My opportunity is to talk about a brief overview, in the spirit of the symposium, of therapeutic needs in metastatic or advanced pancreatic cancer.

Pancreatic Cancer Incidence Is Rising

Here is some very basic epidemiological data about pancreatic cancer. This data comes from the United States. What you see here, similar data is the case throughout the world, this is the estimated new cases and new deaths a year. The top two lines are for total cases below. It is broken down into male and female cases and male and female deaths. You can see that over the last 20 years, as depicted here, there is been a steady increase in the number of people diagnosed with pancreatic cancer and the number of people who die of pancreatic cancer every year in the United States. This is clearly a growing problem. This curve is not the direction we want to see it in. Everything we are going to talk about tonight is to understand how we could change part of this curve. We are not going to address incidents too much, but we are going to address the mortality part of pancreatic cancer.

Prognosis of Pancreatic Adenocarcinoma

Part of the reason why pancreatic cancer has such a frightening curve is that, as you see on the left, and this is on the left side over here, showing data from the SEER database, US database from both white Americans, Black Americans, and all combined. You can see that the five-year survival, which is what is shown on the left here, for patients with pancreatic cancer, overall, the most recent data show that number is around 13%. That is quite different between patients who have localized disease, where it is close to the 40% or 45%, and those who have distant disease, where the five-year survival rate remains in the low single digits, 3% in this most recent data.

On the right, you can see the percentage of patients who are diagnosed with pancreatic cancer and what stage they are diagnosed in, and you see that the majority of patients, almost 50%, are diagnosed with metastatic or distant disease. The majority of patients have advanced disease. Those patients have a very poor five year survival. The incidence is going up. Unfortunately, that means the mortality is going up as well.

Molecular Pathogenesis of PDAC

One of the very important things about treating pancreatic cancer and understanding how we are going to make advances in this disease is understanding what drives pancreatic cancer. This is a report from almost a decade ago now, of over 150 cases of resected, so not advanced, but surgically resected pancreatic cancer that were extensively profiled as part of the TCGA analysis. You can see here, I do not think anyone can read the individual lines here, they are very small, but the vast majority of patients with pancreatic cancer have mutations in KRAS. KRAS is frequently mutated over 85 or 90%, at least, of pancreatic cancer. In addition, there are frequently alterations in what I call the big four genes, so KRAS, P53, CDK, and 2A or CDK, and 2B and SMAD4. These are commonly mutated. Almost each of those, more than 50% of patients with pancreatic cancer. Some have all those mutations, some have 1 or 2 of them, and they associated some of them with poor outcomes.

You can see on the right that there is a small subset of patients who do not have KRAS mutations identified, but those patients also have frequent driver mutations, which has helped contribute to them getting the cancer, in genes including BRAF, HER2, FGFR other genes, as you see mentioned over here, GNAS is more common in those in that small subset. That also gives us an avenue to potentially treat those patients.

There is also defects in DNA damage repair in different genes in that pathway, including BRCA, that are seen in around 11% of patients again in this series. Mismatch repair deficiency is seen in probably 2% of patients. There is pathogenic germline mutations - all this data is somatic - there are also germline mutations in somewhere between 5% to 10%. This study showed 8%, including mutations in genes like ATM, but also BRCA2, being a common germline mutation. This is all really important information because it impacts how we treat these patients.

Genetic and Biomarker Testing Are Critical

Because this information is important, the guidelines recommend and we always like to stress the importance of testing to obtain this information. That includes germline testing for all patients diagnosed with pancreatic adenocarcinoma, as well as tumor testing for at least advanced patients. Likely, it would be beneficial for all patients, partly because many localized patients end up becoming advanced. This information is really important and I encourage everyone to obtain it as early as possible.

Chemotherapy for Metastatic PDAC

Once someone's diagnosed. These are the statistics. They are sobering. There is something that will hopefully give us impetus to talk about how we can do better. How do we treat pancreatic cancer? I am going to first give an overview of what we currently do today, as of whatever today is, May something. Our hope, of course, is that by the end of this conference, we will be talking about new options and we will talk about what might change over time. Currently, for patients who are diagnosed with metastatic pancreatic cancer, the best and really most efficacious therapy that has shown some benefit in survival is systemic chemotherapy.

PRODIGE 4-ACCORD 11: 1L FOLFIRINOX vs Gemcitabine for mPDAC

This comes from several large randomized trials. One of them that was published 15 years ago was called the PRODIGE 4 ACCORD 11 trial, which looked at chemotherapy for patients with metastatic pancreatic cancer. The control group was gemcitabine alone, which was the old standard of care, comparing it to a novel combination regimen, novel at that time, called modified, in this case, it was called FOLFIRINOX, actually, where they gave full dose FOLFIRINOX combination of 5-FU, leucovorin, oxaliplatin and irinotecan.

Patients were quite healthy on this study, and they were randomized 1:1 to either gemcitabine or FOLFIRINOX. As you can see in these curves that were published now 15 years ago, that the survival was improved in those who got systemic multi-agent chemo with FOLFIRINOX from median survival of 6.8 months with gemcitabine to 11.1 months. The median progression-free survival on the right was also improved from 3.3 to 6.4 months, and this became one of the standard chemotherapy combinations utilized in pancreatic cancer.

MPACT: 1L Gemcitabine + Nab-Paclitaxel vs Gemcitabine for mPDAC

Shortly afterwards, a second large randomized phase 3 trial, called the MPACT trial, was presented and published, and this trial had a very similar patient population. First line untreated metastatic pancreatic cancer. Patients here were randomized to either gemcitabine alone or gemcitabine plus a novel agent called nab-paclitaxel. This was a larger global study.

It was a little bit more inclusive of both patient population and certainly of different countries and different groups. This also showed a significant survival benefit with addition of nab-paclitaxel to gemcitabine. You see the survival curve on the left, the progression-free survival curve on the right. This also was statistically significant advance in metastatic pancreatic cancer.

NAPOLI-3: 1L NALIRIFOX vs Nab-Paclitaxel + Gemcitabine for mPDAC

The third randomized trial came out more recently, less than 10 years ago now. This trial actually used, as the control arm, combination chemotherapy. The control in this NAPOLI-3 trial was gemcitabine and nab-paclitaxel. The experimental arm here was a novel regimen called NALIRIFOX, which is a combination of nanoliposomal irinotecan or oxaliplatin, 5-FU, and leucovorin.

This trial again directly compared double dual agent chemo with the NALIRIFOX regimen. Again, NALIRIFOX showed significantly improved overall survival benefit compared to gem nab-paclitaxel. You can see on this slide, on the left is the survival curve and the right is the progression-free survival curve. This was a third positive randomized first-line phase 3 trial.

Key Trials of First-line Treatment for mPDAC

There have been a couple other trials, a little smaller trials, that have looked more recently at dual agent chemo versus triplet. These are nab-paclitaxel versus really, they were both modified FOLFIRINOX in these two trials. One was a US-Canadian trial, one was a global trial. Those two trials did not seem to show a significant difference. You can see the response rates and the median overall survival reported here. We do not have clear evidence in that setting of FOLFIRINOX or modified FOLFIRINOX versus gem nab-paclitaxel, but this is really a summary of the trials that we have that have led to first-line chemotherapy selection in metastatic pancreatic cancer.

