Dr Bishal Gyawali – Brigham and Women’s Hospital, Boston, USA

Will Davies – ecancer Medical Reporter

WD: Hello, and welcome to the ecancer roundup from ASCO 2018. Joining me is an author, one of the ecancer bloggers and social media expert from all across the globe, Bishal Gyawali.

Thanks for taking the time to meet with us today.

BG: Thank you very much, Will. It’s nice to see you again and to provide a highlight of ASCO 2018 with the ecancer team again.

WD: So you’ve had a bit more time on the floor meeting with people, seeing some of the exhibits than we’ve had from filming the interviews.

What’s been catching your eye out in the conference in the wild?

BG: Yes, one main attraction of this conference this year for me was a couple of practice-changing non-inferiority trials because I am usually critical of non-inferiority trials because I don’t think non-inferiority can be used as a basis for introducing new drugs unless they have something else to compensate for that margin of acceptance for non-inferiority.

It could be less toxic, it could cost cheaper, but…

WD: It has to offer something.

BG: Yes. But in this ASCO meeting we saw a number of non-inferiority trials that were very smartly designed as non-inferiority because they had a lot of things to offer to the patients in terms of, for example, avoiding surgery or using a shorter course of treatment or avoiding chemo altogether.

So I was very impressed with very smart use of non-inferiority designs to address some very important questions in the clinic.

WD: Well, starting with avoiding chemotherapy, shall we begin with the TAILORx trial for genetic assays to avoid chemotherapy for breast cancer patients?

BG: Yes, this was a very important trial addressing a very important clinical question that we face in clinics every day, in breast cancer clinics.

That is, we know what to do for patients with a high risk score and what to do for patients with a low risk score but for the patients who have intermediate risk score we do not know what exactly is the proper adjuvant treatment.

So, should we use endocrine therapy alone or should we use endocrine therapy plus chemotherapy?

So, for this group of patients this was a very, very important question and this trial properly addressed that question in a non-inferiority design by checking whether avoiding chemo for these patients is non-inferior to using hormone therapy plus chemo.

And the results were positive in the sense that, yes, there was no harm, substantial harm, in avoiding chemotherapy for these patients and chemo is toxic, chemo leads to various side effects, so this group of patients could safely avoid chemo and use only endocrine therapy as adjuvant treatment and receive the same amount of benefit.

But there were a few caveats, important points to consider about, because they did an interaction test with age and score. For women who were less than 50 years of age, and especially they have a recurrence score above 16, then they seemed to derive some benefit from a regime of chemo compared to women who were more than 50 years of age or who had the recurrence score less than 16.

So these are some points to keep in mind but still the benefit they derived from a regime of chemo was not substantial.

So this is something to discuss with the patient, depending on her age and the recurrence score.

So, yes, I think this is a very practice-changing trial that we can immediately use from today in the clinic.

WD: And then there was also the news for shorter courses of drugs, rather than just avoiding chemotherapy.

Drugs they do have to receive, maybe not as long, maybe not as an arduous process as there has been before.

BG: Yes, this is, again, an interesting trial. It’s a coincidence that in last year’s ASCO also we had one trial of similar design and in this year’s ASCO we have one more trial of similar design.

This is a trial that tested six months of adjuvant trastuzumab versus the standard twelve months of adjuvant trastuzumab for HER2 positive breast cancer patients.

Last year it did not meet non-inferiority definitions but fortunately for this year this trial met the non-inferiority criteria in terms of overall survival and disease free survival.

So the conclusion, based on this trial, will be six months of Herceptin is enough and patients don’t necessarily need to undertake the whole twelve months of Herceptin.

This is also important because Herceptin has cardiotoxicity, other side effects, and this trial also showed that the risk of cardiotoxicity was doubled if you take twelve months of treatment compared to six months of treatment.

But one thing to keep in mind is there are a number of trials, I think about five or six trials by now, that have studied the same question – whether a shorter course of Herceptin is non-inferior to a longer course of Herceptin and we, in fact, did a meta-analysis after last year’s ASCO’s trial.

We saw that when we pool the data we could not say that it was non-inferior, the longer course of treatment was superior.

So we want to air this trial data again and see whether it has changed the overall results.

