can trust the OS data. But this goes on to show why we cannot rely on surrogate endpoints for both reasons. It can underestimate, it can also overestimate the findings. So there was some discussion going on on social media about the role of surrogate endpoint. But what we can confidently say is rather than trying to guess what happens to the surrogate endpoints and trying to find the surrogacy validation for each treatment type and subtype of tumour separately, it’s much better to just go and test for OS so that we’ll have an answer, rather than having to guess all the time is this validated, is this not validated.
After they found that the overall survival was significant in the left-sided colon cancer they also tested for the entire population and they found that it was positive for the whole colon cancer as well. However, when they looked at right-sided colon cancer only, which was an exploratory analysis, we saw what we expect, that is probably panitumumab is harmful, or bevacizumab is more beneficial, for right-sided colon cancer.
So, yes, it is practice affirming, like we are already doing that. For left-sided colon cancer you could have the option of EGFR antibody as well as bevacizumab but, based on this data, I guess it is more appropriate to go with an EGFR antibody up front. But the practice of treating colon cancer has changed in recent years – we have MSI high tumours benefitting from immunotherapy. This trial tested only FOLFOX as the chemotherapy backbone, they have not tested this with FOLFIRI. So those questions are still remaining. But, however, it was a good trial, as I said it is a practice affirming trial, but those questions about why the curves crossed over at the 28 month point and why PFS was negative, those are some things to think about in the future.
The second study in colorectal cancer is the DYNAMIC study that I wanted to talk about. This was published in The New England Journal of Medicine as well, simultaneously with ASCO. The adjuvant treatment for stage 2 colon cancer is not very straightforward. We separate our patients into high risk and low risk and high risk patients do get adjuvant chemo but low risk patients we do not give adjuvant chemo. This study was interesting because they were trying to check whether using circulating tumour DNA can guide in our management and basically whether we can avoid chemotherapy for patients who do not need it, which is a very worthwhile goal to achieve. What they did in this trial is they randomised patients 2:1 into circulating tumour DNA guided management versus standard management. I already described what our standard management looks like but in the circulating tumour DNA arm what they did was for stage 2 colon cancer patients they measured circulating tumour DNA at two different time points and if it is positive then those patients got chemo and if it is negative those patients did not get chemo.
Their primary endpoint was to look at what percentage of patients can avoid chemo and they found that in the circulating tumour DNA guided treatment arm 15% of the patients got chemo and in the standard management arm 28% of the patients got chemo. So there were 13% fewer patients who got chemo with this strategy. So there is definitely some benefit there in terms of 13% of the patients can avoid chemotherapy. But avoiding chemotherapy alone cannot be the goal – if you avoid chemotherapy but go on to relapse then that does not make sense. So they looked at two year recurrence free survival and in terms of two year recurrence free survival they were aiming for non-inferiority. That non-inferiority was proven because two year recurrence free survival was 93.5% versus 92.4%, 1.1% difference. So they concluded that we can use circulating tumour DNA as a strategy to allow less patients to get adjuvant chemo so we’re sparing more patients from unnecessary toxicity of chemo without compromising efficacy. But that’s what the study is.
I have a couple of comments on this study. One is that this was not a very neat way to look into the question that affects us because we already avoid chemo for low risk patients. So a better strategy would have been to avoid chemo for low risk patients, because we’re avoiding it anyway, and then only among the high risk patients they should have done circulating tumour DNA tests and positive got chemo, negative did not get chemo in what happened. Because in this study there are 60% patients who were low risk, they were not going to get chemo anyway.
So that is one important caveat, another thing is if someone like a trainee is reading this paper then they should not be misguided because this is a part of the study. That’s why they did an intense surveillance which is not usual for normal practice. By that I mean they did SEER tests every three months, they were doing CT scan imaging every six months; that is quite intense surveillance follow-up, we don’t do that in routine practice.
Having said that, my take-home message, or take-clinic message, from this trial would be that we would need more studies of circulating tumour DNA for de-escalation of treatment. It is an important goal to work towards. But for low risk patients I don’t think we need circulating tumour DNA unless proven that even low risk patients with positive circulating tumour DNA are at a high risk of relapse which we have not proven yet. But for high risk patients… and those trials are ongoing so we will have an answer in the near future. But our goal is with the high risk patients, whether treating them based on circulating tumour DNA makes a difference.
The other question is the duration of treatment. In this study one other caveat was that for patients who have circulating tumour DNA positive they received oxaliplatin based chemo, most of them. But for patients who were randomised to the standard management arm they mostly, I think 90% of them, received 5FU alone. So that is an important bias there. Standard treatment, most of the patients are getting single agent chemo but in the circulating tumour DNA arm if it is positive then people are getting 5FU plus oxaliplatin, a doublet. So that’s something to keep in mind.