Managing Toxicity for First-line Treatment

Now one, one of the really important details with this information is managing the side effects of chemotherapy. We are going to discuss. Chemotherapy certainly contributes many side effects to patients. Being able to manage those side effects is essential for keeping patients on trial and getting the survival benefit that we expect from a particular chemotherapy regimen.

Summary of CT-TRAEs

Here is a quick summary of some of the treatment-related adverse events, or TRAEs, that we see from chemotherapy. I think everyone who has used chemotherapy knows these are very common. There are treatment-related tox factors that matter, meaning things that are specific to the chemotherapy regimen. Of course, there are patient-related factors, so people have pre-existing issues or conditions that predispose them to certain toxicity.

One of the really important points - I am not going to go through all the toxicities, that would be too much - a really important point is that we can identify ahead of time some of the predicted toxicities based on the person and the regimen. We can talk about ways to manage those toxicities. That is incredibly important because almost all regimens can be modified in ways that allow them to be more tolerable, and usually not always, but usually without compromising efficacy. If we can identify the expected toxicity, we can make changes in order to prevent some of those side effects and allow patients to stay on therapy, they are much more likely to get clinical benefit.

Meta-analysis of First-line Therapy Toxicities Grade ≥3

Here is some data to discuss and show, just to share. This is it is not exactly a meta-analysis. It is an analysis of multiple trials. They are not comparing them directly to each other, but it is collecting information from reported trials at the time of this analysis, which was a few years ago, from these three regimens that I mentioned, gem, nab-paclitaxel, FOLFIRINOX, and NALIRIFOX.

What you could see here, and some of the details are quite similar, if you look on the right at fatigue, which is a very common side effect, it is actually quite similar between those three regimens in these reported phase 3 trials. Again, these are grade 3 or higher side effects, not all side effects. There are many, most of the others actually, that are different between the regimens. In some regimens, there is a higher rate of neuropathy, for example. Other regimens have a lower rate of severe neuropathy. Some have a higher rate of severe cytopenias, others have a lower rate. This is really important in this information in terms of selecting an appropriate regimen for a particular patient.

CT-TRAEs in mPDAC

These are all important to be aware of and to keep in mind. To go through some of them in somewhat more detail, we broke out into three major side effects. There are, of course, are more, but three of the major groups of side effects with all treatment with chemotherapy in advanced pancreatic cancer are cytopenias. Chemotherapy affects blood counts. It leads to lower white blood cells, red blood cells, platelets. Patients become anemic often will need transfusions.

Patients are at risk for infection if they become neutropenic, and we use growth factors to mitigate that side effect. Thrombocytopenia or low platelets are also a big challenge with chemotherapy regimens, including specially gemcitabine based regimens in pancreatic cancer, and often can limit the amount of chemotherapy that is able to be given. That is one to be very alert to.

Diarrhea is a common side effect of many chemotherapies. It is more common with the 5-FU-based regimens and the gemcitabine-based regimens. Diarrhea can be early and late. It could be both. It could be one or the other. There are very effective medications that can mitigate that side effect. Being aware of it, giving prophylactic or early medication is really important in allowing a person to stay on therapy despite that side effect.

Then peripheral neuropathy so something that we talk about a lot. Every one of the three regimens I mentioned has a drug that is associated with peripheral neuropathy, either oxaliplatin or nab-paclitaxel. There are different types of neuropathy based on the agent used, based on the dose given, based on how it is administered, and based on patient pre-existing conditions. It is something to be really aware of. Think of adjusting the dose to mitigate that, and something to allow patients to stay on trial.

RECITE: Romiplostim for Chemotherapy-Induced Thrombocytopenia (CIT) in G1 Cancers

This is actually a very interesting novel study that is come out quite recently, looking at a pharmacologic intervention that might help mitigate some of these side effects. This was the RECITE trial, which was recently published in the New England Journal of Medicine. This trial evaluated the use of a thrombopoietin mimetic, called romiplostim, in chemotherapy-induced thrombocytopenia in GI cancer. This was actually a very innovative trial, quite an interesting design.

Essentially, they took patients with GI cancers who are at high risk for thrombocytopenia, for low platelets, and therefore for holding their chemotherapy. And they essentially took patients with, as you see here, colorectal, gastroesophageal, or pancreatic cancer who are receiving chemotherapy, in this case with oxaliplatin based multi-agent chemotherapy. These were people who had persistent CIT or chemotherapy-induced thrombocytopenia, and had already received some chemo and were planned to receive more. The question was, could giving romiplostim allow patients to remain on chemotherapy and not have to have dose reductions or dose delays due to thrombocytopenia?

They randomized patients to either get romiplostim weekly or placebo, 2 to 1 randomization. The primary endpoint, besides, they looked at safety, but the primary endpoint was whether you had to have thrombocytopenia induced chemotherapy induced thrombocytopenia related modifications in chemotherapy in the subsequent cycles. They were given the drug, and they were going to have at least three more cycles. They looked at cycle two and cycle three.

Romiplostim for Chemotherapy-Induced Thrombocytopenia (CIT) in G1 Cancers: Efficacy

The answer on the left here is that use of romiplostim significantly reduced the frequency of chemotherapy modifications due to thrombocytopenia, so you see that around 84% of patients were able to receive their doses as opposed to 36% in the placebo group. This was quite statistically significant. On the right, there is a breakdown among diseases. You could see a few patients with pancreatic cancer were included on the trial, 20 altogether. They had a similar benefit to those with other GI cancers. This is a very interesting and novel agent that may be helpful in allowing patients to stay on chemotherapy despite toxicity by addressing their thrombocytopenia.

Treatment Adjustments Matter

One other, and I think final, comment about the importance of dose modifications. This comes from a very interesting - this is a poster that was presented, I think, last year, a year and a half ago, GI ASCO, looking at data from the NAPOLI-3 trial. Again, the NAPOLI-3 trial randomized metastatic pancreatic cancer patients to NALIRIFOX or gem nab-paclitaxel and showed a survival benefit and a progression-free survival benefit with the use of NALIRIFOX.

Interestingly, the investigators went back and looked at patients who had dose modifications and what they found was and you could see each of these bars - the one above is the ones who had doses that were reduced, and the one below is the ones doses that were not reduced. This is a survival graph. You can see that among the overall population and the North American, as well as the rest of the world, there was significantly longer survival in different groups in those who had dose reductions compared to those who did not have dose reductions.

That probably reflects a couple of factors. This is the data, and it is post hoc analysis, but it shows that patients could be dose reduced, very likely people who stayed on therapy for longer. They were getting benefit, and more exposure to drug and therefore they needed to get dose reduced. It is essentially a surrogate for staying on therapy longer. What it shows, very interestingly, is that if you reduce doses according to the schedule in the protocol and the schedules that are advised, you potentially can keep people on therapy longer and get survival benefit.

This reinforces a principle that I think is well known and is something we are going to discuss when we get to novel agents, which is that we have drugs that are effective. We know they cause side effects. One of the most important things we can do is anticipate those side effects, give prophylactic or treatment medications in anticipation or after those side effects, and support patients so they can continue to get therapy that will prevent them from having to stop therapy for their pancreatic cancer. So, this is a really interesting piece of data from the NAPOLI-3 trial.