So that will be very interesting to keep in mind because there are other trials that are also looking at the same question.

But, another thing to keep in mind with regards to interpreting these trials is the shorter course of trastuzumab was not the same in all these trials.

Some trials used only nine weeks of trastuzumab and this trial used six months of trastuzumab.

So I think we should also look at whether six months is non-inferior to twelve months rather than just nine weeks of treatment.

So these are some things that we need to keep in mind.

WD: For most, it seems, at least for breast cancer patients and their doctors, we’re coming away with the prospects of giving people less medication rather than just piling on the new stuff and that’s a welcome change for many.

BG: Yes, exactly.

The best takeaway from this conference for breast cancer patients is, if we have to keep it in a phrase, then it is less is more.

And especially this trial, when I want to think in terms of low and middle income countries or its impact on global oncology, especially as Herceptin has a very important impact on global oncology.

Even in our meta-analysis when we found that shorter Herceptin was not non-inferior but we still concluded that patients in low and middle income countries could get shorter Herceptin instead of longer Herceptin, depending on the affordability because the margin of benefit was low.

So with this trial now presented, patients in low and middle income countries can feel more confident and get a shorter course of Herceptin.

Because, while I was working back in Nepal, there were some patients who said they could afford only a certain number of courses of Herceptin but they could not afford the whole twelve months of treatment.

So now, for those patients, we can confidently tell them that getting at least some Herceptin is better than not getting any Herceptin at all and it might be non-inferior to getting a whole one year of Herceptin.

So it is very, very important for people in low and middle income countries.

But regarding TAILORx, still the 21 gene assay is not routinely and cheaply available in low and middle income countries so we need to figure out how patients all over the world can make use of this information.

WD: And you mentioned the global oncology perspectives there of who is getting which treatment.

That does tie in to the local, for us now at the moment, news of the Washington patients receiving the same treatment as those just across the border in Vancouver for double the cost with no benefit.

BG: Yes, that was a very interesting study.

That was a very smart analysis across the border. One interesting finding was there was no difference in overall survival.

WD: Why should there be?

BG: Yes. And the US was paying double for achieving the same outcome.

When we were talking about health disparities we are talking about low and middle income countries versus high income countries but I also want to mention about this study in prostate cancer which showed African-American patients are more likely to die of prostate cancer compared to the white patients.

So these disparities, they don’t occur only between low and middle income countries versus high income countries but they also occur within high income countries themselves.

So this is something we need to keep in mind and this is something that we need to address.

These two studies were eye-opening in the context of realisation that there is a huge disparity within the same country and some of the patients in high income countries fair actually worse than some patients in low and middle income countries.

The other interesting finding was this has been seen consistently across multiple disease types because a couple of months ago there was another study in breast cancer which also showed there was very much difference in survival among breast cancer patients within the US depending on their ethnicity.

WD: I suppose we are a heterogeneous population, to put things in familiar terms.

BG: Yes, there could be a number of reasons to explain for that.

One is a biological reason that we all try to figure out but can’t exactly put a hand on what exactly is making this difference in survival.

But other differences, as we saw in that Washington versus Vancouver study, there is a difference in drug prices and there is a difference in what patients can afford, depending on their income.

So, depending on, let’s say, a patient who can’t afford treatment and he or she has to abandon treatment midway, not undergo treatment at all because of financial reasons, then those patients are going to fare worse, no matter where they are.

It doesn’t matter which ethnicity they belong to.

So this is speaking more about the socio-economic disparities than health disparities, in my opinion.

WD: Let’s bring things back to the highlights, say, from lung cancer.

We had a few yesterday looking at the role of chemotherapy being supplanted, it seems, in first line by PD1 targeted therapy.

BG: Actually the treatment of non-small cell lung cancer first line treatment is getting a bit complicated but it’s good news because we have seen a lot of positive trials in recent months, including a couple of trials that were presented at the AACR meeting a few months ago.

So the first-line treatment when we are talking about immunotherapies are pembrolizumab, that has overall survival data.

We also had nivolumab plus ipilimumab combination in TMB high patients which was presented at AACR but I don’t think it’s practice changing yet because pembrolizumab has more robust data across PD-L1 types based on this presentation because they stratified depending on PD-L1 cohort values of 1%, 20% and 50%.

