OncologyTube: [00:00:00] Okay, we’re here at ASCO GI 2024 and we have Dr. Ghassan K. Abou-Alfa, MD, medical doctor from Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York. Dr. Abu Alfa, thank you so much for joining us today.
Ghassan K. Abou-Alfa, MD: Thanks so much, Alan. Nice to be
OncologyTube: here. Today, we’ll be discussing PROOF 301, results of an early discontinued randomized phase three trial.
Dr. Abu Alfa, could you please provide an overview of the PROOF 301
Ghassan K. Abou-Alfa, MD: study? Well, thanks so much, Alan, and, uh, by all means, it looks like a lot of words for a great effort that I’m very grateful on behalf of my co authors and colleagues. Uh, to present it today. Uh, if anything, really the big thanks is for the, uh, scientific committee at ASCO to accept our abstract because as you can see, it’s really implying something that really did not work or rather failed.
Uh, this study is straightforward. We looked at patient with [00:01:00] intrahepatic cholangiocarcinoma with the genital alteration of a FGFR2 fusion. And we’re looking at one of the NT fgfr. Two therapies that are well known. It is the one was called Ingratin, which historically has been known as BJ 3 98, and the idea was to see if it can move it to first line therapy, randomizing patient for gem cine plus cisplatin, which was at that time the standard of care before the advent of the checkpoint inhibitors like durvalumab.
And the idea was to compare G CCB plus cisplatin versus ingratin in a two to one randomization In favor, of course of the INGRATIN study.
OncologyTube: Great. Okay. Could you elaborate on the challenges and implications of conducting confirmatory studies in biomarker selected subpopulations of rare tumors as highlighted by the early termination of the PROOF 301 trial for infigratinib in FGFR2 rearranged CCA?
Ghassan K. Abou-Alfa, MD: As we mentioned, we are definitely delighted, and this looked like a [00:02:00] very straightforward study. You have simply patients who will receive infigratinib. versus patient will receive the standard of care, GEMC means cisplatin at that time. This is all for patients who are FGFR2 fusion. Uh, however, as the title implied, this was a challenge because number one, we’re looking at a specific genetic alteration that occur only in about what we did anticipate might be about 10 to 15 percent of the patients.
And if anything, trying to see if we can provide that. Study for them and see what the outcome will be. This was a big challenge. Because the first challenge, as we know, to really get the genetic alteration evaluation and the patients who are really on first line therapy, it takes a while. And that’s why the delay time when people and patients understand they are eager to start therapy was not really in our favor.
The second challenge is that we really need to look specifically what are we looking at in regard to how common or uncommon a genetic alteration is. [00:03:00] I know we’re going to talk about the data, but to at least start with, we screened close to about 1, 200 patients and only close to about 70 to 80 patients were really positive for the genetic alteration.
Give us a of about like seven to eight percent of the patients who have genetic alteration, which is really lower than what we anticipated to be 10 to 15 percent. So the challenge is difficulty to really get to the screening, and number two, if you get the screening, the reality is this is a very rare genetic alteration that occurs, and as such, you’re doing a huge study for only a very small subset of patients that can be on the study.
OncologyTube: Hmm. Considering the preliminary, preliminary, uh, signal of efficacy observed with infe gradinib as a first line treatment for FGFR2 rearranged CCA, what are the potential implications for future research of clinical approaches in this patient population?
Ghassan K. Abou-Alfa, MD: So, as we [00:04:00] saw from the data that we presented, and it will be very clear why did we present the data, because understand we were talking about here only 29 patients that are randomized to the infigratinib, and 19 patients randomized to the gemCM plus cisplatin, because remember it’s two to one randomization.
And as such, to really conclude anything data wise from 29 versus 19, eh, probably it’s a little bit difficult, because after all, uh, We could not really conclude anything in regard to survival, actually meaning it was never even met, but to be fair, there’s no patients there to really meet that end point.
And number two, yes, there was probably a great suggestion of a better response in regard to the infigurative compendium semen cisplatin, but within the confine of this limited data, we can’t really tell more than that. However, one more time, the reason we really presented that data, and we felt an obligation to report the end points of the study as we just mentioned them, Add to, of course, the adverse events, but still, at the end of the day, we’re trying to show and prove that studies of that nature in a rare [00:05:00] cancer with a rare genetic alteration to do a phase three clinical trial is not doable.