RAS and Precision Oncology in Pancreatic Cancer

That is a perfect segue, I think. I am going to pass it on now. That is a summary of the current treatment landscape. There is a lot coming, including the RAS studies that I mentioned earlier. I am going to pass it on to my colleague, Dr. Ko, to present the second section. Thank you.

Dr. Ko: Well, thanks, Dr. Oberstein. It is good to see you all here this evening. I think many of you are probably here because of tremendous excitement in the field of pancreatic cancer, which we cannot always say. I am not usually one for hyperbole. I think we are really at the cusp of a transformative time in pancreatic cancer. I think I get the exciting section of this symposium in terms of talking about RAS biology, and particularly RAS inhibitors, which are going to be a big central piece of this ASCO meeting and certainly in the months and years to come.

Paul set the stage well in terms of where we have been with regards to chemotherapy. I do not think chemotherapy is going away, to be very clear. I think it is still going to be a very important part in how we treat folks in the advanced metastatic and neoadjuvant, and adjuvant settings. I think with the advent of this new class of drugs, I think we are going to be thinking a lot more in terms of where each of these respective treatments come into play during a patient's journey.

Mutations in RAS Oncogenes (KRAS, HRAS, NRAS) Are observed in Many Solid Tumors, with the Highest Incidence in Pancreatic Cancer

So, RAS. There is really three main RAS types. There is HRAS and RAS, but KRAS is the one that is really very commonly mutated in pancreatic cancer. In fact, of any solid tumor, the presence of KRAS mutations are the most common in pancreas, more than lung, more than colorectal. If you look at different data sets, it is close to 90% of pancreatic cancers that harbor a mutation in KRAS.

Now, the majority occur in codon 12. Normally, codon 12 you have a glycine residue there. The incidence of types of KRAS mutations start with G12D as the most common, followed by G12V, G12R, and then, even though there are small molecule inhibitors already for G12C, that is a relatively less common allele seen in pancreatic cancer. What I think it is important to point out is that KRAS mutation occurs actually quite early in the stepwise process of pancreatic carcinogenesis.

If you look early on and take a look at a precursor, a Panin lesion, a pancreatic intraepithelial neoplasia, even before it becomes frankly invasive and malignant, you can find these KRAS mutations, which just maybe what is our appetite in terms of thinking of even chemoprevention strategies moving ahead.

RAS: A Molecular Switch That Controls Cellular Growth and Differentiation

The basic biology of these RAS molecules, so KRAS cycles between a GTP bound "on state” and a “GDP-bound off state". It toggles back and forth, spending the majority of time in the GTP-bound on state. When you have a mutation in the RAS gene, what that leads to is a decreased GTP hydrolysis. You actually accumulate the mutated RAS protein in its active GTP-bound state. In that active state, it basically is driving proliferation, survival, growth, and spread of pancreatic cancer.

RAS: Previously Considered an "Undruggable" Molecule

Now, I think all of us have probably learned f- or those of us who are in medical school or did your training at any point - probably heard that RAS is undruggable. For the longest time, this has been the holy grail of pharmacologic drug developments. For a number of reasons in terms of why this just seems so difficult to target with small molecule inhibitors or other approaches to inhibit its signaling.

If you look at the topology of the RAS protein, it is actually very smooth. Typically, when you have a protein or in a key protein where you are trying to develop a small molecule inhibitor, they have these deep pockets, and you can more readily develop inhibitors that can bind these pockets and basically inhibit signaling through it. If you have got a very smooth molecule like RAS, then that is just very tough. Even at the nucleoside binding site, where the GDP, the GTP bounds, it actually binds so tightly at a picomolar level. In that case, it is just difficult to develop a GTP competitive inhibitor.

Then I mentioned the constant conformational changes as it goes back and forth between the on and off state. It is like a moving target that adds to the challenge in terms of developing drugs against RAS.

Therapeutic Approaches to Targeting RAS

Times are changing. In the past decade, there have been a number of advances that now have allowed us to more effectively inhibit RAS signaling. That said, I am going to give a shout-out to my colleague at UCSF, a really brilliant scientist named Kevin Shokat, who was the first to identify this so-called switch two binding pocket, which really took some brilliant biochemistry in terms of unearthing this or unmasking this pocket, because that really paved the way for the initial class of RAS inhibitors.

Now, this was specific to the glycine to cysteine, the G12C mutation, which is more commonly seen in cancers like lung cancer, colon cancer less frequently seen in pancreatic cancer. These initial small molecule inhibitors would bind to this switch two pocket. Primarily, in its off state, and that represents one of the limitations of those first generation of G12C-specific inhibitors.

Daraxonrasib, which we will talk certainly more about as the data are coming in, that have us all very excited. This takes a little bit of a different approach. Basically daraxonrasib as I will show in a subsequent slide, actually inhibits RAS signaling through formation of what we call a tri complex inhibitory complex by binding to a chaperone protein that then, when it complexes together with RAS, actually shuts down the ability of RAS to interact with its effector molecules. So, RAF downstream map kinase signaling, so it is essentially able to shut off RAS signaling through the formation of this complex. I will show you momentarily what by that.

Finally, there is other approaches, so I will just mention these KRAS degraders, so-called protacs, which actually use a very cool approach of using the cell's own degradation machinery to target certain target proteins, such as mutated RAS and thus degrade RAS that way. Then we will not talk too much about, but there are certainly RAS vaccines that are used are being tested primarily as a way to try to prevent recurrence in folks after they have undergone surgery for their pancreas cancer. A little bit less for more advanced stages of disease.

Posttest 1

I am going to take a brief pause, and we will come back to a question that Dr. Oberstein presented at the beginning. This is post-test question number one. What is the most common KRAS mutation found in pancreatic adenocarcinoma? Is it G12C, D, R, V or Q61H? Separate from codon 12. Please put it in your answer.

We see that the vast majority of folks now recognize that G12D is the most common KRAS mutated allele. This also will be relevant as we talk about some of the allele-specific RAS inhibitors.

Direct KRAS G12C-Specific Inhibitors: Efficacy in Pancreatic Cancer

I mentioned before that the first generation of direct RAS inhibitors were specific to G12C. While these are actually approved agents for non-small cell lung cancer that harbor G12C mutations, which are much more common, and in combination with EGFR inhibitors for colorectal cancer patients, you can see here that there are some data specific to these commercially available G12C inhibitors, sotorasib, adagrasib. You can see here that from these waterfall plots that, yeah, patients with pancreatic cancer, granted, it is only 1% or 2% of the patient population who have these G12C mutations, but they can respond to these small molecule inhibitors. The duration of response tends to be fairly limited. Patients do eventually break through. We can talk certainly about some of the resistance mechanisms to these, as well as other RAS inhibitors, because that is going to be a very active area of exploration as these RAS inhibitors become more widely used.

Daraxonrasib (RMC-6236), a Pan-RAS Inhibitor Impactful for All (or Almost All) Patients With Pancreatic Cancer?

Let us talk about Daraxonrasib. This is a, I call it here, a pan-RAS inhibitor, I think maybe the more accurate term is a multi-selective RAS inhibitor. Obviously, this is potentially very impactful for pancreatic cancer because, as I noted, 90% of folks have some type of KRAS mutation. This could be potentially applicable to almost all patients with pancreatic cancer that we see and treat in our practice.

As I mentioned before, this small molecule inhibitor binds to this chaperone protein called Cyclophilin A, then when it binds to RAS in its on state, it forms this tri-complex that basically occludes or prevents RAS from interacting with RAF with downstream effectors, and so is able to effectively shut off RAS signaling via this mechanism.