The overall finding was there was improvement in overall survival and there was also improvement in overall survival across these subgroups based on PD-L1 cut-offs.

But there is a catch that if you look at patients who have PD-L1 between 1% and 49%, then they actually did not have a significant improvement in survival, which is an exploratory analysis so we need to keep that in mind.

But we need to think of that finding in terms of the other trial that was presented at AACR in which they saw a pembrolizumab plus chemo combination up front improved overall survival across any PD-L1 positivity subgroup.

So they key question now would be whether to use PD-L1, pembrolizumab alone or pembrolizumab plus chemotherapy, in first line treatment.

It would be just an extrapolation but probably if PD-L1 is more than 50% then you could be confident of using pembrolizumab alone, based on the trial that was presented yesterday.

But if the PD-L1 is low then maybe you would prefer pembrolizumab plus chemotherapy up front.

WD: Alternatively atezolizumab and chemotherapy which was found to increase progression free survival as well.

BG: Yes, it was in squamous non-small cell lung cancer. But the OS data were not mature at the time of presentation but the immature data shows that OS has not improved.

So improvement in PFS alone in a disease as lethal as squamous cell cancer does not give me high hopes.

Because we also have nivolumab which has improved survival in second line so you’d have to debate between using atezolizumab, which has improved PFS in first line, versus using nivolumab, which has improved OS in second line.

Because atezolizumab and nivolumab are PD-L1 and PD-1 inhibitors so they most probably have the same mechanism of action so probably it is not meaningful, and we don’t have any evidence at all, to use nivolumab after atezolizumab.

Because using two PD-1 or PD-L1/PD-1 inhibitors in sequence, there is no evidence because they are like “me too” drugs.

So I would not recommend using them in sequence so the question would be what would you prefer – would you want to use atezolizumab plus chemo up front and not have any options to use later or would you want to use chemo up front and use nivolumab as second line?

WD: And then there was the other headline in lung was that the development of a blood-test for lung cancer.

There has been a lot of reporting in English media of a holy grail for blood cancers which was maybe a little more hype, maybe a little more hope, than is necessarily due.

But when it comes to the work from Geoffrey Oxnard in developing, at least, a blood test for one region of cancers then it seems like there is reason for hope.

BG: Yes, I was tagged by a couple of Twitter friends about those news articles that were calling this blood test as the holy grail.

That was a lot of exaggeration, to be honest.

This was a study done in 120-some patients; it was a preliminary study so that we can take this to the next level of actual trial to confirm the utility of this study.

So it’s premature to call it a holy grail, it’s very premature.

I think we should group the holy grail with other terms such as game-changer and breakthroughs that actually don’t convey the true message, the results of the study.

So this was an interesting study but we need to remember that this was done among patients who already had cancer so we don’t know whether it will have a similar type of efficacy results when used in patients who are asymptomatic because that’s the ultimate goal of screening, to screen asymptomatic patients, people who don’t have the disease yet, and to find out if they have the disease that would not have been detected otherwise at an early stage.

So one caveat is this study was done among patients who already had cancer.

The other thing was about screening out the noise mutations that the researchers thought was just creating nose and is not helpful as a marker of cancer.

But we don’t have enough information to say which mutations are noise and whether we can safely take them out as noise.

WD: Yes, it was raised in one of the comments and discussions following the presentation that if you are filtering for the shed mutations from white blood cells, how do you know you’re not missing out on some potentially very important genetic changes in the patients’ blood?

BG: Yes, I share that concern.

WD: Let’s move on, heading down to some of the headlines from today then.

For colorectal cancer that the use of heated chemotherapy, peritoneal heated chemotherapy, didn’t have any significant benefit for patients with colorectal cancer.

BG: It came as a surprise because this is called HIPEC, heated intraperitoneal chemotherapy.

This HIPEC chemotherapy has been tried in ovarian cancer too and for colorectal cancer.

Like some other practices this had been adopted in a lot of centres without evidence.

So there are already many patients across the world, and even I personally know some of the centres that have been practising HIPEC chemotherapy for any patients that had peritoneal metastases, like ovarian cancer patients, colorectal cancer patients, without any randomised evidence.

