Round 2: The Role of Targeted Therapy in mPDAC and Tolerability Considerations

The panel examines RASolute 302 efficacy findings in the overall study population, then takes a closer look at the safety data, discussing treatment-related adverse events and practical approaches to their recognition and management. 

To review discussions related to interpreting clinical data for targeted therapy in mPDAC, see Round 1.

Meredith Pelster, MD: So as we already talked about, the dual primary endpoint of the study was in the RAS G12 population, so those are the outcomes that we've already looked at. Here we are looking at the overall population. So we've lumped in those patients that had G13, Q61, or no RAS mutation. I'll draw your attention to the text on the side of the slide, which shows the very small absolute number of patients that had an "other" mutation, or no RAS mutation, 9 versus 7. So we're adding a very small number in to what was the bulk of the patients in the study that had the G12 mutation that was the primary endpoint. 

So we can see that adding these patients in did not appreciably change these curves. Progression-free survival is still significantly more with daraxonrasib than chemotherapy, 7.2 versus 3.6 months, hazard ratio of .49. And then overall survival, still significantly different, 13.2 months versus 6.7 months.  

I think this is a good opportunity to talk about testing. Inclusion for the trial, as we discussed, you just had to have a known mutation status. This could come from tissue. So you could have performed NGS on a core biopsy, FNA, or you could do a liquid biopsy. I personally, when I'm meeting new pancreas cancer patients in an effort to look for frontline trials, I've gotten in the habit of doing a liquid biopsy for my patients so that I get quick results and can make a decision, do I have a frontline trial or not? However, we have to think really carefully about the results of liquid biopsies and whether or not we might be seeing a false negative. So if we have a liquid biopsy with a low tumor fraction and there's no RAS mutation, I'm automatically thinking, "Do I believe this?” and I need to follow up with tissue. So I'm trying to get liquid and tissue on all patients.  

So all of this to say is we have to take these patients that have no RAS mutation identified, or any patient that has no RAS mutation identified, with a grain of salt and some skepticism, because we expect 90% to 95% of these patients to have a RAS mutation. And if they don't, they probably have a different driver. So just something to think about.  

I think the last data slide from the overall population is just showing that the objective response rate remains improved with daraxonrasib versus chemo, as we would expect. 

Efrat Dotan, MD: I think I'm going to ask Mary to talk a little bit about the adverse events that we saw in the RASolute trial, how we're managing them, and put this a little bit more in perspective and then we can discuss this further. 

Mary Larsen, MSN, RN, OCN: Yes. So just comparing the adverse events between the daraxonrasib arm and the chemotherapy arm, just data to help a clinician guide this decision for the next line of therapy. You can see that basically most people, over 90% in both group, had some treatment-related adverse event. But as Meredith had discussed earlier, just the breakdown of what adverse events occur in the daraxonrasib group versus chemotherapy are much different. 

So, maybe just going back to our question in this case, maybe the first immediate next step should be discussing with the patient what their goals are, really, because these are just so different and it's figuring out what the patient's going to be most comfortable with and what you as a clinician are most comfortable with. So back to the data, the daraxonrasib arm, the rash is the biggest side effect, 85.5%. And then neutropenia, anemia, liver function test abnormalities, those are all a lot more present in the chemotherapy group. We really don't see too much of that in daraxonrasib.  

Just reviewing what adverse events actually led to dose modifications. So, many, about 50% in the daraxonrasib group; more, around 70%, in the chemotherapy group. The overall number, only 3 people discontinued for treatment related AEs and 24 in the chemotherapy group, which still isn't a lot of people, but… There is recommended skin prophylaxis, which with a topical corticosteroid to the face and chest, which is, as Meredith said earlier, that's usually the first places where the rash presents, sometimes like scalp as well or upper back, but in general, face, chest, and prophylactic oral antibiotics. Also limiting sun exposure and using daily sunscreen.  

I would also add to this, and I believe this actually is in the daraxonrasib guidance, also just, a moisturizer in general, just keeping the skin moisturized is also helpful. And yeah, I think this is now also back to the consideration of how motivated is a patient to keep up with these regimens, because it is work. I think especially a prophylaxis with the topical steroids, it's just hard for people to wrap their heads around. Understandably, if there's no rash there, they don't want to put the cream on.  

And there's a lot of questions about antibiotic resistance, or they're worried about GI side effects with the antibiotics. So these are discussions. It's not as clear as just when you suggest daraxonrasib, you give them this prophylactic regimen. 

And then for the mouth sores, mucositis, stomatitis, they recommend a steroid-containing mouthwash. But typically, yeah, not necessarily as prophylaxis, but to initiate it early on, an antidiarrheal, anti-nausea regimen from the start. 

Efrat Dotan, MD: One of the hardest things is the fact that these people are getting oral therapy. They don't have to come see us. So for those that can take care of themselves, that's great, but not having the ability of the nurse in the infusion room to see the patient and call us and say something doesn't look right is a little scary. 

Meredith Pelster, MD: I'll go over how I initially manage these patients that are starting on daraxonrasib. Any new patient that I have that's starting on treatment, I send them topical steroids, triamcinolone and hydrocortisone, doxycycline, Zofran. I have them all pre-medicate with Zofran 30 minutes prior to daraxonrasib, and I discuss with them if they want to take it in the morning or at night. Sometimes taking it at night can help with that initial nausea since you're kind of sleeping through it, hopefully. 

I make sure they all have Imodium on hand and have the instructions for that. I do talk quite a bit about sun exposure. That makes a big difference, and I've seen rashes flare a lot when patients have been out in the sun. They're also on doxy, so which also has sun exposure issues. So that's actually a very important part of the counseling.  

When we started the EAP at my site, and we didn't have a technical protocol, so we had to decide how are we going to monitor these patients. What we decided to do was to see them at 2 weeks and then at 4 weeks when they would be due for their next pickup and then monthly thereafter. So that has been my typical standard monitoring. I think it's important to see them at 2 weeks to make sure they've made it through those acute gastrointestinal toxicities, because in my experience, it's really those first couple of weeks where they may have significant nausea, vomiting, and diarrhea. So I just want to make sure they're managing through that.  

At a month is when you may start to see the rash, and you want to see, is this going to be one of the people that has a really significant rash from the outset where you're already going to need to be thinking about potentially holds or modifications and then monthly thereafter.