Phase 1/1b study of Daraxonrasib a Pan-RAS Inhibitor

The early studies looking at daraxonrasib. This phase 1, 2 study, and I just want to point out that this specific to pancreatic cancer, just came out hot off the presses in the New England Journal of Medicine this past month, this actually included other solid tumors harboring RAS mutations. We are going to just obviously focus tonight on the data specific to pancreatic cancer. This included a dose escalation phase starting from very low subtherapeutic doses to establish safety, all the way up to what turned out to be the recommended phase 2 and, actually, the established dose at 300 mg once daily.

That was taken forward in dose expansion. You see in this pancreas-specific cohort, that included primarily patients who had previously received chemotherapy, one, two, sometimes more lines of chemotherapy. There was a subgroup carved out in this study who were untreated, so new diagnosis of metastatic pancreatic cancer. We have some data on patients previously untreated with chemotherapy getting this. We will talk about that briefly, although it was not really covered in the New England Journal paper.

You can see in the pancreas cohort, which included more than 100 patients, that the distribution of types of RAS mutations accurately reflects what we see in our practice. As I mentioned before, G12D G12V, most commonly, others it included non-codon 12 KRAS mutations, it included some folks without KRAS mutations at all. It was really quite a broad patient population studied in this initial phase 1 two-study. You can see here in terms of the number of prior lines of therapy that the vast majority received one or more lines of therapy. We will tease it out specific to the second line cohort, those who had received one prior line of chemotherapy, as well as those who had received two or more lines of therapy.

Daraxonrasib for Previously Treated Advanced PDAC With KRAS G12 Mutation: Antitumor Activity

If we focus - and these are waterfall plots specific to patients who received - now, I mentioned the total pancreas cohort across all doses, across all prior lines of therapy was more than actually 160 patients on this study. If you look specifically at the subgroup of patients, second line, one prior line of chemotherapy, who were treated at the full dose of 300 mg daily, you see here in this waterfall plot, actually, the response rates in this group of patients.

Really, we are talking about a 35% response rate in that second-line setting. Even in the third line setting, you are actually seeing an appreciable number of patients with objective responses. Some of the earliest patients on this study actually remain on treatment now, one, two plus years later. The responses can be very durable, highly encouraging. This really formed the basis of the phase 3 study, the RASolute 302 trial that we are going to hear about at the plenary session at this year's ASCO meeting.

I also want to point out that even though this 35% response rate was specific to the majority of patients who had that codon 12 mutation, in fact, there were also responses seen even in other RAS mutations outside of G12. In fact, the overall survival rate in the all comers was even a little bit better than those with G12 mutations. As we talk about where daraxonrasib is going to become useful once it is FDA approved, I think it is going to be very interesting in terms of whether we will be required to assess the patient's RAS mutational status before treating with this drug. It will be interesting to see how the FDA decides to approve this.

Now again, if you look at these data with this again, this oral drug by itself in the second-line setting. Compare that to what we expect with chemotherapy in the second-line setting. What do we use typically? We use 5-FU nanoliposomal irinotecan. If patients are on FOLFIRINOX, we use gemcitabine and nab-paclitaxel. With those second-line chemo regimens, the response rates typically, if we are lucky, 10%, 20%. Again, seeing these response data for just this oral agent is obviously very exciting.

Daraxonrasib for Previously Treated Advanced PDAC With KRAS G12 Mutation: OS/PFS in second-line Cohort

Even more so when you look at progression-free survival and overall survival. Again, looking at this group of second-line patients treated at full doses. You can see that the progression-free survival specific to the codon 12 mutant KRAS patient population was eight and a half months. That is basically double what we typically see with just our standard chemotherapies. Overall survival 13 months plus for the KRAS G12C mutated, 15.5 months for just the all RAS mutated patient population. Second line for chemotherapy, six to 7 months typically. These data granted relatively modest numbers. We all recognize the need to proceed with some caution. This obviously had us all very excited when we had these preliminary data.

Daraxonrasib: Safety

I do want to mention the importance of the safety and tolerability of this multi-selective RAS inhibitor. The vast majority of patients do develop a rash on the face, trunk. It varies in degree of severity. I have had a lot of patients who, I think, were a little bit freaked out with former Senator Ben Sasse interview with 60 Minutes in New York Times, where he came on camera, and you saw he had this horrendous, cosmetically just very striking rash.

There are very specific pre-emptive and mitigation strategies, oral antibiotics, topical steroids, and sunscreen, early referrals to dermatology, and you will say the rash varies quite a lot in terms of severity. For some, it is just a very mild rash. You can actually treat through it quite readily because the half-life of the drug is relatively short. If you interrupt the drug, typically within a week, that rash subsides enough that you can resume that drug, even at the same dose or sometimes at a slightly lower dose level.

Other common side effects oral sensitivity, mouth sores. It is common to prevent or treat that with an oral dexamethasone, rinse,. Then occasionally GI side effects, particularly diarrhea. You do not get things like neuropathy, hair loss, immunosuppression with this molecule.

RASolute 302: Daraxonrasib in Previously Treated mPDAC

The data I showed you in the phase 1, 2 study prompted this international phase 3 study called RASolute 302. That is what we are going to hear about at Sunday's plenary session. This was comparing second line after one line of chemotherapy. It could have been FOLFIRINOX or NALIRIFOX, or gem nab-paclitaxel. Patients in the second line were randomized to either get daraxonrasib 300 mg daily or investigator's choice of whatever second-line chemotherapy would have been standard for that patient population.

I will say, as an investigator for this study, the challenge was making sure that patients to maintain the integrity of this study understood that, hey, you need to be committed to this study even if you are randomized to the less sexy arm of just chemotherapy there was not crossover on this study, but the primary endpoint of this study, progression free survival, overall survival, specifically in that codon G12 RAS mutated patient population.

We got a press release just last month saying, hey, this read out very positively. We will hear the granularity of those data on Sunday. I will say those of us who have been eagerly awaiting these data were very pleased. The hazard ratio for overall survival was 0.40, almost unheard of in those of us who have done a lot of studies in pancreatic cancer, to have not just a significant, but a really strikingly positive improvement as indicated by this hazard ratio. So, stay tuned. I hope many or all of you are going to go to the plenary session so we can hear more specifics and breakdown of those data. I can say without equivocation, this is going to be absolutely practice-changing for our patient population. It is a welcome and exciting change.

Current Availability of Daraxonrasib

Well, it is so exciting that the company announced this expanded access treatment protocol. Until the FDA approves this drug, which is anyone's guess, but it is the committed to an accelerated approval process, there is this expanded access protocol so that ideally, we can get eligible patients access to this drug before its approval.

It does require jumping through quite a few hoops. I have already have a long list of patients who have lined up because this is just absolutely not just excited the oncology community, but certainly our patients are well aware of it. For those of you who care for patients with pancreatic cancer, if you haven't yet, I encourage you to enroll on this expanded access protocol and do it sooner rather than later, because it does require a few steps to go through.