So it was very nice to see this trial because it was a very important question to test and the results were negative unfortunately.

So a lot of those interventions that we were doing without evidence were actually futile and not helping the patient.

So this is a reminder that before adopting any new intervention, no matter how attractive it looks, we need to have a proper randomised trial evidence to incorporate that into practice.

We could say the same about the earlier lung cancer screening test.

So before exaggerating the benefits and before hyping it so that every patient from tomorrow wants to come to you and get that blood test – ‘I heard about this in ASCO 18, I want to get the blood test done.’

But we need to make sure that we have proper data before implementing it into the clinics.

WD: And then other headlines from this morning included the advances for pancreatic cancer which has been… people have been coming up against a brick wall, it seems, for so long that finally having any news to report is remarkable.

BG: Yes, but if we are talking about FOLFIRINOX treatment after pancreatic surgery as an adjuvant treatment, this was an exceptional improvement in overall survival.

There was an improvement of more than 20 months which is unprecedented in pancreatic cancer.

So it was very, very encouraging.

But, at the same time, we need to remember that FOLFIRINOX is not a very easy regimen to administer, to undertake, because we know that from using FOLFIRNOX in metastatic pancreatic cancer patients where it is a standard of care in first line.

So FOLFIRINOX is not an easy treatment to take and why I am mentioning this is because there is a Japanese trial in which they tried S1 as an adjuvant treatment in patients who had undergone pancreatic cancer surgery and there was also a substantial improvement of nearly 20-21 months in overall survival.

S1 is an oral drug with fewer side effects compared to FOLFIRINOX.

So, yes, for countries in Europe and North America where S1 is not available FOLFIRINOX will be the standard of care now.

But where S1 is available, and I also want to emphasise that why not test S1 as well in this part of the population.

Taking adjuvant chemotherapy like FOLFIRINOX after the patient has already undergone a huge surgery of pancreatic cancer, pancreatic surgery is not an easy surgery, it’s too difficult for the patient.

That brings me to another trial that was conducted in pancreatic cancer and in that trial they tested chemotherapy before surgery rather than after.

That also showed some improvements in disease free survival. So that trial could also be important, keeping in mind that a substantial number of patients are not able to undertake FOLFIRINOX after surgery.

But the benefit is not as substantial with this pre-surgery regimen compared to what we saw, more than 20 months of survival benefit, with FOLFIRINOX.

So the key would be to improve the tolerability of FOLFIRINOX after surgery or to test whether S1 provides the same amount of benefit and use S1 because that’s much more tolerable.

WD: We’ll have to wait until someone gets around to doing the work for that. For now these are at least options, these are opening avenues for, if not research, then for the patients who can tolerate the treatment then it is there for them.

BG: Definitely. It’s very good news for pancreatic cancer patients.

WD: Then one of the other headlines was possibly practice-changing again in kidney cancer, that the role of surgery for intermediate risk patients there were doubts.

At least now we have an answer that there might be a limited role for nephrectomy going from low to high risk, somewhere in the middle it’s not for everyone.

BG: Yes, I was very, very impressed with this study. I was very happy listening to the plenary results when this was presented and the presenter was very humorous as well.

I think this is practice-changing, (a), and (b), I think the onus is to prove doing surgery is helpful because this was a non-inferiority trial in which we showed not doing surgery is non-inferior to doing surgery.

Still there was some debate about we should be doing surgery for some patients but in order to do surgery you need to prove that it is helpful because doing surgery is a big thing for the patient.

So nobody would want to undergo surgery unless they knew that that’s definitely going to improve their survival.

So I think we should have a very high threshold for doing surgery in metastatic patients.

This debate also arose because we saw that in this trial, in this CARMINA trial, for the patients who were randomised to surgery around 15-20%, I don’t remember exactly, but around 20% of patients did not take sunitinib after surgery.

So there was some complaint that maybe this is biasing the result and maybe we should do an analysis not on the basis of intention to treat but on the basis of this randomisation.

But what it shows for me is the effects of surgery in the real world.

So that means if you are doing surgery there are 20% of patients who are not going to be able to receive sunitinib after surgery so that is reflecting what happens to patients.

