[MUSIC PLAYING]

Good evening, everybody, and welcome to this Expert-Led Conference Insights from 2021 ASH annual meeting. It’s a pleasure for me to have all of you here, and let me introduce the faculty tonight. Beside myself, we’ll have Delphine Rea from the Hopital Saint-Louis de Paris, Fausto Castagnetti from the Saint Orsola-Malpighi University Hospital in Bologna, Italy, and Valentin Garcia-Gutierrez from the Hospital Universitario Ramon y Cajal, Madrid, Spain. And our three speakers will present different topics.

You can see here the agenda. Three presentations, 15 minutes each. Delphine Rea from TKIs in CML, Insights from pivotal phase III trial. And then, Fausto Castagnetti will discuss a number of abstracts and presentations at ASH dealing with lower-than-usual dose or full dose of second-generation TKI in CML. And last, Valentin Garcia-Gutierrez will discuss about the new TKIs, new guys– ponatinib and beyond. And at the end, final thoughts and close at 7:00 PM, more or less.

I remember you that the webinar will be recorded and available on demand, OK? Three sessions, 15 minutes each. Each presentation will be followed by a discussion. So you may post at any time during the presentation your questions, and then they will be presented and discussed all together.

Of course, your comments are very welcome. There is a feedback form available on the platform, and you can eventually send your comments by email. So now, my pleasure to give the stage to Delphine Rea for the first presentation, TKI in CML: Insights from Pivotal Phase I Studies please, Delphine.

Dear colleagues, dear friends, I’m very happy to be with you tonight, and I’ll right away start with the first study, which is named ENESTPATH, a company-sponsored study dedicated to patients on imatinib with chronic phase CML who managed to get the CCyR but who didn’t have a deep molecular response. So they could be in CCyR or in MMR, but not in MR4.

After at least two years on imatinib, they were proposed to be switched to nilotinib at 300 milligrams BID, the goal being to gain a deep molecular response, at least to MR4. And they were on nilotinib for at least two years. After two years of nilotinib treatment, the patients who had a deep molecular response were randomized between stopping their treatment immediately or being treated with one more year of nilotinib and stopping their treatment afterwards. Of course, upon maintenance of a deep molecular response, and the goal was to compare the TFR rates in the two arms, the question being whether one more year of nilotinib would translate into a gain in the TFR rate.

The answer is here on this slide. You can see that the patient in both arm 1 and arm 2 who managed to gain the MR4 and then to stop the treatment had a TFR probability at 12 in red, 24 in blue, and 36 months in gray, which were very comparable between the two treatment arms, with a few which was not significant. And you see that we managed to bring between 32 and 37 patients into TFR.

This is not a very big difference. It’s not statistically significant. But the question is whether a longer time on nilotinib treatment would have led to a better TFR rate in the arm where the nilotinib treatment was longer. But we’ll never have the answer to that question within the trial.

And you see here the patients who managed to maintain an MR4 and the patients who managed to maintain an MR 4.5. The relapse definition in this trial was very consistent with what we know in other trials. It was a loss of MMR or loss of a confirmed MR4. With respect to the tolerance issue of nilotinib and with adverse events during the TFR phase, there is nothing surprising with respect to what we already know. We have been knowing the nilotinib treatment tolerance profile for a long period of time, and there is no new safety signal here.

So to conclude from this trial, we didn’t find any significant incremental benefit in terms of our success from an additional year of nilotinib consolidation for chronic-phase CML patients who achieved a sustained deep molecular response after two years on nilotinib following a switch from imatinib. But please remember that the nilotinib treatment time was pretty short– two years in arm 1 and three years in arm 2.

Irrespective of consolidation duration, switching to nilotinib 300 milligrams BID provided the opportunity for many patients who were unable to reach sustained DMR with first-line imatinib to achieve GFR. And this is very important. The safety profile was consistent with previous findings, with no progression– this is very important– no progression to accelerated phase or blast phases during the TFR phase, no new safety signal, and I would like to add that the patients who lost their deep molecular response after nilotinib cessation and who lost MMR were able to regain optimal responses after the drug was restarted.

The second trial I’m going to present right now is very different. It’s, again, a company-sponsored study, and it’s a phase III randomized trial dedicated to patients who received at least two lines of therapy and who were either intolerant or resistant to the most recent TKI. This trial was dedicated to– was meant to compare asciminib, the very new allosteric inhibitor, to bosutinib in this setting. So patients with different T315I or V299L mutations were excluded because these are known resistance mutations to bosutinib.