OncologyTube: Okay. Given the manageable adverse event profile of emphygratinib in previous studies, could you provide insights into the safety and tolerability findings from this trial, especially in comparison to gemcitamines, cisplatin, which you’ve already kind of went over, but if you could just put a fine point on it.
Ghassan K. Abou-Alfa, MD: So, to recall one more time, before we come to the adverse events, this is a study for a drug, Infigaratinib, which historically, as you might know, started with the name of BDJ 398, evolved until it became the Infigaratinib, and this actually is one of the other anti LGFR2 that can cause some adverse events, among which, of course, the, uh, retinal changes that can occur.
hyperphosphatemia that can occur at, of course, tardiness, fatigue and other some components in regard to metabolic and hematologic malignancy, uh, adverse events. To be fair, uh, [00:06:00] Infigratum, same like other, the, uh, other, the anti inflammatory therapies. will depend quite a bit on experience. And as such, uh, the more experience we have, the more we’ll be able to manage the adverse events, preventing them from becoming a, a grade 3 or more.
In that study, because of the limited number of patients, as we mentioned, we have seen some of the grade 3 Uh, adverse events that can occur exactly as anticipated and from the ones that I just mentioned were, of course, more present in regard to the infrared compared to the GMC MSIS PLATIN because, after all, we don’t expect them with the GMC MSIS PLATIN.
Uh, will it matter? Truly not. Because, again, to go back to the story, and it’s very important, this study, because it failed, and, uh, we really tried to accrue, and we really, Sadly, failed to do that. We actually, uh, with the discussion with the sponsor, the sponsor decided to pull out the drug and the drug technically does not exist anymore.
It doesn’t, not really available. Uh, so why are we really talking about all of this? And this is what we’re going to talk about maybe the next question. [00:07:00] Well, that
OncologyTube: was my next question was, what are the takeaways from this, uh, study? Where do we go from here?
Ghassan K. Abou-Alfa, MD: So, again, to summarize one more time what we spoke about today, it’s a study which is impressively looking into an anti AFGFR2 called Infigratinib versus Jim C.
Misesplatin in first line therapy for patients with intrahepatic cholinergic carcinoma. This study was designed to become a phase three clinical trial. This study was a two to one randomization, patients with the anti FG 4, with the FG 4 2 therapy were subjected to either the anti FG 4 2 therapy of the Infiguratinib or Gemsimesis platen, and if anything, we screened close to about 1, 200 patients, and we could not end up accruing except to close to about 70 patients.
We concluded that this will really Translate into a challenge to cut the crew that study the outcome that we saw the study to be fair within the context of the limited data that we have will not really mean much. Nonetheless, yes, it reminds us that yes, infigurative [00:08:00] like same like any other individual to therapy is an effective therapy because of the response rate that we spoke about that was really quite impressive.
Adverse events, as we said, with the experience will probably learn more, even though should acknowledge the adverse events that occur with the end of jeopardy therapy per se. However, why did we report that? I mean, yes, it’s a negative study. Yes, it’s actually, it’s a failure per se, but it’s very important.
We felt all of us obligated and give credit also, even the sponsor understood the obligation that we have because. Hopefully, this message will become available to all of us in the academic community and also to our colleagues in the different practices, how they, you know, do things in the community as well.
And of course, also to the agencies, uh, because after all, having a rare cancer to begin with, with the rare genetic alteration, to do a face retrial. doesn’t work. And if anything, we really would like to innovate how we can really address and make sure that those drugs are available. And ultimately, and after all, maybe a phase two [00:09:00] trial will be more than needed for proving that this drug or any other drug will work.
Sadly, Infigurative is out of the picture now. It’s already has been retracted by the sponsor and it’s not available. And I hope that Abstract will provide a very important key message to the agencies. Uh, uh, to really ensure that after all, a phase two trial may be enough for proving that we have an effective therapy.
OncologyTube: All right. This has been an interview with Dr. Ghassan K. Abou-Alfa, MD, medical doctor from Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York. Dr. Abu Alfa, thank you so much for sitting with us today.
Ghassan K. Abou-Alfa, MD: Thanks so much, Allen. Thank you again for having me.