KRAS-Targeted Therapy in Metastatic Pancreatic Ductal Adenocarcinoma

Tanios Bekaii-Saab, MD, Mayo Clinic, Phoenix, Arizona, presents a case of a patient with advanced pancreatic cancer that highlights the growing role of molecular profiling and targeted therapy.

Following progression on first-line chemotherapy, the patient was found to have a KRAS G12C mutation, enabling treatment with KRAS-targeted therapy and achieving meaningful disease control in a setting where standard options are limited. This case underscores the importance of comprehensive genomic testing to identify actionable alterations, including KRAS mutations and rare targets, and to guide the use of emerging targeted therapies in pancreatic cancer.

Transcript:  

I'm Tanios Bekaii-Saab, professor in oncology at Mayo Clinic and I take care of gastrointestinal cancer patients with a great focus on pancreas cancer.

Today we'll be discussing a case of a patient who was diagnosed with pancreatic cancer and ultimately was started on standard chemotherapy, had a decent response for a whole year, [and] unfortunately progressed. At that point, the patient decided that she does not want to proceed any further with cytotoxic therapy, understandably, since the response rate tends to be relatively low and the toxicities certainly may not be acceptable, at least to this patient. 

The important aspect of managing this particular patient, but I think that transcends to all our patients with pancreas cancer today, is the two things that I think are very important to have in hand to help you with a decision. One is certainly assessing for germline mutations– specifically for BRCA, but also ATM. These would be important, especially when making decisions on how to best treat patients in the first line because they may open the door preferentially for platinum-based combinations, but also may open the door for PARP inhibitors, this is a small percentage of patients but certainly important to keep in mind. The other is next-generation sequencing and assessment of genetic alterations or genomic alterations within the tumor. I think those are important guides for us in the sense that they allow us to decide on some agents that are either already approved or that will be making their way hopefully soon.

The most common alterations that we're going to find in pancreas cancer is mutations in RAS– KRAS specifically, and the most common is KRAS G12D in around 45% of the patients, then G12V at 35%, then G12R. G12C is less common, in about 1% or less of the patients. Now, curiously, those patients with a RAS wild-type, meaning do not have mutations in RAS, end up actually having a number of alterations of interest that could also help with introducing other agents such as NRG1 fusions, BRAF mutations, and others where we have some approvals already. So I think it's very, very important to have a good understanding of alterations.

This particular patient ended up having one of the rare alterations, KRAS G12C mutations, and that's important because that allows us essentially to consider RAS-directed therapies that are approved. Two agents approved today to clinic, adagrasib and sotorasib as single agents, are approved broadly for lung cancer and for colon cancer in addition with an EGFR inhibitor, but included in the NCCN guidelines for essentially the single agents to treat patients with KRAS G12C mutations and this is based on two studies that were published that included both agents. Adagrasib showed a response rate close to 33%. Sotorasib as a single agent, had a response rate of 21%, although the disease control was above 80% –and these tended to be durable responses.

 If you think about it, the response rate with chemotherapy at this stage of the cancer in second line and third line is typically between 5% and 10% max, with a progression-free survival that tends to essentially be less than 3 to 4 months. With adagrasib, for example, the median PFS in the published data was 5.4 months, with the median overall survival that matches or outmatches chemotherapy. I've had many patients on adagrasib as we were leading part of that study that had responses that lasted for close to two years in the refractory setting, so for some patients, it actually is quite meaningful. The toxicities appear to be relatively few, grade 1/2, very few grade 3, and no grade 4 toxicities.

The question, of course, is where do we go next. This is only 1% or less of patients with pancreatic cancer and since RAS is a major driver, KRAS is a major driver, actually the most mutated oncogene in human cancer, but in pancreas cancer, it's 90% to 93% of patients. The good news is that there are a number of trials that actually have completed and many more underway that have explored essentially many other KRAS inhibitors that are in the pipeline, going from the allele-specific 12D, 12V, 12R and others, to the pan-RAS and pan-KRAS inhibitors. One example is RMC6236, daraxonrasib, which essentially is a multi-RAS inhibitor. There's a study that just recently completed, RESOLUTE 302, that ultimately we're eagerly awaiting the results because this was a phase 3 randomized study that looked at essentially RMC6236 versus investigator choice of standard-of-care chemotherapy, with the primary end points of PFS and OS. Again, depending on the readout of the study, we may have an approval in pancreas cancer, first approval for a RAS inhibitor. Again, I don't know yet, we're going to have to wait for the results to be presented and then published, and this ultimately, if positive, to make its way to the FDA. So fingers crossed that will add valuable agents to our armamentarium.

Now, I will tell you that the initial data with daraxonrasib as a single agent in second-line pancreas cancer from smaller cohorts, these reports were close to 30%, and in the G12 group, 35% response rate, and close to 90% plus disease control rate. There was even some intriguing data with daraxonrasib in the first-line treatment of pancreas cancer where the response rates match what we see with chemotherapy, 47% and disease control rate of 89%. When combined with chemotherapy, with gem/nab-paclitaxel, the response rate gets close to 55%. So a lot of promising data, and that essentially has led now to a number of studies looking at daraxonrasib in the first line, with single agent or in combination versus gem/nab-paclitaxel. 

Allele-specific agents are also making their way, and there are a number of them that are being looked at–these are some of the direct inhibitors. Allele-specific inhibitors include agents like zoldonrasib or another compound called GFH375. And then we have an Incyte compound, INCB161734, all showing promise with more than 30% to 40% response rate. These tend to be durable responses and these are moving forward now, mostly in combination with chemotherapy, both with gem/nab-paclitaxel and FOLFIRINOX. There are many others that are in development. There's also a class of agents called PROTAC, which are a little bit different, they're degraders, and one of those agents is ASP30A2, which is a 12D-selective protein degrader. And that's also moving in combination with chemotherapy in pancreas cancer. So a lot of activity in that sense, targeting other aspects of RAS, pan-RAS, pan-KRAS, allele-specific RAS beyond 12C, so 12D, 12V, and others. All these are in development and this is becoming a very exciting time for pancreas cancer, where 90% plus of the tumors appear to be driven by RAS mutations.

To conclude, when I think back to 10 to 20 years ago when we thought RAS was undruggable, that it would have been impossible to target RAS, that made essentially pancreas cancer a very difficult disease to go after in terms of molecular targets. Today, I can say that every patient with pancreas cancer should have the opportunity to have their tumor sequenced, and I emphasize every single patient. And that's because KRAS is so omnipresent, and because we have 12C approved in guidelines, we have 12D, 12V coming in, we have pan-RAS coming in. But also in the KRAS wild-type patients, which is about 7% of the patients, we find fusions in FGFR, RET, ALK, NRG1 fusions, we have BRAF V600E mutations. We have agents like zenocutuzumab that's approved for NRG1 fusions, we have dabrafenib, trametinib for BRAF V600E mutations. So, a lot of exciting times in pancreas cancer. We have MSI-high, of course, I haven't spoken about this, that's a rare element in pancreas cancer, 0.5% of the patients, but pembrolizumab would certainly be an agent that would be used in this particular instance.

Learn more about this case here:

KRAS-Targeted Therapy in Metastatic Pancreatic Ductal Adenocarcinoma