The randomization ratio was 2:1, and the primary endpoint was quite ambitious, because it was MMR rate at 24 weeks between the two arms. We already know from the Blood paper that was published very recently that the results are in favor of the asciminib arm, with a 24 weeks higher MMR rate in asciminib arm than in the bosutinib arm, and what was presented at ASH are the results from week 48– so with one more year of follow-up. And this is very important to note, that this difference in favor of asciminib remains.

You see here that after 48 weeks, 29% of the patients were in MMR, only 13 patients in the bosutinib arm, and the difference here is 16 points. When we look at patients who manage to obtain a BCR::ABL transcript level below 1%, which is an equivalent of CCyR. The difference between the two treatment arms is even larger, because you see here that 42% of patients had less than 1% BCR::ABL at two years, and only 19% of patients did so in the bosutinib arm.

With respect to the tolerance profile of the two drugs, there were adverse events in both treatment arms. With bosutinib, the adverse events are very well-known, and they are mainly during the first three months of therapy– diarrhea, nausea, and there are also some increase in liver enzymes. And this was much more frequent on bosutinib than on asciminib.

On asciminib, we could observe some cytopenia at the beginning of the treatment, but most of the time, they were not responsible for treatment discontinuation. You can see only 3% of patients discontinued asciminib because of thrombocytopenia, and 2.6% of patients who had neutropenia. The majority of patients who received bosutinib discontinued the drug early, unfortunately, mainly because the drug was badly tolerated, but also because the drug was not sufficiently efficient in these patients.

So to conclude, in the patient population, although I couldn’t show you the whole detail who are previously very heavily treated, because they were third line patients, fourth line patients, or more than at least five line patients, we conclude that ASCEMBL is the first randomized controlled study versus a second-generation TKI in patients with chronic phase CML previously treated with at least two TKI, but even more in this study. After a median follow-up of 19 months, so now we have the week 48 analysis, asciminib continues to demonstrate a sustained efficacy, and this efficacy is superior than that of bosutinib.

Asciminib’s safety profile remained consistent with that of the primary analysis, so the 24 week analysis, and also the safety profile from the phase one trial that was published two years ago in The New England Journal of Medicine. And there were no safety findings here. And we will get probably in 2022, one more year of follow-up. So week 96.

The last study I’m going to present is the very famous EURO-SKI, sponsored by the European LeukemiaNet. This is a study about discontinuation of tyrosine kinase inhibitors. We proposed to European patients discontinuation of their TKI, either imatinib or second generation TKI that were given for at least three years.

And this is dedicated to patients who were at least in MR4 for at least one year. Patients could be treated in first or in second line, but when it was second line treated patients, they could not have a history of resistance to the first TKI, only intolerance to the first TKI. They stopped the treatment, and then there was a follow-up that lasted for three years.

Results were already presented many times during several congress, but here are the final results. And you see that at 36 months, the cumulative incidence of loss of MMR is 50%. Fortunately, the majority of patients who lost their major molecular response regained an optimal response. And here you see that the molecular recurrence-free survival, which is defined as patients who remain in MMR, is 46%.

A few patients restarted their treatment despite the fact that they didn’t lose a deep molecular response. So the molecular recurrence and treatment-free survival is a little bit less, 45%. So what was important here in this study is that it was the analysis of prognostic markers of TFR.

And you know that in prior presentations for earlier relapses, those happening within the first six months of treatment discontinuation, it was the length of the deep molecular response that was found as a very important factor for a successful treatment-free remission. And here what was found is for relapses that happened a little bit later after six months, it seems that the duration of the deep molecular response is not so much important, but it is the total duration of treatment that is more important. And I don’t have any explanation for that.

Maybe the mechanisms of late relapses are not the same as the earlier relapses. And we will need our scientists, colleagues to look at this phenomenon. So to conclude, first and secondary primary endpoint in EURO-SKI were met. Molecular recurrence-free survival probabilities were 62% in one year– at six months, sorry. 46% at 36 months respectively.

So there were early relapses but also some late relapses. Prognostic analyzes support the importance of the duration of TKI treatment and also the duration of the deep molecular response prior to stop for early MMR loss. However, for late MMR loss, between 6 and 36 months in EURO-SKI, only TKI treatment duration was found of prognostic importance.

There will be other prognostic analyzes that will follow. I hope we will hear about this year. Thank you very much for your attention. And I am ready to answer your question if you have some.