Efficacy of Daraxonrasib in Previously Untreated mPDAC Patients in RMC-6236-001 Trial

I mentioned before that the initial approval will be in the second plus line setting based on the data that I showed you, particularly the RASolute 302 trial, but I mentioned that that phase 1, 2 study did include a cohort of patients with newly diagnosed, untreated disease. You can see here, patients in the frontline setting responded even better, as you might expect, objective response rate in the cohort of 38 patients with untreated pancreatic cancer, this was just presented a few months ago, was 47%. That beats our chemotherapies. The ones that Dr. Oberstein told you about. It beats NALIRIFOX FOLFIRINOX, gem nab-paclitaxel. Now, I want to be cautious. It is not ready yet for prime time in the frontline setting, but it at least whets our appetite to say, hey, maybe we can get some traction even earlier than in the post-chemotherapy setting.

Additional Randomized Phase III Studies With Daraxonrasib

It is actually spurred actually many successor studies, starting with RASolute 303. I told you the data about RASolute 302 for second line. Obviously, there is now a study that is underway in the frontline setting. It is a three-arm study. Patients are going to be randomized to either get standard chemotherapy with gem nab-paclitaxel chemo plus daraxonrasib. There is some mechanistic evidence of why you might want to combine chemo with a RAS inhibitor. I will note that on this study, the gem nab-paclitaxel is given at attenuated doses on every other week dosing schedule or directly daraxonrasib alone.

As I said this could be a game-changer. Imagine patients that you see in your practice who, with a new diagnosis, who may one day you will just be able to prescribe a pill instead of setting out for a port and chemo and all of that. We are not there yet, but this is obviously going to be really compelling data to pay attention to.

Adjuvant setting. RASolute 304 is going to be saying, all right, patients who have early-stage disease, they get surgery, they have completed their neoadjuvant and/or adjuvant modified FOLFIRINOX. RASolute 304 is going to randomize patients just to either monitoring as we would be doing ordinarily, or up to a two-year period of adjuvant daraxonrasib.

Posttest 2

Post-test question number two. You have got a patient who is preparing to start treatment with daraxonrasib. During counselling about potential adverse events and symptom reporting, you explain to them that the most common toxicity is which of the following?

1. Anemia;
2. Diarrhea;
3. Fever and night sweats;
4. Nausea and vomiting; or
5. Rash.

Please take a few seconds to vote.

I think uniformly folks recognize that rash is going to be the one that all of us are going to have to get a good handle on. Rope in your dermatologist colleagues as needed, once daraxonrasib becomes more widely available.

Classes of RAS Inhibitors

I have a couple of minutes left, and I just want to close by just mentioning that daraxonrasib is obviously first in class. It is a pan-RAS or multi-selective RAS inhibitors, but there are others. There are pan-RAS inhibitors. There are pan-KRAS inhibitors. Then what I want to mention is there are allele-specific inhibitors. That is why we drill down about the different KRAS mutant alleles, because there are, in development, these inhibitors specific for KRAS G12D and coming down the pike, even G12V. Now this obviously captures a smaller percentage of patients, but it may actually have certain favorable characteristics in terms of side effect profile.

KRAS G12D-Specific inhibitors

The efficacy that have been reported so far granted preliminary, look very promising. These waterfall plots for revolution medicines, zoldonrasib, another G12D specific inhibitor. You see, actually, response rates that seem quite similar to what we see with the Pan-RAS inhibitors, with, importantly, potentially less toxicity, such as that rash that is going to be a major issue with the Pan-RAS inhibitors.

RAS inhibitors in clinical development

We do not have time to get into this, but this just shows that there are many RAS inhibitors in development across all types. The allele-specific, the Pan-RAS, the Pan-KRAS, those that bind KRAS in the on state, off state or both. There is going to be, I think, just a lot of movement in this field.

Future of RAS inhibitors: The Sky Is the Limit?

I think the sky is the limit, folks, in terms of where we are going with these inhibitors and why those of us, my colleagues here, many of you in the room, are so excited about this. This is a tremendous advance, one that we have been looking for for a long time.

I do not want to oversell it, but I do want to emphasize that this is going to be just a transformative way in which we treat patients. Starting with chemotherapy, refractory disease, but I can readily see a future time where it is going to be moved into earlier stage settings, frontline, adjuvant, neoadjuvant, maybe in the maintenance setting, combined with other agents that have activity in pancreatic cancer, combining with other targeted therapies, maybe immuno oncology agents, where there is potential opportunities for seeing synergistic activity.

Innovations in Pancreatic Cancer Therapy

With that, I will close. We are going to have hopefully some time to discuss at the end with the round table discussion. At this point, I would like to pass it off to my colleague, Dr. Dotan, to bring us home with some other innovations in pancreatic cancer that are worth talking about.

Dr. Dotan: Thanks, everyone. Hopefully you have energy because my colleagues had the easy job of very focused discussion. We are going to do a fire walk through all the other targets that are available in pancreas. Very exciting time for us in pancreatic cancer. I am going to try to focus on all the things that are aside from RAS inhibitors. Get ready.

Molecularly Targeted Therapy in PDAC

This is from a paper that talked about various targets in pancreatic cancer. You can see there are so many targets here. I marked in green the RAS targets, which are clearly the most revolutionary and practice-changing things we are going to come out of this meeting with. Everything else that you see in red are targets that are being studied in pancreatic cancer, some of which we already have treatment for. The field is evolving faster than we can all keep up with. It is almost every week, we have to add another new drug or a new target to this list.

DNA Damage Repair: BRCA and PARP1 Inhibition

Let us walk through some of these targets and talk about them. I am going to start with targeting BRCA. This is an old story. I hope many of you that treat pancreatic cancer know about this. BRCA is mutated in about 5% to 9% of our pancreatic cancer patients. It is now recommended to test every patient for BRCA, germline BRCA mutation. As you can see in the graph in the image here, patients that have germline BRCA mutation their DNA repair is dependent on the protein PARP. Using a PARP inhibitor has been shown to be very effective for those patients.

POLO: Maintenance Olaparib for gBRCAm Metastatic Pancreatic Cancer

The POLO study was a study that really established PARP inhibitor olaparib as a treatment option for these patients. What this study did is it randomized patients after receiving chemotherapy with oxaliplatin based treatment for about four months with stable disease to olaparib alone as maintenance versus placebo. The primary endpoint was progression-free survival.

POLO: PFS and OS

Here are the results. The results showed improvement in progression-free survival compared to placebo. Again, this is for BRCA germline, meaning patients that have family history. You tested them. They have either BRCA1 or BRCA2 mutations, and keeping them on Olaparib after they have been on chemotherapy is a great way to keep the disease under control without the toxicity of chemotherapy.

SWOG S2001: Maintenance Olaparib ± Pembrolizumab in Metastatic Pancreatic Cancer With gBRCA1/2 mutation

We are going to have a presentation at this ASCO. This is being presented on Monday, I believe in the rapid oral abstract session. Looking at the combination of olaparib with immunotherapy in the maintenance setting. It will be interesting to see if we can even improve on the efficacy of this PARP inhibitor.

EA2192 (APOLLO): Olaparib Following Resected Pancreatic Cancer With Pathogenic BRCA1/2 or PALB2 Mutation

I also wanted to give a plug to a study that is ongoing in the adjuvant setting using PARP inhibitor olaparib after resection and adjuvant oxaliplatin based chemotherapy for patients with germline BRCA 1 or 2 or Palb2 mutation. Again, these are all germline mutations, not tumor-specific mutations.

