Round 1: Interpreting Clinical Data for Targeted Therapy in mPDAC

A case involving a patient with a KRAS G12D mutation who progresses after first-line therapy prompts discussion of second-line treatment selection. The panel examines RASolute 302 efficacy findings in the RAS G12 population and provides an overview of the trial’s safety data. 

To review discussions related to the role of targeted therapy in mPDAC and tolerability considerations, see Round 2.

Efrat Dotan, MD: The first round is going to focus on selection for second-line therapy for metastatic pancreas cancer. So I'm going to start by going over the actual case. So this is a 61-year-old man who presents with metastatic disease. He has liver metastases. At presentation, his ECOG performance status is 1. He gets next-generation sequencing and is found to have a KRAS G12D mutation. No other actionable mutations are noted in his analysis. He starts treatment with modified FOLFIRINOX, gets 6 cycles, has a partial response, everybody's happy. And then oxaliplatin is discontinued because he has some neuropathy. He continues just with FOLFIRI. He's doing pretty well, but then at restaging scan at 6 months, he's found to have new peritoneal implants and growing liver lesions. CA 19-9 is rising. Otherwise, his performance status is preserved. 

Just to put this patient into context in terms of social history, he has a spouse that is the primary caregiver. She's with him for every visit. He has reliable transportation, good insurance coverage, and good social support. His daughter is a nurse and really helps with symptom management.  

We really want to think in this case, what are the factors that weigh in into our decision? What are the social factors that weigh in? What is the data that really drives our decision? So to talk about that, I'm going to let Meredith talk a little bit about the RASolute data to start us off. 

Meredith Pelster, MD: Yes. So I'll walk you through the RASolute 302 data, which supports the recent FDA approval of a new option for us, our first targeted therapy in pancreatic cancer. So the RASolute 302 study was a large open-label randomized phase 3 trial for patients with metastatic pancreas cancer that had progressed on one prior line of therapy in the metastatic setting, either 5-FU or gemcitabine-based, good performance status, and with a documented RAS mutation status based on local testing. So any patients were included. You could have a KRAS mutation of any type, could be wild type, but we just had to know what mutation status was present. About 500 patients were recruited to this trial and randomized in a one-to-one fashion to receive investigator's choice of chemotherapy, which included gemcitabine nab-paclitaxel, modified FOLFIRINOX, nanoliposomal irinotecan, and 5-FU or FOLFOX, or the experimental arm, daraxonrasib, a pan-RAS inhibitor, dosed at 300 milligrams by mouth daily based on the phase 1 data. 

The dual primary endpoint of this study was a combination of overall survival and progression-free survival in the RAS-G12 population, which is the vast majority of our patients with pancreas cancer harboring a KRAS-G12 mutation. Key secondary endpoints included overall survival and progression-free survival in the overall population, so any RAS status; response rate; as well as time to deterioration in pain and quality of life, patient-reported outcomes; and, of course, safety.  

Here are the baseline characteristics of the patients that were included in this study. We can see a median age in the mid-60s, fairly even split between male and female. And as we would expect for a study in pancreas cancer, we do see a split fairly evenly between a performance status of 0 and 1. 

A little over 60% of the patients in both arms had metastatic disease at their initial diagnosis. And there was a split between prior chemotherapy regimens, modified FOLFIRINOX and gemcitabine nab-paclitaxel being the most common, with a little under a quarter of the patients receiving another regimen. 

Between 33% and 36% of patients in the two arms had had a prior pancreatectomy and around 70% of patients had liver metastases at baseline. So this gives us an overall picture of the population with respect to some factors that we know are important for prognosis, including de novo diagnosis and the presence of liver metastases. And we can see that those things were all very well split and balanced between the two arms.  