Thank you, Delphine. So far I cannot see any question posted in our chat. But I have one, probably of general interest. As far as ENESTPath or, if you want, the policy of switching from imatinib to nilotinib to achieve a deeper molecular response than TFR. Roughly, there are 1/3 of all patients reaching, more or less.

Is there any influence of the duration of imatinib before switching in determining the probability of achieving a deeper response? Those patients who switched earlier, probably, they have a higher probability of obtaining DMR or not. Is my speculation or–

It’s difficult to answer that question. As far as I remember, both in NS-TMR where it was demonstrated that upon a switch from imatinib to nilotinib, at that time it was 400 milligrams BID, but it doesn’t make a big difference in terms of efficacy. Indeed, the probability of gaining a deep molecular response was about 30%. But as far as I remember, so it’s roughly the same in ENESTPath.

In both studies, the best prognostic factor for gaining a deep molecular response is to rapidly achieve an MMR within the three first months of the switch. And I have not seen any data about the importance of the length of imatinib before, but we may speculate, or it’s only speculation that if you wait too long before switching, there may be little resistance clones that may exist, and that may not be in favor of the gain of a deep molecular response. So intuitively, we, indeed, would prefer, if this is true, not to wait too long before deciding to switch if the patient is eligible for a switch to a next generation tyrosine kinase inhibitor rather than waiting and letting resistant clones accumulating over time.

1. Thank you. I ask first to Fausto and Valentin if they have a question for Delphine.

I can see two questions on the screen. I don’t know– yeah, yeah.

Indeed.

Sorry. Yeah, OK. Is there data available on the likelihood of obtaining a molecular response? I think there have been–

So for sure, in ENESTPath for sure. Here, it was a short summary of the study, but this was presented at ASH, and I hope in more detail in publication this year. Yes, there was no resistance after restarting nilotinib and all patients regained either major or deep molecular response. The follow-up after treatment resumption is a little bit heterogeneous.

So some patients are not yet in DMR, but there is absolutely no resistance or transformation that occurred after patients restarted their treatment. And there is another question Gianantonio.

There’s a question about the loss of MMR after three years as–

Well, we have some, not in this trial. Unfortunately, EURO-SKI stopped after 36 months. I know that Susanne Saussele is trying to get data, long-term data in patients, but this is not in the trial. Now, what we know from other studies that lasted longer, such as the French studies team– we now have at least 5– between 5 and 10 years of follow-up– is that very late loss of response is possible, but it’s quite a very rare event. Nevertheless, the recommendation is to follow the patient’s life long. Although, after one, two or three years, they do not need to come back every three months for a PCR test.

Sure. Thank you, Delphine. Many other questions, probably, but now we should move on with the second session with Fausto Castagnetti about challenging and defining– affected those of second generation TKI. Fausto, please.

Thank you very much, Gianantonio And good evening to all of you. The optimization of TKI dose is a very relevant issue today when deciding how to treat CML patients.

Many studies have been presented at ASH, dealing with the optimization of TKI dose. I have selected three abstracts regarding nilotinib particularly in the context of treatment-free remission, three abstracts dealing with dasatinib in the context of first line treatment, and two abstracts regarding bosutinib. The first study– sorry. OK, the first study has been presented by an Italian group, the name of the study is DANTE study.

This is– I know– a phase two study trial exploring the possibility of deescalate the nilotinib dose because treatment discontinuation. Where the patient enrolled, we received at least three years of treatment with nilotinib, and sustained a deep molecular response for at least one year. After the enrollment, all the patient enter the consolidation phase with the 300 milligrams daily of nilotinib.

After one year, the patients aren’t able to maintain a sustained deep molecular response discontinued the treatment. The patient who maintained a major molecular response, but who lost a deep molecular response remained on nilotinib at reduced dose. And the patient who lost the major molecular response returned to the standard treatment.

At the ASH meeting, preliminary results of this study have been presented. Only 52 patients had completed the consolidation phase. So very limited data being shown. Only five patients discontinued the study during the consolidation phase due to MMR loss in two case. Adverse event in two case, and patient decision in one case.

So 47 patients were able to complete the consolidation phase. The great majority of them maintained– sustained a deep molecular response and entered the treatment-free remission phase. So the nilotinib dose reduction had no impact on the possibility of maintaining the sustained deep molecular response in most patients.

Another similar trial has been presented by the a Czech group, was the HALF study that was dedicated not only to patient in treatment with nilotinib but also to patient on treatment with imatinib or dasatinib. All patients had at least four year of treatment before entering the study. And all of them, at least two years of stable MR4.