Immunotherapy for Pancreatic Cancer: Biomarker Testing and Treatment Selection

Let us shift gears to another very rare subtype of pancreatic cancer, those that are MSI high. Extremely rare. I think over my career, I have seen one, but they do exist. This is data that came from a dataset from Memorial. They had a 0.8% of patients that had MSI high. Obviously, those patients would be highly responsive to immunotherapy.

High TMB Pancreatic Cancer as Predictive Biomarker for ICI Efficacy

Another category where we think about immunotherapy is TMB high pancreatic cancer patients. Again, these are very rare. I am sure we all see reports of TMB of 10, and some of us have tried immunotherapy. I have to say the results are not that exciting, but there is a cohort of patients, and it is estimated about 1.5% or so that actually have TMB high. Those patients have a very different phenotype compared to what we usually see in pancreatic cancer.

As you can see in the graphs, they usually will have more P53 mutations and then a whole slew of other mutations that could be found. On the Kaplan-Meier curve on the side, this is from a study that actually looked at their outcome, showing that those with TMB high definitely do have better prognosis. Immunotherapy is approved, and I think is worth considering in these patients.

The KRAS Story

Shifting gears, I know I said I am not going to talk about the KRAS story, but I am going to talk about those that are RAS wild type. We know RAS is a very early thing that occurs in pancreatic cancer, so something else has to happen in order for the cancer to develop if it is not a RAS mutation.

Molecular Alterations in KRAS WT PDAC

There was a large analysis that looked at multiple samples, evaluating those RAS wild-type tumors. This is looking both at NGS, IHC and fusions, and you can see the categories of mutation, and there are so many. It is almost like finding a RAS wild type needs to put you on this expedition to figure out what is driving the tumor, because you are very likely to find some target that would be a treatment option for that patient. Actually, the most common gene that is altered is actually BRAF, for which we have a target, but you can see a whole list of other things. There are fusions that are identified, and we do not have enough time to go through every single one of them. I picked the most common one to talk actually about the treatments, which we will get to in a second.

KRAS WT Tumors Are Enriched With Targetable Alterations Compared to KRAS Mutant

More data from the same paper. This is looking at specific mutations. On the left, in the pink color, you can see tumors with RAS mutation - you can see they do not really have a lot of other things that are abnormal- versus on the right, the blue area, that is what you see with wild-type tumors. A lot of other alterations. Studies also show that those patients with wild type have better survival, and some of them you might find MSI high, TMB high. It really opens up a whole treatment box that you can use in this setting.

BRAF V600 Mutated PDAC: Dabrafenib + Trametinib

Let us talk about a few targets that we can actually treat. BRAF V600E, this is from a study that included mutated pancreatic cancer patients with BRAF V600E, giving them dabrafenib and trametinib with significant responses. This is an approved regimen that definitely should be considered.

Treatment Options for NTRK fusions in PDAC

NTRK is found in about 1% of those patients. Here you have listing of all the drugs that are approved for NTRK. I just found my first one. You have to look for them, they do exist.

Treatment Options for NRG1 Fusion-Positive PDAC: Zenocutuzumab

NRG1. This is a really interesting protein. NRG1 is a protein that results in the dimer or induces the dimerization of HER3, and by that activates cellular growth and proliferation. Patients that have NRG1 fusion basically have this dimerization on, and the cells just on and on proliferating. Zenocutuzumab is a drug that actually blocks this dimerization and prevents the growth. Look at this survival data. In pancreatic cancer, I believe this statistics is about 6% of these KRAS wild type will have NRG1 fusion, and those patients have great response to zenocutuzumab.

I think again, you just have to look for these mutations and make sure the NGS testing that you conduct actually looks at fusions and not just DNA. Both DNA and RNA fusions to identify this.

RET Fusion in PDAC: selpercatinib

Then RET fusion. Another one. We have a RET inhibitor. I can never say this name. selpercatinib. I think I got it right. Anyway, but response rate 43%. This is pretty amazing. I almost think you have to get all the patients to have RAS testing. Now, we are going to need RAS testing for all these RAS inhibitors. If you do not find a RAS inhibitor, that may not be so bad, because maybe one of these targets will pop up and allow us to treat the patient with a novel agent.

S2433: Second-line CT With or Without Panitumumab for KRAS, Locally Advanced or Metastatic Pancreatic Adenocarcinoma

I wanted to put another plug for a really good trial that is actually active now. This study is looking at patients with RAS wild type and randomizing them to receive in the second line chemotherapy alone or chemotherapy with an EGFR inhibitor. Basically, doing what we do in colon cancer and trying to use an EGFR inhibitor to treat these RAS wild-type tumors.

The nice thing is that this study allows the patients to receive, before they go in the study, any targeted therapy. If they have an NRG1 fusion and ALK fusion and NTRK fusion, whatever it is, treat them with that, and when they progress, they can go in this trial. Hopefully, in a few years, we will get some data from this.

MTAP Deletion and PRMT5 Inhibitors in PDAC

Another target that is very hot and being tested in pancreatic cancer is MTAP deletion. MTAP deletion, this is a protein that is deleted in about 20% of pancreatic cancer. It is interesting. It usually comes together with CDKN2A deletion. What happens when the tumor loses this protein? It becomes dependent on a protein called PRMT5. The whole cascade is here. I wish I had more time to go into this, but there are now drugs that inhibit PRMT5, and initial reports from these studies are very encouraging.

MountainTAP-30: BMS-986504,an MTA-Cooperative PRMT5 Inhibitor + Nab-P/Gem in mPdaC

This is one of these drugs. It is a drug that has shown good activity in the phase 1 setting and is now going into phase 2/3 study to evaluate the efficacy in combination with gem nab-paclitaxel in the frontline setting of MTAP-deleted metastatic pancreatic cancer. If you find an MTAP deletion, please send your patient to these studies. There are multiple of these drugs that are being evaluated.

Targeting Claudin 18.2 in PDAC

Finally, Claudin 18.2. Claudin 18.2 is a target that we know from gastric cancer. In fact, it is expressed in pancreatic cancer, and there are many studies looking at targeting Claudin 18.2. The image that I have there is actually showing the different way that we are targeting Claudin 18.2 antibody drug conjugate bispecifics CAR T monoclonal antibodies, and you can see how many studies are actually being conducted.

TWINPEAK: Spevatamig ± Chemotherapy and/or ICI in Advanced G1 Cancers

I picked one of them. This is actually a bispecific antibody that targets Claudin plus CD47, I believe, and together, trying to get the immune response into the cell to kill the tumor. Currently, in phase 1, 2, but this is a target that we are again going to try and leverage to treat pancreatic cancer.

Targeting Claudin 18.2 in PDAC: Spevatamig

Multiple targets. This is the phase 1 data from this drug, spevatamig. You can see the overall response rate of about 40% in these patients. These were all patients heavily pre-treated with multiple other chemotherapies, and the median survival, as you can see in the graph below, was 13.2 months. Seems like a very active agent.

Precision Medicine in PDAC

I never thought that I would give a talk in pancreatic cancer and have a slide like this. Look at how many treatment options we are developing for these patients. We are in the forefront of really changing how we are treating pancreatic cancer patients. Please test patients for genetic alterations.

It is easier said than done. Sometimes, we do not always have a lot of tissue, but this is something that we really have to work on, whether it is using circulating blood-based assays or additional biopsies, and trying our best to get this analysis, but we are really in the forefront of opening a lot of treatment options for this patient population.