So we can’t just ignore those patients so I think intention to treat analysis is the analysis to conduct.

Based on this study for poor and intermediate risk patients nephrectomy should be avoided.

This was appropriately designed as non-inferiority because the standard of care was doing surgery so the researchers wanted to test whether avoiding surgery is non-inferior.

So the standard of care of surgery in metastatic renal cell cancer patients was because of the trials that were done before all these drugs were available, in the interferon era.

So now with all these drugs the onus is to prove that surgery improves survival in metastatic renal cell cancer patients because without that data how can we ask the patient to undergo huge surgery and not be able to tell them that they were going to live longer as a result of that.

If you look at the survival data, then the patients in the sunitinib arm were actually living longer than the patients who were randomised to the surgery arm.

So that also reflects surgery’s complications and other downstream effects that you would expect from surgery.

From the patient’s point of view, you, me, I can ask anyone, if you have the option to avoid surgery and not have any effect on outcomes would you like to do that?

And everybody will say, ‘Yes, why would I want to undergo surgery?’

Not shooting in one’s own foot but that’s how science should progress – we should question ourselves.

So the more we question ourselves the more we question the practices that we are doing every day, the more wise we become.

WD: Not taking surgery for granted, not taking HIPEC for granted either. Even if we’ve been doing it for so long just because everyone else has been doing it for so long, that doesn’t mean it’s the best course of action.

BG: Exactly.

WD: And then proving that things are worthwhile in terms of medical treatment, precision medicine has gone from a pipe dream to taking a lot of roles in the headlines and then the presentation for the match mutations of improving survival, precision medicine and targeted therapies having survival benefit for patients.

The entire field is validated somewhat.

BG: No, I don’t think so. Because that analysis, the IMPACT analysis about survival in precision approach versus non-precision approach was a retrospective analysis.

Rather, it was interesting to me that there was a presentation of the study, the three arms from the trial – the PI3K mutation arm, the FGFR mutation arm and the HER2 mutation arm and the response rates were very, very sobering and that did not make much news because that question of precision medicine.

So this is the hype that we are living in – if some results support your hypothesis then it becomes big news but if those results don’t support the hypothesis then it just gets drowned out in the ocean of other information.

So in this study we used a PI3K inhibitor for patients who had PI3K mutation and the response rate was zero, there was no response.

For patients who had an FGFR mutation the response rate was 4%.

The population who had a HER2 mutation the response rate was 8% with a HER2 inhibitor, ado-trastuzumab.

So these are very, very sobering pictures for me. I think we need to keep testing, I don’t mean to say precision medicine is wrong or it has been invalidated.

No, I think that precision medicine has yet to stand the test of a trial so that’s where precision medicine is because we don’t want the precision medicine approach, the genomic approach, to be another HIPEC, we don’t want it to be renal surgery.

WD: Maybe it will be one of those holy grail situations.

BG: Hopefully, because I want precision medicine to work, I really want precision medicine to give us good results but I want to see the data that it is improving outcomes.

WD: I believe that covers a lot of the headlines. Has there been anything else that you would like to talk about while we’re here?

BG: Finally I want to mention one important titbit that caught my attention.

That is, I was at the plenary and I was looking at the four trials that were presented at plenary and three of those trials were public government funded trials.

I was very impressed.

I don’t mean to discredit industry, industry has a big role but public government institutions are not getting the credit that they deserve so I want to give the credit where it is due.

So government and public institutions have done quite a lot to answer very important questions that we need answering every day in clinic because a trial of whether or not to do surgery for renal cell cancer if the government or public institution doesn’t fund it then it is impossible to do.

So this was a very pleasant experience for me.

I knew that government has a substantial role and public funding always plays an important role in cancer research and outcomes but they are not getting the credit frequently.

So I think we should applaud the government and public funding and we should encourage more of these trials that answer very important questions which would encourage more funding for such types of trials, (a).

And, (b) the other titbit that caught my attention was the rhabdomyosarcoma trial that was presented at plenary.

And what it shows is, this is a rare tumour, and what it shows us is with the help of collaboration we can conduct randomised trials to answer important questions in rare tumours as well.

Because there is a huge argument in the oncological community about whether or not we should do randomised trials for rare tumours because they are so rare.