After the study enrollment, the TKI dose was reduced to half of the standard dose. And up to six months, further dose reduction have been performed to alpha of the standard dose every other day. Also, in this case, only preliminary results have been presented. 74 patients completed the consolidation phase with reduced TKI dose. And only four patients lost the molecular response to resume treatment.

A third study have been presented by the French group. It is probably accepted that second-generation TKI are able to increase the possibility of achieving deep molecular response and they are able to increase the possibility of achieving treatment-free remission. But unfortunately we have not direct comparison between nilotinib and dasatinib, and it is not expected that we will have a direct comparison in the next years because no prospective trials are ongoing today.

So retrospective analysis are probably the only source that we have to understand if some difference may be agreed between nilotinib and dasatinib in the context of treatment-free emission. In the study, the French group performed an analysis on patient receiving nilotinib or dasatinib as first line treatment. 47 patients received nilotinib and 25 received dasatinib.

The two groups were comparable according to the median follow-up, according to the duration of treatment before treatment discontinuation, and according to the stability of deep molecular response before discontinuation.

Well, the results of the study suggest that the possibility of achieving a stable treatment-free remission is higher when the patient received nilotinib if compared to dasatinib, and this has been confirmed in a multivariate analysis. It is important to underline that many patients who received reduced nilotinib or dasatinib or those before entering the study, so before treatment discontinuation. So this is an indirect proof that also had used those may lead to treatment remission.

What about dasatinib as front line treatment? Only one study has been selected as an oral presentation. The study has been presented by the MD Anderson Cancer Center.

The study was designed to compare standard dose of dasatinib, so 100 milligrams daily of dasatinib, versus a low dose of dasatinib, 50 milligrams daily. A propensity score matching have been performed, and 77% of patients– 77 patients in each cohort– in two cohorts have been compared.

The overall follow-up was significantly longer in the cohort of patients treated with standard dose of dasatinib, and it is not unexpected. Well, in this comparison, dasatinib, at 50 milligrams daily, was able to achieve higher response rate. In particular, the response rate seemed to be significantly higher according to the deep molecular response.

The toxicity was lower in the low dasatinib dose arm. And as expected, the overall survival was similar in the two groups. Another experience have been presented, coming from Japan. Elderly patients, patients older than 70 years, were treated with a very low dasatinib dose, 20 milligrams daily. 56 patients were enrolled.

The major molecular response rate at 6 months was 37%. And measure molecular response rate at 12 months was 60%. It is very important to underline that the great majority of patients in major molecular remission after one year were on treatment with 20 milligrams daily of the dasatinib. So a very low dasatinib dose were able to achieve an optimal response in elderly patients– in elderly patients in Japan.

The last experience with the low dose dasatinib has been presented by a Chinese group. It is very interesting study because it was a phase III trial, so a randomized trial comparing 70 milligrams daily of dasatinib versus standard dose dasatinib. Unfortunately, the data– the results have not been presented according to the intention to treat principle.

So it is very difficult to understand the difference between the two arms. However, the data presented seems to suggest that no significant difference occurred in the two arms. What about bosutinib? Bosutinib have been investigated mainly in the second line setting or in later treatment lines.

It has been presented an update of the phase four BYOND study with an update longer than three years. In the BYOND study, only one out of four patient maintain the full dose of bosutinib. The great majority of patients reduced the dose to 400 milligrams to 300 milligrams, so 200 milligrams daily.

Well, the reduction of the dose did not jeopardize the efficacy of the drug. And in the graph presented, patients who achieved MMR for the first time, who maintained the MMR after dose reduction, and the rate of response were higher in patients receiving lower bosutinib dose. So apparently the dose reductions of bosutinib do not compromise efficacy, and they are able to minimize the toxicity.

Finally, another study dealing with the use of low bosutinib dose have been presented by the German group, was the BODO trial. In that trial, a low starting dose of bosutinib has been investigated to minimize the incidence of adverse events on bosutinib, and in particular the incidence of gastrointestinal toxicity. The starting dose was 300 milligrams daily. After two weeks, the dose was increased to 400 milligrams daily.

And after additional two weeks, the dose was increased to the target dose of 500 milligram daily. Well, despite the study design, the lower starting dose was not able to minimize the toxicity of bosutinib. And the incidence of gastrointestinal adverse event was high in the study. 60% of patients had a grade two to a grade four gastrointestinal toxicity.