Moving on with GI cancers, there was a very interesting study from rectal cancer – neoadjuvant treatment with a PD-1 antibody, dostarlimab. This is a new immunotherapy and actually the study was designed such that they wanted to test whether giving immunotherapy as a neoadjuvant strategy can avoid surgery and chemoradiation. Because surgery and neoadjuvant chemoradiation has a big quality of life toll on the patient so can we avoid it, that’s a very important question to ask.
The study was designed that they would give this new immunotherapy as a neoadjuvant treatment and if patients achieved a complete response then they would just wait and watch. If patients did not achieve a complete response then they would move on to get chemoradiation and surgery and then they would look at the pathological complete response rate.
However, interestingly, they recruited 16 patients of which 12 patients have six months of follow-up and that’s the data that they are presenting now. All of them had complete response so the other arm was not even necessary. None of them had less than a complete clinical response. That’s why it created a big buzz, like it was 100% complete clinical response. This is something actually quite remarkable. However, again there are some caveats to that. It’s a very small sample size and the median duration of follow-up is 12 months, ranging from 6-25 months. There are only four patients who are responding more than one year after treatment. Yes, this is really remarkable, this is not something that you see with chemoradiation all the time, however, the caveat is can these patients avoid surgery because surgery is curative treatment. These patients, after they undergo surgery, many of these patients will be cancer free for several years, some of them will be cured. But with this strategy it’s still too premature to say that we’ll have similar outcomes, long-term cure, by using just immunotherapy. As a patient it is risky to think, okay, I’ll get immunotherapy and I’ll not undergo surgery. Because if you undergo surgery you can be confident that your chances of cure are pretty high but with this you never know. We don’t have long-term data; relapse rates could be high. The longest followed-up patient is 25 months, we need 60 months data, we need five year DFS rates. But this is quite promising, that is why with just a 12 patient sample it got into The New England Journal as well. I was quite surprised to see it in The New England Journal with 12 patients but, having said that, it’s not a random 12 patients it’s according to the statistical plan so I don’t have any complaints about that. I just want to caution patients and physicians that, outside of the setting of a trial, probably just getting immunotherapy and not undergoing surgery might be a risky strategy.
Continuing with our GI group, I want to talk about the SEQUENCE trial. The SEQUENCE trial was very interesting. In pancreatic cancer we usually give gemcitabine Abraxane as the first line treatment or FOLFIRINOX, depending on the performance status of the patient. For very fit patients we give FOLFIRINOX because they have not been compared head-to-head but it is an impression that FOLFIRINOX probably gives longer survival. For other patients we give gemcitabine Abraxane. But this trial tested whether giving gemcitabine Abraxane followed by FOLFOX and compared that with gemcitabine Abraxane and they tried to see whether there is a survival advantage. It makes sense, in a way, because not all pancreatic cancer patients maintain good performance status to get two lines of treatment, the majority of them get only one line of treatment and then they decompensate. So this was a nice strategy to test whether we could give all possible good drugs while the patient has good performance status up front.
They gave gemcitabine Abraxane routinely but after gemcitabine Abraxane was complete at the four week time point they gave FOLFOX. So this was a six week regimen and they compared it with the standard gemcitabine Abraxane regimen. They found an OS difference – 13.2 months versus 9.7 months. It’s very difficult to make cross-trial comparisons and to see how it compares with FOLFIRINOX but these survival results are quite comparable with what we saw in the trial of FOLFIRINOX. So this could be a very good strategy. I want to read the full paper about this, I have only seen the abstract, but once I see the full paper I think I might be convinced that this might be a good strategy.
There was in pancreatic cancer one more trial of nimotuzumab, which is an EGFR antibody. This trial came from China and they compared this EGFR antibody called nimotuzumab plus gemcitabine versus gemcitabine in KRAS pancreatic cancer. They found a survival difference of 10.9 versus 8.5 months. However, the problem here is that the comparator arm is gemcitabine alone. If the patient is fit enough we would prefer to give gemcitabine Abraxane or FOLFIRINOX, not gemcitabine alone. However, in the local setting Abraxane is also an expensive drug and this is a locally developed drug in China and it has shown clear survival advantage here against gemcitabine. So I think it will be an effective and a good treatment option to have, at least for the local population.