Regarding the baseline RAS mutation status, we saw that close to 80% of patients had a G12D or G12V mutation, with 12% to 13% in each arm having a different G12 mutation, with less than 10% having a G13, Q61, or no mutation identified. And you can see the absolute numbers there are quite small, 20 and 21 in that rare mutation or no mutation. And this, again, mirrors what we would expect for pancreatic cancer patients with the G12D mutation being the most common followed by G12V. So we see the majority of patients in that group. 

So on to the primary outcome. Here we see the Kaplan-Meier curves for progression-free survival and overall survival in the RAS G12 population. If any of you were at ASCO this year, these are the data that generated the standing ovation and a lot of emotion when Dr Wolpin was presenting this data. So looking at the PFS curve, we can see that with daraxonrasib, there was a median progression-free survival of 7.3 months compared to 3.5 months with chemotherapy, with a statistically significant hazard ratio of 0.45. We see a similar splitting of the curves for overall survival with a median overall survival with daraxonrasib of 13.2 months versus chemotherapy 6.6 months, with a hazard ratio of 0.4. When we look at the landmark 12-month overall survival rate, we see that it is over 50% for the patients who received daraxonrasib versus less than 20% for the patients who received chemotherapy. So this data generated a tremendous amount of excitement.  

Looking at another outcome, our objective response rates in the G12 population. So we saw with daraxonrasib that 33.2% of patients were achieving a RECIST partial response compared to 11.8% with chemotherapy. So an absolute difference there of a little over 20%. 

This study did include some patient-reported outcomes; in particular, time to deterioration in pain and global health status was reported for the two groups. For daraxonrasib on average, patients did not experience progression in pain until 9 months compared to 3.7 months. And for global health status, it was 5.6 versus 2.4 months. So this is delaying time to deterioration, which I think is important that we consider these outcomes in addition to the safety data and consider these all together, which we'll talk about subsequently.  

And as far as the safety overview, we can see that 100% of patients had some adverse event with daraxonrasib versus 97.7 with chemotherapy and grade 3 or greater events did occur in over 60% of daraxonrasib patients and close to 70% in chemotherapy. Of course, the toxicity profile of daraxonrasib is very different than chemotherapy. Chemotherapy, of course, we see the expected fatigue, cytopenias, GI toxicities. The daraxonrasib side effect profile is really driven by rash, which occurs in 85.5% of patients. This is an acneiform rash typically with a predilection for the head, neck, and upper body at the start. Patients also frequently experience diarrhea, mouth sores, nausea, and vomiting, and the GI side effects tend to occur early in the course of treatment. 

Efrat Dotan, MD: Meredith, would you give the patient that we just presented daraxonrasib, clinical trial, or second-line chemo? 

Meredith Pelster, MD: So, I think that this patient that was described with his excellent performance status and his great family support, if he had a clinical trial available, that would be my decision. However, unfortunately, not every patient has that available. And so if I could not enroll a patient on a clinical trial, then I would go with daraxonrasib. 

Efrat Dotan, MD: Mary, any thoughts about social factors that you think about or other factors that would sway you in one way or another? 

Mary Larsen, MSN, RN, OCN: With an oral therapy, there's just less trips back and forth to a cancer center. You can manage more of it on your own if you're self-motivated. So I do think maybe with a weaker support system, in theory, you could manage with an oral therapy and managing side effects better than a chemotherapy or more so a clinical trial actually where you have so many trips back and forth from the cancer center. So I do think social support plays a role, not that it's the deciding factor, but it plays a part in the decision. 

Efrat Dotan, MD: Absolutely. I just wanted to bring up one point. This patient did have neuropathy. Does that play a role at all in your thinking, Meredith? I don't know if you... 

Meredith Pelster, MD: So certainly we know that if we continue this patient on our next chemo arm or chemo line, which would be before daraxonrasib, our only option really would've been gemcitabine nab-paclitaxel. Neuropathy is going to get worse. So I think a definite benefit of daraxonrasib is that is not part of the side effect profile. I'm making the decision primarily based on efficacy, but it's certainly a major benefit to these patients who often are debilitated by neuropathy after all of the chemotherapy that they receive.