So the study showed that the efficacy of the drug is not jeopardized by a lower starting dose, but the impact on safety and on the tolerance is very limited. So in summary, many studies seem to suggest that a lower dose of second generation TKI or dose reduction of second generation TKI is able to increase the safety of these drugs and seems to suggest that the efficacy is not compromised by the use of lower dose. However, further confirmation are required to extend the use of lower dose of second generation TKI in the clinical practice. So thank you very much, and I’m open to questions.

Thank you, Fausto. I have two questions in the chat, but OK. This question are for Delphine.

Yeah, I think so. Yeah.

Waiting question for you. I can forward these two questions to Delphine.

Maybe the second one– No. Right, right. I think both the questions are for Delphine.

Yeah, the first one is 100% for Delphine, and the second one can be split between you and Delphine.

I’m sorry, because I don’t want you to– I mean, this is Fausto’s time. Also, I will be very quick. Whether asciminib should be used, should, should. I don’t know if they should.

At least what we would like to have is more studies to know where is the advantage, where and when and who we have an advantage to use combinations. We know it’s feasible, but we don’t know what is the best patient population to target. So we need more studies.

Yeah, but probably the company in this field is– my perception is more oriented to use asciminib by a single agent.

Right, right. But there may be a few institutional trails.

Yeah. And this is for Delphine, and the second one for Delphine and Fausto. Fausto already answered in part because there is an active experimental side running, dealing with this concept of dose optimization. But the question for Delphine. Why outcomes, or TFR duration are different according to second-generation TKI? Use, are they different? Why are different?

If you refer to the poster the French CML group presented during the last congress saying that the GFR rates are a little bit lower after dasatinib discontinuation. I would be very careful. I’m not sure this is a definitive conclusion, because, as you see, the P value is extremely– a little bit below 0.5, so I suggested to continue the study with a larger group of patients and to make sure that the two patient populations are comparable.

Thank you, Delphine. This is 100% for Fausto, but I am not the anonymous one, but I’m sharing the same. So would it be–

That was from me.

Would it be.

I’ve understood that. Yeah.

Could it be convertible, Fausto, in using 50 milligrams in high risk patients?

This is a comment that I agree. I agree absolutely with the comment because, also, the authors concluded that caution should be reserved to high-risk patients because the number of patients with high risk was very limited in that study. So honestly, I would not suggest the use of low dasatinib dose in high-risk patients, but I can mention the Italian study on high-risk patients treated with 400 or 800 milligrams of imatinib.

And surprisingly, the high-risk patient treated with high imatinib dose, so 800 milligrams daily, were not able to achieve superior result, higher response rate, because of higher hematologic toxicity and higher rate of discontinuation. So honestly, I’m not comfortable to treat high-risk patients with low dose dasatinib, but I don’t know– I don’t know because–

And another question for Fausto. And in the Japanese study, what would– would be, in your opinion, the advantage of using 20 milligrams of dasatinib in elderly patients as compared to imatinib?

In which study? In the–

Japanese, probably–

Japanese. Yeah. I suppose that the point is that 20 milligrams of dasatinib have higher potency if we compare it to standard dose imatinib in any case. So my opinion is that it’s a good idea. We made some similar in the second line setting with bosutinib, very low dose.

I think that in the elderly patient, very low dose may be promising. And 20 milligrams of dasatinib have higher potency against the target. The patient without optimal response may increase the dose to 40 milligrams or 60 milligrams or 80 milligrams, or 100 milligrams daily, but the number of patients who require a dose increase was very, very, very low.

Very, very low. Don’t forget that probably the patient weight is not so important with TKI, but of some importance. And Japanese and Chinese personnel generally, with respect to western countries, the average weight is much less. So thank you, Fausto.

And now we move– OK, Valentin, your last question, I keep it for the final five minutes. But you probably– no, no, we can, because your question is linked to my previous one. Do you think we can extrapolate data from Japan to Europe? It’s probably a comment similar to my last comment about the body weight, which is–

We had the French study exploring the effect of dasatinib blood levels on toxicity. Yeah. You can remember.

Yeah, yeah.

Yeah. That’s how probably

It’s a very long story now.

Maybe blood level may answer the questions. I don’t know.

Yes, I really– I don’t know. Anyway, time is suggesting to move to Spain, to move to Valentin Garcia-Gutierrez– will present data on ponatinib and BYOND. Please, Valentin, you have the mic now.