In the same vein, there was one more trial from China but this was in prostate cancer, hormone sensitive prostate cancer, a new androgen receptor inhibitor. I think it does not even have a name yet but, again, compared to other expensive new generation androgen receptor inhibitors that we have I think this will be, again, a very good option. There have been a number of newer ‘me too’ drugs that are coming out of China and I touched on that and the regulatory and scientific and ethical issues of these trials in my talk as well. So I won’t comment much about it but these are good options to have and it’s good to see several of these newer drugs that are being locally developed and that will probably have a price competition.
Breast cancer
This ASCO was a very important event for the breast cancer community. There were especially three important trials that were presented. The first trial is DESTINY-Breast04, it was presented at the plenary session, received a standing ovation, a huge cheer from the crowd. This is a trial of trastuzumab deruxtecan, an antibody drug conjugate, against treatment of physician’s choice. The reason this trial got so much applause and is exciting is for a couple of reasons. One, obviously I’ll talk about the magnitude of clinical benefit and the results, but the second is it changed the way we think about breast cancer categories. We used to say there is HER2 positive cancer and HER2 negative cancer and we used to define it based on IHC and FISH. IHC of 1+, we say this is HER2 negative, IHC of 0 or 1+ negative; 2+ we would say equivocal and do a FISH and if FISH is positive we would say this is positive; if FISH is negative we would say this is negative; 3+ and more we would say this is positive.
In this trial they defined a category called HER2-low, so not just positive and negative but HER2-low. So how do we define that? If it is IHC 0 then it’s clearly negative but 1+ is low, 2+ and FISH negative is also low. So this category of tumours is what we’re studying here and we have never studied this category of tumours formally as a clinical trial before and we did not have positive results before. So that’s why, from a biology point of view, it is exciting.
I’m going to talk about the trial design. As I said, this was a trial of trastuzumab deruxtecan versus treatment of physician’s choice for patients with hormone receptor positive breast cancer. These patients had received previous endocrine therapy and these patients had also received previous chemotherapy. So this is for patients who had received at least 1-2 lines of chemotherapy in the past and must have received endocrine therapy.
The treatment of physician’s choice arm included capecitabine, eribulin, gemcitabine, paclitaxel and Abraxane, there were five different choices that the physicians could use. First let’s go to the results. They found that the median progression free survival increased by almost five months, 4.7 months, and the hazard ratio was almost 0.51, in the range of 0.5, so almost a 50% reduction in the hazard of progression free survival. Overall survival increased by 6.5 months and this had a hazard ratio in the range of 0.6. So that’s what got all of us excited and that’s why it received applause because increasing overall survival by more than six months after the patient has already received a number of lines of treatment is something that we don’t see every day.
However, again, there are a couple of things that we need to consider that we have not been talking about because we got super excited about the data. Again, this is not to say that this trial is not practice changing but a couple of things that we need to consider in interpretation of the results is, one, we do not know which chemo the patients have received previously. We have been told that the patients had received at least one line of chemo but how many of them received just one chemo and how many of them received more than one line of chemo and what those chemos were. I just don’t want to see that a patient who had progressed on paclitaxel is again getting paclitaxel in the trial; other patients who progressed on capecitabine is getting capecitabine. So what were the chemotherapies the patients had previously received before the trial, that is the data that I want to see. I had some time to look into it in the publication, I didn’t have too much time to go into detail, but in my brief look at the supplementary appendix I could not find that information.
The other thing to consider here is that the enrolment from North America is pretty low, it is mostly enrolled in Asia and Europe. So we need to know what the post-protocol treatments were. Did patients get the same balanced treatment post-trial? If there is a huge imbalance in that we need to consider that into the magnitude of benefit. Is that biasing the magnitude of benefit? The other thing is we need to also consider the side effects when we make a decision because this drug is not easy. There was 12% incidence of interstitial lung disease. Let’s forget about other side effects, interstitial lung disease alone is a big deal with this drug. There were 12% of the patients who got this and 0.8% of the patients actually had fatal interstitial lung disease. So when we are using it, because the eligible patient population is going to be huge, 0.8% will translate to a huge number of absolute lives. That is something that we need to consider, so how are we going to be vigilant about it? Because this is in a trial setting; if in a trial setting 0.8% of the patients are dying from interstitial lung disease alone then that is something that scares me.
To connect with that, the same drug was also tested in biliary tract cancer, called the HERB trial; this was from the Japanese group. Because it’s the same drug I wanted to connect it here. They showed a 36% response rate in this trial, it was a phase II trial. It is worthy of being investigated in a phase III but the interstitial lung disease rate in this trial was 25% and 6% of the patients had fatal interstitial lung disease. 6% is pretty big. We have some drugs that are approved on the basis of 6% response rate and we’re talking about 6% fatal adverse event from a drug. So this should be really well thought out before we start treating our patients. We need to monitor any respiratory symptoms, we need to do long focus CT scans and we need to really keep an eye on our patients’ respiratory function.