Maybe we should not conduct randomised trials, we should accept drugs based on response rates and things like that.

But I think precisely because they are rare they don’t deserve inferior treatments.

Why should a patient with a rare tumour deserve a treatment that is based on a lower quality of evidence versus a patient who has a cancer that is common?

That is unfair, that is unethical, in my opinion.

So this trial tells us that it is possible to conduct randomised trials of rare tumours but what we need is collaboration across the world.

So a rare tumour is rare in one location but if you talk about the whole world it no longer becomes rare.

So that was another take-home message that I got from this ASCO.

WD: Global oncology is a pretty big sample size.

BG: Yes, exactly.

WD: Has there been anything that you’ve seen that has caught your eye, work in progress?

Something to follow up with over the next couple of years? Where do you see some future headlines coming?

BG: Yes, I have been impressed with a couple of trials that are ongoing about drug repurposing which will have an impact on global oncology.

Because if we can prove the efficacy of the cheaper drugs then this will be very, very useful for low and middle income countries as well as high income countries, of course.

With regards to trial design there are a lot of platform trials that are increasing lately so that will make, actually, conducting of trials easier for repurposing of drugs.

Because you don’t need to design a whole new trial to test, let’s say, whether aspirin improves survival in colorectal cancer, you could add that as another arm in an already ongoing big platform trial.

So that is one particular aspect that I’m excited about for global oncology.

The other information that caught my attention with regards to policy work is even our poster was about quality of life endpoint in cancer drug trials.

So I saw that a number of people are now being more aware of the importance of quality of life in cancer drug trials and the need to include them as endpoints and the need to report them.

Because quality of life has not been an endpoint to approve drugs by regulatory authorities often and that’s why whenever we talk about quality of life people come up with the excuse that there has been no drug that has been approved on the basis of quality of life alone.

But I think we need to change that and I was impressed to see more and more people talking about quality of life and patient reported outcomes.

By the way, there was a French trial that was reported in 2016 at ASCO and that showed seven months of improvement in overall survival just with the use of web-based patient reported outcome monitoring versus routine standard of care.

At this ASCO they presented the updated follow-up data from the same trial and that benefit is still maintained.

So you can improve survival of seven months in lung cancer just by monitoring patient reported outcomes.

WD: Maybe there should be approvals for patient reported outcomes. If they’re not going to be reported for quality of life from a drug, treat patient reported outcomes as the drug – they improve survival.

BG: Yes, I think we should patent prozumab, PR-ozumab.

WD: Yes, that sounds catchy.

BG: Yes, so prozumab might be attractive enough for people to use rather than saying, ‘Let’s monitor patient reported outcomes.’

WD: Very well tolerated, I’m sure.

BG: Yes, very well tolerated.

So these are the things that are exciting me in terms of the future and I think these patient reported outcomes and quality of life inclusion in trials will increase over time.

In our paper we particularly studied about quality of life inclusion as an endpoint and we saw that nearly 50% of the trials don’t include quality of life as an endpoint at all.

Of those trials that include quality of life as an endpoint, 25% don’t report it.

And of those trials which report it we saw that progression free survival is a very poor surrogate for quality of life.

So we have been talking about surrogate endpoints and we say that PFS is a weak surrogate for OS but our question was is it a good surrogate for QL then?

If it improves quality of life then maybe it’s a good marker to use.

But we saw that it’s not a good surrogate for QL either.

So the question is what are patients gaining from PFS then if they are not gaining survival, if they are not gaining quality of life? 

I try to stay realistic.

There are a lot of exciting news, which we discussed; there are a lot of positive news.

But my approach is cautious optimism – I am optimistic but my approach is cautious optimism because optimism without a dose of caution can make you undertake bad decisions.

WD: Let’s hold out for smart decisions and smart medicine in looking after patients as well as looking after their disease.

BG: Yes, let’s hope for a more rational and wiser future in oncology.

WD: Well if that’s all, then, thank you very much for taking the time to join us at this year’s ASCO and I suppose we’ll see you at ESMO later on this year?

BG: Thank you very much for having me. It’s always a pleasure.

WD: Thank you very much.

BG: Thank you very much.