So thank you so much because I’m really delighted to join you in this session. So thank you very much for the invitation. What I’m going to do in the next 10 minutes is to show you what are, in my opinion, the most relevant presentation regarding a common situation that we have to face when treating a single patient. And that’s the fact that some patients are resistant to second-generation TKI.

And I’m going to present data regarding what our current option with ponatinib and some other novel TKIs, besides asciminib that has already been very nicely presented by our colleague, Delphine Rea. Regarding ponatinib, what has been presented is an update and a post hoc analysis from this optic trial that I made sure that many of you are familiar with, because the primary end-point has already been presented in previous congress, but also has already been published.

So this trial randomized very heavily pretreated patient who failed at least two TKIs, and also in patients including the T315I mutation to three different ponatinib starting dose. 45 milligrams, 30 milligrams and 15 milligrams. With a primary endpoint of the achievement, a desirable level below 1%, which is the closest to complete cytogenetic response.

As I mentioned, the primary endpoint has already been presented. Almost the whole population benefits from the dose of 45 milligrams. What authors tried to show in this study is what could be those patients that could benefit the most from this 45 milligrams starting dose.

I’m afraid that I still have a problem with the– no. OK. And they showed us how the patients that benefit the most from the 45 milligrams starting dose are those that could be considered the poorest of the high-risk patients. Those patients with BCR::ABL1 level, above 10% at baseline, we can see how the patient that benefits the most from those patients that is starting from 45 milligrams.

It’s very important to highlight and to remember that this was only starting a dose, and all patients– that all patients, even those in 45 milligrams and 30 milligrams, and once they achieve an optimal response must reduce dose until 15 milligrams if possible. So the randomization is only for a starting dose. Some other patients that really benefits from the 45– from the 45 milligrams starting dose are those patients that harbor the T315I mutation.

And as we can hopefully see in the next slide– as we can see, those patients that harbor the T315I mutation were the ones that benefit the most from this ponatinib 45 milligrams starting dose. There was no difference in terms of progression-free survival for the entire– for those patients without the T315I mutation, but there was a benefit in progression-free survival for those patients harboring the T315I mutation.

In this presentation, also was updated the safety of the data regarding the safety of this trial. And it’s very good news to find out how these benefits from the 45 milligrams starting dose did not translate in the adverse events that is commonly related with ponatinib, which is, as you all know, the probability of suffering occlusive cardiovascular events. We can see here how this occlusive cardiovascular events were a little bit higher with the ponatinib 45 milligram dose, but nothing really very different. This 10% what we can commonly see with some other second generation TKIs.

Therefore, it seemed that this reduced optimization scale for ponatinib is really promising, and we are going to be able to reduce this occlusive cardiovascular event for those patients that start the 45 milligrams dose.

Next.

So the conclusions are that the patients that benefit the most from the 45 milligrams dose are those very high-risk patients, those patients above 10% at baseline, and those patients carrying the T315I mutation. And this 45 milligrams starting dose did not translate in a higher probability of suffering from cardiovascular events. The next presentation– the next study that I’m going to present is regarding to vodobatinib.

Vodobatinib is a novel TKI that was designed looking to minimize the side effects by inhibiting ABL in a more selective way. We have to say that this in vitro– this compound is effective for most of the ABL mutations with the exception– notable exception of the T315I mutation.

So in this phase one study that it includes two different cohort, one dose escalation cohort and dose expansion cohort with up to 50 patients, all of these patients were very pretreated, heavily pretreated patients, but without the T315I mutation. But some of these patients had already been exposed to ponatinib. The primary endpoints are very similar, what we commonly use for this kind of phase one study to determine the maximum tolerated dose and the dose that is going to be chosen for next studies.

Next.

So regarding the safety, we can see that related to the design of the drug. I want you to remember it was designed in a very selective ABL. We can see how the tolerability was excellent with only very few side effects, grade three, four. It was related to unique patient. And the hematological toxicity was really also very low.

However, we have to highlight that there were some cardiovascular events that were found in this study. Up to nine patients– and we can go to the next slide. And up to 9 patients out of these 52 suffer from cardiovascular events.

And we have to mention that only one of these events were related to the drug, but we know that this can be always, always discussed, whether or not, the side effects are related to the drug. Excellent. Again, excellent toxicity profile for hematological toxicity. Regarding the efficacy, the drug was obtained very nice response.