But going back to the DESTINY-Breast04, those are a couple of points that we need to consider about pre-trial chemotherapy, post-trial treatment. Interestingly, CDK4/6 inhibitors were received by 65% of the patients, it was not 100%, but they did do a subgroup analysis and they showed benefit across the subgroups. But I look forward to reading the publication in further detail. But this hazard ratio and magnitude of benefit was quite substantial and that’s why it got all of us excited but let’s not forget some other parts as well. But I do believe that it is a practice changing trial but I want to see the pre-trial and post-trial treatments that the patients got.
The next breast cancer trial that was presented was the TROPiCS-02 trial of sacituzumab govitecan versus, again, treatment of physician’s choice for hormone receptor positive HER2 negative breast cancer. They showed that median PFS increased by 1.5 months, 4 versus 5.5 months, OS was not yet mature. Again, for these hormone receptor positive, HER2 negative patients who have already progressed on endocrine therapy and chemotherapy. So this was more like a last line treatment and this drug does have significant toxicities that we cannot ignore.
People were saying that this is a practice-changing trial, this is a game-changing trial, I do not think that it is. We do not have OS yet in almost the last line of treatment. So I would somewhat understand if this was first line of treatment, that you would say it would take five years, six years for hormone receptor positive patients to find OS; there are so many post-trial treatments which will confound the results. But if you cannot improve OS in the last line then I’m not convinced. So when the OS becomes mature it might show a positive benefit, then I’ll say okay, but the magnitude, even for PFS it’s just 1.5 months. It’s just delaying your scan by 1.5 months and if OS does not pan out this is not worthwhile.
The funny thing is, let’s compare with DESTINY. DESTINY improved OS, DESTINY significantly improved OS, so when DESTINY improved OS by six months, more than six months, we were like, ‘Wow, that’s great,’ and here if it did not improve OS, this sacituzumab govitecan, we should be saying, ‘Oh, it did not improve OS so this is not practice changing.’ How difficult it is. In DESTINY-Breast04 it is a good drug, it did improve OS so if your drug is good OS will improve. If you have to come up with different excuses in last line of treatment for why OS does not improve then that’s not a good drug.
The third breast cancer trial was called the LUMINA trial, I do not have data about it today, it will be presented in a couple of days and I will talk about it at that time.
Lung cancer
Moving on to lung cancer, there was one Lung-MAP trial that was testing ramucirumab plus chemotherapy versus ramucirumab plus pembrolizumab among patients who had already failed an immunotherapy. That was interesting but, again, we do not have the publication so there is only the abstract to look at. However, it is interesting to think what the role of ramucirumab here might be. Ramucirumab is a marginal drug, as we know, from its REVEL trial – docetaxel versus docetaxel plus ramucirumab. In this case ramucirumab is there in both arms, in the interventional arm as well as the control arm, it’s pembrolizumab plus ramucirumab versus chemo plus ramucirumab. Of course there are biological theories as to why immunotherapy plus an angiogenesis inhibitor might work together but I really doubt the efficacy of ramucirumab here and what added benefit it might provide. So basically is it similar to pembrolizumab, immunotherapy, after progression on immunotherapy? So we really need to look at the publication because we do not know for how long a duration the patients were responding in the previous immunotherapy, what the previous immunotherapy was – are these patients progressing on nivolumab, atezolizumab or pembrolizumab itself and are they again getting pembrolizumab? It was intriguing but it’s definitely not practice changing in my opinion. And, on top of it, it’s a phase II trial and we know that phase II trials mislead us a number of times, it’s not a phase III.
The other lung cancer trial was the trial of adagrasib, which is a KRAS inhibitor for lung cancer patients with KRAS G12C mutation. This was, again, a phase II single arm trial, a response rate of 43%, progression free survival median 6.5 months. It’s interesting but I would not get too excited about it because in phase II single arm trials the patients are highly selected. You do not select your everyday patient there, you select very fit patients. Previous studies, retrospective studies from the precision medicine cohorts have also looked at patients with this mutation in lung cancer and even those patients have a PFS of 4.5 months, 5 months on average, and this is a PFS of 6.5 months. So without a comparator, without a control arm, it’s really difficult to say anything.