Other Emerging Therapies and Ongoing Studies

I did not even touch on so many other areas. Vaccines, treatment using the immune system, genetic therapy, HER2 type therapy, HER3, we talked a little bit about it. P53 targets. There are so many ongoing studies, and the field is just going to keep changing every day. We mentioned earlier an abstract that is also going to be presented on Monday, looking at a MEK inhibitor. Please keep your eyes out for that.

Posttest 3

We are going to go to our third post-test question. This question is a little tricky. Let us think about it. Patients with advanced pancreatic cancer that has KRAS G12C mutation but also is a BRCA germline mutation carrier. They completed six months of FOLFIRINOX. The question is, what will you use for maintenance?

1. Adagrasib;
2. Capecitabine;
3. Olaparib;
4. Rucaparib; or
5. No maintenance.

Please pick your answer.

It looks like most of us found what we were looking for, so olaparib. Yes, olaparib is the right answer. Yes, the patient has G12C. Adagrasib may be an option, but it has not been approved as maintenance therapy. Olaparib is the only FDA-approved maintenance therapy that we currently have.

Supportive Care

I am going to take the last few minutes to talk about supportive care. I think we all know how challenging pancreatic cancer is, and supportive care is a big part of what we do every day.

PANOVA-3: TTFields + Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma

I wanted to talk for a little bit about the PANOVA-3 trial using the treatment field device. This was a study that looked at locally advanced pancreatic cancer. I have to say, this is an area where we really do not have a lot of data. There are very few studies that evaluate locally advanced disease. We struggle with these patients. I feel like those are really different than the metastatic patients.

What happened in this trial, patients received standard of care gemcitabine and nab-paclitaxel and were randomized to receive just the chemotherapy or together with treatment field using the device at least 18 hours per day. They were followed until progression with the primary endpoint being overall survival. Of course, they looked at multiple other endpoints, including PFS, one-year survival, overall response rate, safety, but also pain-free survival.

PANOVA-3: OS and Pain-Free Survival

Here are the two main takeaway points from this study. On the left is the overall survival data, and you can see that there was an improvement in overall survival 16.2 versus 14.2 months. On the right is the pain-free survival. Look at this difference 15.2 versus 9.1 months. Pain is such a significant factor in this disease, especially for the locally advanced patient. For those that can tolerate the treatment field device, I think these data are quite compelling. It is used in GBM with good utility from patients. I have tried it in a handful of patients now. I think patients tolerate it, so really worth considering this outcome.

PROACC-1: Ponsegromab for Cancer Cachexia

Then I just wanted to mention a molecule that is being developed. Looking at cachexia with pancreatic cancer. As you know, that is a very big issue that we deal with. This molecule targets GDF15. GDF15 is a protein that affects cachexia. You can see from the graph, this was the early study with this agent that basically showed with the doses, the increasing doses. If you look at the dose of the 400 mg compared to placebo, there was a significant difference in the weight of patients when they took this drug. There is an ongoing phase 2 three-study looking at adding ponsegromab, I think - ponse, that is what they told me to call it ponse. Ponse to chemotherapy versus placebo.[01:13:04]

Posttest 4

Post test number four, so patient with locally advanced pancreatic cancer is considering gemcitabine plus nab-paclitaxel and asks about using the tumor treating field device. You are discussing the outcomes of the PANOVA-3 trial and asking about the results. The question is what was improved in this study, and what was not improved, basically?

1. Overall survival;
2. Pain-free survival;
3. Overall response rate; and
4. Distant progression-free survival.

We are looking for what was not improved on this trial.

Overall response rate was the only thing that was not improved. I think everybody picked what was improved.

Dr. Ko: I do not think you shared the data.

Dr. Dotan: Oh, right. We did not we did not share that. That is true. The overall response rate was not improved, but the distant disease-free survival was actually improved on that particular study. Overall survival was improved, pain was improved, and the distant disease was also improved, which was interesting. You would have expected the overall survival. You are right. We did not share it on the slide. This is the rationale.

Conclusions

To conclude our symposium before we open it for questions, in our case, we really hope you leave today thinking that there is room for optimism in this disease, that survival has significantly improved. With the additional therapies, we are going to see more improvement, and that understanding the biology of the tumor is really the critical part that will help us take better care and improve outcomes in this disease. NGS testing is critical, and we have to get that done for every single patient. Clinical trial participation is the only way that we can move the needle forward in this disease.

I want to end with just another plug for PanCAN. We are all closely working with PanCAN to support our patient. PanCAN has supported all of our patients in terms of finding clinical trials and has a robust amount of patient resources to manage this disease. If your patients have not heard about this or have not contacted them, please encourage them to do so. Here are the list of all the things that PanCAN has for patients, and we really hope you can encourage your patients to contact them.

Then, finally, on June 25th, there will be a symposium or an event, a virtual event for patients focusing on some of what we about talked today, the new era of pancreatic cancer, and the new treatment options. Hopefully, you can encourage your patients to participate.

Dr. Ko: Actually, Dr. Dotan, because there are a lot of questions that we want to address, rather than talk about the case, which is quite lengthy, we wanted to actually give you the opportunity, since we know you are an expert in management of care for older, frailer individuals, and actually led a very important cooperative group study on that. If you could, before we start addressing some of the questions, just maybe share a couple of minutes in terms of your thoughts about specifically treating that special patient population, which I think all of us may struggle with.

Case for Panel Discussion

Dr. Dotan: I think we all see in clinic older patients with pancreatic cancer. It is because the median age of pancreatic cancer is 70. Most patients are diagnosed either 70 or even older. I am amazed every day by the 80s and 90-year-olds that I see in clinic that I am actually thinking of giving them chemotherapy. That is what led to the clinical trial that we ran.

Older Adults With mPDAC: GIANT Study (EA2186)

I do not know if I can - here we go. This was a clinical question that was brought up. What do we do with these patients who want to get treated, but we worry about their ability to tolerate chemotherapy because of age, but also maybe because of other comorbidities or other frailty concern. The GIANT study actually enrolled patients over the age of 70, and every single patient had to have some vulnerability. It had to be either by age criteria, they had to be over the age of 80. But if they were 70 years old, they had to have either functional comorbidity or cognitive issues that really made them vulnerable. Then we randomized them to dose-reduced chemotherapy, which was what people were using in clinic. They either received gemcitabine and nab-paclitaxel dose reduced every two weeks or 5-FU and liposomal irinotecan given in a dose-reduced fashion. The primary endpoint was overall survival. In addition to collecting a lot of geriatric assessment and quality of life evaluations.

GIANT Study (EA2186): OS (Primary Endpoints) and PFS

Here is the data. PFS was not different between the two arms, but was three months in gem abraxane and 2.4 months in the 5-FU liposomal irinotecan. Overall survival was 4.7 months for gemcitabine and abraxane versus 5-FU in liposomal irinotecan 4.4 months. Very poor outcome in this vulnerable patient population. As you can see, there is a sharp drop at the beginning. Many patients could not even tolerate more than one cycle of chemotherapy, or did not even make it to start the treatment. Which really raises a question, should we treat these patients with chemotherapy?