We can see in the next slides how there were an important proportion of patients without complete cytogenetic response at baseline is that achieve complete cytogenetic response further on, further on. And progression-free survival for this heavily-pretreated population for the chronic phase was very nice, close to 80%. So in conclusion for this vodobatinib data from the phase one trial, we can affirm that vodobatinib is a very well tolerated TKI. However, we need to keep an eye on those cardiovascular events from for previous– for next– for a while, and for the next study that are already being conducted with this drug.

Because the cytogenetics– the efficacy seems to be very good. Important proportion of complete cytogenic response in heavily-pretreated patients, but we have always to remember that the patients with the T315I mutation were excluded. If we move to the next slide, I’m going to present the updates from the phase one data with olverembatinib, which is also another novel TKI.

This TKI, in contrast with the previous ones, has efficacy in vitro against all kind of ABL mutations, including the T315I mutation. However, it’s important to mention that in this trial, a patient with previously exposure to ponatinib were excluded. Again, the patients that were included in this study were heavily-pretreated patients. Again, excluding ponatinib, and need to fail to two or more previous TKI with the exception of those patients with the T315I mutation that could be included with only one previous exposure to TKI.

And this is important when we will go to the data regarding efficacy. If we can go to the next slide, we can see the data regarding the efficacy, and that’s what I wanted to mention. We can see very nice proportion of complete cytogenetic response. And we could think that as happened in the patients starting with ponatinib that this drug could work better for those patients that harbor T315I mutation.

We can discuss this further on, but this is probably related that because patients with the T315I mutation commonly are treated in previous lines regarding to the patient without the T315I mutation. With 36 months of follow-up, a high proportion of complete cytogenetic with some patients achieving major molecular response. However, again, we have to mention that none of these patients were previously exposed to ponatinib.

Regarding to the safety index slide, we can also see very nice safety profile. It’s important to mention that an important proportion of patients suffer from a skin hyperpigmentation. It’s not a but– an important adverse event, but it’s important that we take it into consideration because it seems that this adverse events last during years.

Other than this skin pigmentation, the rest of the side effects were not very frequent and with this novel TKI. So in conclusion, we can conclude that olverembatinib is a very well tolerated TKI with a very nice efficacy profile with those patients with any kind of mutation, the T315I mutation. I also want to highlight that some of these patients harbor a compound mutation, and some of them achieved nicely response.

So it’s a drug that we need to keep an eye out for with the next trial that are already being conducted. So the last presentation is regarding this so-called fourth generation TKI, the PF-114. This study includes close to 50 patients. Again, very heavily pretreated– very heavily pretreated patients.

This study include patients with any kind of ABN mutation, including T315I mutation, and some of these patients were already exposed to ponatinib. Regarding the safety profile, we can see here how the drug was very well tolerated. The maximum tolerated dose occurred at 600 milligrams.

We are going to see how the chosen dose was half, 300 milligrams. And even at the maximum tolerated dose, there was no occlusive cardiovascular event. This is very important when we take into consideration treatment options for patients with the T315I mutation.

However, regarding the efficacy, probably, the data are not so good as the previous TKI that I mentioned. Totally, probability of achieving complete cytogenetic response were around 20% with the highest proportion of patients from the dose of 300 milligrams. We have to take into consideration, again, that they was very bad patients because they were very heavily-pretreated and some of these patients were previously exposed to ponatinib.

There were some patients, two patients, around five patients that had already received ponatinib that achieved a complete cytogenetic response. So there are still some patients, even for those ponatinib resistant patients, that could have an opportunity with some of these novel TKIs. So in conclusion, in the next slide. And this is the last one for those patients that failed to– at least two TKIs, including the T315I mutation.

This PF-114 TKI has shown a very nice safety profile with only skin and because– regarding the most important side effects, we have demonstrated some efficacy for these patients. And at this moment, a phase three study at the dose of 300 milligrams is being evaluated. So thank you very much. I’m sorry for the problem with the system. And I’ll be very happy to take questions.

Thank you, Valentin. No problem. It’s normal in the digital era some small issue. There are a couple of question for you.

And one is from Delphine. Yes. I see. Well, the first one is about the mechanism of resistance to vodobatinib. Has this been investigated? I am not…

You mean the mechanism of the system for vodobatinib?

Yeah.

Not as far as I know. The thing is that– I mean, the question could be related to the– it has another effect on the T315I mutation. But, I mean, I don’t expect that it’s related to the non-inhibition T315I mutation. And there are not so many patients that are refractory– that are resistant to vodobatinib, because they obtain close to 70% of patients achieving complete cytogenetic response in patients without that responsive deadline. But regarding the mechanism of resistance, I have no information.