GU cancers
I want to talk about a couple of GU cancer trials. Only a couple have been presented by now. So in the prostate cancer the TheraP trial OS data, those are very interesting to me. This is a trial of lutetium-PSMA versus cabazitaxel done by the ANZUP Group in Australia and New Zealand. Actually, I like this trial because previously the VISION trial was published last year for the same drug, lutetium-PSMA, but they used a control arm that I believe is an inferior control arm. The appropriate control arm would have been cabazitaxel but that trial did not use cabazitaxel as a control arm. There were several arguments given as to why that cannot be done but the TheraP trial did use cabazitaxel as a control arm so it can be done. The other thing is this is an academia sponsored trial so they used the right control arm, that’s why we need to fund more academia-led trials and not just rely on the industry sponsored trials.
The results here: OS was not improved. Obviously the VISION trial showed that OS improved because they used a bad control. Here, when you use the standard control, the OS was not improved. Does lutetium have a place? It may because they showed that the OS numbers are similar but obviously we had expected to see if OS would improve and it did not. So the cost of lutetium should be considered here and I’ll be talking about cost at the end for most of the drugs that we’ll be talking about today. But, again, last year the industry sponsored trial made us believe that lutetium improved survival, here we see that it probably does not but the crossover effect should also be considered. I look forward to reading the full paper.
There was also the update of the ENZAMET trial by Dr Ian Davis which confirms the result of the ENZAMET trial that was published three years ago. It is very interesting, three years ago was the last pre-pandemic in-person ASCO and the ENZAMET trial was presented at the time. Three years later when we are back in person we have the updated OS results from the same trial and the results do not change. The addition of enzalutamide to androgen deprivation therapy does improve survival.
Ewing sarcoma
Finally I’d like to talk about the Ewing sarcoma trial that was presented in the plenary, the rEEcur trial. I liked this trial for several reasons. One, this is a rare cancer and a disclosure that I don’t treat this cancer so I don’t have the clinical expertise on this cancer. However, I like this trial for several reasons because this checks all the boxes for an ideal trial. One, it’s a rare cancer and people always tell you that because this is a rare cancer we can never do a randomised trial. That’s the most frequent argument I hear why someone cannot do a randomised… “Oh, it’s rare cancer. How can you do a randomised trial?” This is a rare cancer, they did a randomised trial. They enrolled almost 400 patients in four cohorts so with international collaboration it can happen. This is an academia sponsored trial with public funding.
Second, the objectives were quite clear – they said they wanted to know, among four different chemotherapy options that we have, which is the best one, which we should give to our patients, a, and, b, which should form the control arm for our future trials because you want to use the best possible treatment as a control arm in future trials.
Third, they started with the phase II format, looked for the overall response rate and, based on that, they took to phase III and used event free survival as the primary endpoint which is relevant in this case. But they also measured overall survival as a secondary endpoint and they have data for both EFS as well as OS in Ewing sarcoma. They showed that ifosfamide is probably a better chemotherapy compared to the other regimens, based on EFS and OS data, but the randomisation was quite pragmatic because it’s an international trial, maybe all four treatment options are not available everywhere or patients may not be fit for everywhere. So as long as the patient was eligible for any two options the patient could be randomised. That was quite a pragmatic approach that I liked.
The other best part of this trial was they report quality of life data. Actually for this trial one of the other plenaries reported quality of life information, this trial reported quality of life information. Again, all the more important because this is a younger population, they reported quality of life information not only for the patients but also for the guardians, for the caregivers, because that also matters. So I can’t find any fault with this trial, this is a fantastic trial. I just wanted to congratulate this team.
Treatment costs
Finally a comment I would like to make is about the cost of these treatments. Yes, we saw significant benefit with trastuzumab deruxtecan, we had a standing ovation, applause, but what percentage of patients globally would be able to receive this drug? I would say very few, very few, only a select group of patients in countries like the US, Canada, high income countries, might get it. But the global breast cancer burden is outside of high income countries. The majority of the breast cancer patients are not going to get this drug for almost a decade. These are super-expensive drugs. So with that applause we need to have a commitment about how to reduce financial toxicity, how to reduce the cost of the drugs.
What is the point in having a drug that nobody can take? So, yes, the results are exciting but more exciting should be our commitment to ensure that if our results are good our patients will benefit from it and how do we do that. That’s the theme of our ASCO as well – equitable access, how do we ensure that there is equitable access? Just getting a new drug is not enough. The same is true for immunotherapy that I talked about for rectal cancer – if it pans out how do we make sure that our patients get it? Circulating tumour DNA in adjuvant, circulating tumour DNA is a new technology. Patients in low income countries don’t have access to it, how do we ensure that they get it? So these are the things that we need to think alongside cheering for these new results and cheering for new innovations. Innovation is cool, innovation is good but it should be affordable.