GIANT Study (EA21886): OS by ECOG PS and Age

Here is the data broken up by ECOG performance status. If a patient was in ECOG performance status two, survival was 1.4 months versus ECOG performance status of zero median survival was 6.9 months, which is maybe more in line with what we would have expected. Age did not really matter. It was not the age that drove the these findings.

GIANT Study (EA2186): OS by Number of Prior Treatments

To me, the most important part of this study is actually this slide. This was an analysis done on patients that were able to stay on treatment for one month or more. You can see that the median overall survival is eight months, which is pretty much the same as what we saw in the MPACT study of gemcitabine and nab-paclitaxel without any dose reductions. This is vulnerable patient dose-reduced therapy.

If we identify the patient that can really stay on treatment for more than one month, those patients actually can derive the same benefit from a lower dose of treatment compared to the other population or more fit patients, I should say. I think this is food for thought and really helps us discuss the risks and benefit of chemotherapy with our patient in clinic, especially the older and more frail ones.

A Final Poll

Dr. Ko: Maybe the data you shared, which is pretty sobering for chemotherapy, and what we have talked about with RAS inhibitors, might open up a different line of therapy for this very vulnerable patient population.

Dr. Dotan: Right. Whereas I used to say, what is the point in putting a vulnerable patient through a biopsy and looking for mutation or looking for NGS testing? Now, maybe that is the right way to go, because if they have a RAS mutation, they may be candidate for a RAS inhibitor, and if they do not, they may have another target, which may be much better tolerated than chemotherapy for this patient population.

Dr. Ko: Why do not we open it up and just try to answer a few of the questions that came up.

Dr. Oberstein: Yeah, I think there is a lot to cover. It is really exciting so much in pancreatic cancer. A lot of questions came up. I do not think we are going to be able to address every single one of them, but we are going to try to hit some of them that had common themes that many people asked about. I will start. I will take one. Everyone will do round robin.

One of the questions that came up pretty frequently was a question about the rash management with daraxonrasib. We asked that question. It is a common toxicity. It happens in over 90% of patients at some level, many have grade 3 rash. The question that specifically came up was, what is that going to look like in the community post-ultimate approval and wide adoption of daraxonrasib?

That is a hard question. We do not know exactly. I would say a couple of things that we do know. One is that the data has been presented from the phase 1 trial of daraxonrasib, where essentially we went into that trial not knowing what exactly to expect and how to manage it. One of the really notable things is that although many people had the side effect, no one was reported to have stopped the study because of rash or because of that side effect.

Patients essentially in that phase 1 study were able to be modified, supported through all kinds of dermatological interventions, and were able to stay on therapy. One of the very interesting modifications is dose holds, dose delays. If you take a pause from daraxonrasib and things improve significantly, and usually you can go back on it without a very long delay. I would say those interventions were utilized in the phase 3 trial. There was an established plan for how patients should be managed with their rash that was used in the global randomized phase 3 trial. We have not seen the data yet for how many patients either stop, study or had adjustments because of the rash. I think we will see a lot of that on Sunday and in the subsequent manuscript, but that data is really going to inform what it is going to look like in practice. Our hope is, that with that modification and that dose recommendations, people will be able to stay on treatment even in the community and even in general practice.

Dr. Ko: Adding to that, when patients are going to start on daraxonrasib at the same time, they should be starting on daily oral minocycline or doxycycline. They should be getting a topical hydrocortisone on the face and trunk, just the vulnerable areas. Those can be peeled off after eight, 12 weeks if the rash just is manageable. I have had a number of patients, all of whom, on protocol required to start on those who can back off.

As I mentioned before, I think you will want to quickly ally with your dermatologists because, for very severe cases, you are going to want derm input. There are certain drugs, in fact, that only our dermatologists can prescribe, like Accutane. Did not know that we cannot prescribe that ourselves. There is even much more extreme measures for those severe situations.

Another question that came up was regarding to resistance mechanisms. I think this is going to be very important because even though I was touting how wonderful these RAS inhibitors are and they are going to be., unfortunately, invariably patients are at some point going to develop resistance. Now, what we know, and so far, in terms of what we have seen with some of the daraxonrasib data, as well as some learnings from earlier studies for from our lung colleagues with the G12C inhibitors, there is a number of different reasons why patients develop resistance to these RAS inhibitors. Some actually are non-genetic. There can be this so-called epithelial to mesenchymal transition. There can actually be histologic transformation into other subtypes. In terms of the genetic types of mutations that occur, those come in different varieties that they can involve RAS amplification, or they can involve actually a trans RAS mutation, or, as we are talking about, RAS biology changes upstream or downstream, so MAP kinase mutations that develop. Occasionally, patients may develop HER2 amplification.

I think it is going to be very important for us as we understand more, is hopefully either through ctDNA or maybe post-progression biopsy is to actually understand those resistance mechanisms because that might help inform choices in terms of later lines of therapy beyond that. Really interesting and really important question that we are only starting to understand.

Dr. Oberstein: One of the interesting things about daraxonrasib and that is going to be presented, it was a single agent tested in second line. Single agent daraxonrasib, we saw that there is an ongoing phase 3 trial in the first line, RASolute 303, which is looking at the combination of chemotherapy plus daraxonrasib. The sky's the limit.

There is potential to combine this with many other agents. Either things in the pathway to prevent resistance potentially chemotherapy, other therapies. Obviously, tolerability will have to be evaluated, but there is certainly a lot of potential to combine this with other agents to hopefully improve and reduce that resistance or allow people to stay on it for longer. A lot of exciting stuff.

Dr. Dotan: I will try to pick off a few of the questions here. There was a question about gem nab-paclitaxel three weeks on, one off, versus every two weeks. I think there are some data out there showing that the efficacy of every two weeks is not very different from three weeks on, one week off. My experience and my colleagues can comment as well, especially older patients, the three weeks on, one week off is very difficult to tolerate. You get thrombocytopenia and neutropenia very early on, first, maybe second cycle, and to get the last week, the third week is extremely difficult. I either start off the bat with every two weeks or switch very quickly to that.

I think there was another question here about the FOLFIRINOX without bolus and oxaliplatin 75, 150, what is the dose? I can talk about what I do. I think we are very similar - all of us mostly use modified FOLFIRINOX in which we eliminate the bolus, reduce the irinotecan usually to 150, 165, depending on how fit the patient is. I give GCSF to everyone up front. I do not wait till they have neutropenia.

Dr. Ko: Can I just ask, and we are going to have to close the next minute or two. Are you guys all doing DPD and UGT1A1 testing on everyone?

Dr. Dotan: I do DPD on everyone.

Dr. Ko: Paul?

Dr. Oberstein: I do both, but DPD especially.

Dr. Ko: That is obviously another hot area that we will not dive into at this moment.

Folks, I know we are about at time, and we want to be sensitive to everyone's time. I will just say, with regards to the daraxonrasib, and hopefully this at least not only spurs excitement, but gets you thinking in terms of when it is used. Its approval again is going to be in that second line plus setting for metastatic disease. I can certainly envision folks and patients clamoring to receive it even upfront, or maybe there is going to be just a very easy threshold to say, I will start them on chemo. If they do not tolerate it that well, immediately switch over. I think there is going to be a lot of ways that people are going to "game the system", probably compelled by patient pressures. I will say in my practice, I am probably going to try to stick mostly with its use, as indicated, until more data come out to support its use in earlier settings. Certainly, this is going to really change how I think many of us practice.