This is another question about vodobatinib. Vodobatinib is potentially a good drug, but as far as I know, the pivotal phase two trial is– I mean, meeting a lot of problems in the number of patients enrolled. So it’s in a sort of standby. But anyway, which is your perception of vodobatinib in the treatment landscape? It’s a very difficult question.

I mean, the phase one study, as I mentioned, there were very nice results. But as you mentioned, they are having some patients with the recruitment. Probably at this moment, they are– fortunately, there are not so many patients that are resistant to current TKI, and now we have an opportunity also to treat patients with asciminib. And probably the patients that are being enrolled in all these studies with this novel TKIs are those patients that fail to all of TKIs, and we are selecting a very bad population, and that’s the problem. That’s probably something that we need to take into consideration when discussing the data.

So we continue. We’re still– wow. Olverembatinib– I’m sorry. Proteinuria and renal toxicity seems to be higher than with other TKIs. Is there any explanation or clue or what.

Yeah, I didn’t mention, but it’s true that the proteinuria was– it was not very frequent with olverembatinib, but the thing is that it seems that it’s a side effect that has not previously seen, and at least in this percentage with previous TKI. It could be related to the inhibition of some other kinases. And this is something that, again, we need to take into consideration in the next clinical trial, because it’s a kind of a new– could be a new toxicity for a new drug.

The second one about PF-114, which is until now a regional TKI. Has never been– in Russia only. If it’s a arterial occlusive event associated with KIT inhibition, as well as NET. Does PF inhibit KIT? Personally, I don’t remember.

Neither do I. I have not information whether the inhibition were NET or KIT. Probably– we know that all ATP competitor, TKIs almost inhibit all kinases. Probably, we don’t know the concentration that need to inhibit KIT or not, but probably doesn’t inhibit KIT here.

But anyway, my comment to this question is that arterial occlusive events with TKIs are associated with a number of different factors and probably even with KIT inhibition, but not only, and with nilotinib and ponatinib, but there are different factors that are adding. So it’s quite a complex scenario.

Yeah, probably– we are not seeing so many cardiovascular events with all these new compounds because all this trial has been designed in a way, probably, in a way similar to the OPTIC trial in which very high cardiovascular patients are commonly excluded from all of these trials. So we also have to take this into consideration, that commonly in this trial have– very high cardiovascular risk patients are commonly excluded, and that’s one of the reasons why we do not see so many cardiovascular events with all these novel compounds.

Good. Now, we have two minutes left, but probably the last question should deserve 25 minutes. The process of adjudication of cardiovascular events carried on inside the optic trial. They are not selected cardiovascular, but they went through a process of an independent committee which evaluated– which term of cardiovascular toxicity uploaded by investigator into the files of the trial where really cardiovascular adverse events, drug-related. What is your opinion on that? Valentin.

It’s really different to have an opinion when there are some experts which are the ones that commonly adjudicate these cardiovascular events. But my opinion is that, in total, we have to think that it’s not really so important whether or not the adverse events are adjudicated to ponatinib or not. What is very important to know is what is the proportion of patients that suffer cardiovascular event with one drug in order to take into consideration for making treatment decisions for those cardiovascular risk patients. But it’s really very difficult to say that one event is adjudicated or not to a drug.

Yeah. No, in fact, last minute. This committee did a very huge and complex work in blinded to understand which events are really cardiovascular and attributed to the drug.

[INTERPOSING VOICES]

I have just a comment. The point is that the question was mine. The point is that it is difficult to compare the study to other study because other studies have not a commission able to evaluate cardiovascular events.

The final result was that those– a reduction of the incidence of cardiovascular adverse events. And the point is that I am convinced that it was a very important work. The point is that no other studies had similar.

No, no, but not exactly. Inside the optic and pace trial after the adjudication process, the severe adverse event were a little bit reduced, and the not severe remained, more or less, unchanged. But there was a redefinition, which should be done in any trial, because the terms about cardiovascular toxicity included are sometimes generic and not really related to a cardiovascular event.

But now, it was a very nice discussion. And now it’s 5 minutes after 7:00 PM Central Eastern time. And I believe that we should close this webinar. And I thank Springer, I thank Novartis for the grant supporting this webinar.

Thank you, Madam– Mademoiselle Delphine, and Fausto and Valentin. Have all of you a great weekend. And many, many thanks. Goodbye.

Bye, bye.

Bye, bye.