KRAS Mutations Represent Important Target in Expanding Treatment of Pancreatic Cancer

Philip A. Philip, MD, PhD, FRCP

Although combination chemotherapy remains the standard frontline treatment for patients with localized or advanced pancreatic cancer, genetic mutations such as BRCA1/2 have started to shift the field toward more targeted therapies. KRAS mutations represent the most common genetic alterations for patients with pancreatic cancer and finding more viable treatments to target that pathway would serve as a major boost for a patient population with many unmet needs, according to Philip A. Philip, MD, PhD, FRCP.

“Combination chemotherapy remains the mainstay of treatment. That hasn’t changed, and it’s not going to change anytime soon, whether we’re talking about localized disease or advanced disease,” Philip said. “However, exploiting DNA repair defects in the form of BRCA1/2 mutations is now an established form of treatment, and we’re trying to expand that into other mutations.”

In an interview with OncLive^®, Philip detailed his presentation from the 2022 ESMO World Congress on Gastrointestinal Cancer on new treatment options in pancreatic cancer. He highlighted unmet needs for these patients, emerging targets and agents in the space, and his hopes for future developments in the field. Philip is the direct of Gastrointestinal Oncology, co-director of the Pancreatic Cancer Center, and medical director of Research and Clinical Care Integration at Henry Ford Cancer Institute.

OncLive^®: What characteristics affect choice and sequence of therapy in pancreatic cancer?

Philip: We [have to consider] the stage of the patient and a number of other factors. For patients who have localized disease and are resectable, certainly we’d like to get them to surgery, either giving them neoadjuvant chemotherapy and then doing surgery, or surgery up front. [Then there are] patients with locally advanced, unresectable disease, or patients who come to us with metastatic disease—the latter [comprise approximately] 50% of patients with pancreatic cancer. Those patients are started off with combination chemotherapy, keeping in mind that not every patient can get combination chemotherapy.

In [some] patients who have metastatic disease, but also some of the patients who have locally advanced disease or even resectable disease where we would give them adjuvant treatment, they cannot get systemic therapy either because of age, performance status, or comorbidities. But certainly, in patients who we can get combination treatment, we prefer to do that, whether it’s to downsize the tumor or to treat advanced disease, whether localized or metastatic.

What’s happened in recent years is that we are now recognizing and appreciating the value of doing genomic profiling because that helps us to give treatments that are more tailored to the patient. It’s no different than other areas of oncology where we’ve been trying to use targeted therapies based on molecular profiling. That’s now being done [in pancreatic cancer]. And the way that impacts patients is by doing some tests, and the most important [aberrations to test for are] BRCA1/2 mutations. Here we’re talking about genomic mutations, but also it’s applicable to patients who have somatic mutations. And for those patients, because they have vulnerabilities in DNA repair, we hit their tumors with platinum-based treatments. That will increase the response rate and has been shown to extend their survival significantly.

The other thing we do is that after giving patients initial treatment, usually between 4 and 5 months of treatment, if they have a good response or even stable disease, then we have the luxury of maintaining them on a single oral agent. In this case, the FDA approved drug is olaparib [Lynparza], so that would be a maintenance treatment until their disease progresses.

The strategy has [shown a] prolongation in the survival of patients with BRCA1/2 mutations, and you’re talking about [survival] exceeding a year and much longer. Compare that with all-comers and patients who do not have BRCA mutations whose median survival with combination chemotherapy, at this point in time, is still just under a year.

What are some of the biggest unmet needs for patients with pancreatic cancer?

[In many] patients, even if they have what appears to be localized disease, resectable disease, or [potentially] resectable disease, there is still a significant possibility of the cancer coming back through recurrence or progression. And for that reason, the unmet need continues to be developing better systemic treatments.

One of the challenges of pancreatic cancer is that unlike other cancers, where immunotherapy made inroads and a proportion of the patients get benefit—you can maybe even call it a cure—or prolonged survival, in pancreatic cancer, that did not happen. The unmet need here is to try to make immunotherapy work. And here, the thought is that trying to combine regular immunotherapy, the immune checkpoint inhibitors, with other drugs that can make the immune checkpoint inhibitors work. These drugs are by and large working on the microenvironment of pancreatic cancer, which is typically not immunogenic, and trying to convert that into an immunogenic microenvironment, so that adding drugs like immune checkpoint inhibitors work. This is work that’s currently ongoing.

We talked about BRCA1/2 mutations, but that can be also extended to other gene mutations involved in the DNA repair pathways. If you can target them, you can also get some very interesting drug activity, and that’s something that is currently being developed. One of the challenges of that is to identify which patients have the phenotype of an altered DNA repair, based on the altered molecular underpinnings, and trying to target those patients. Apart from using platinum compounds and PARP inhibitors, we have to think of other drugs that can be used in those pathways.

What role do KRAS mutations play in patients with pancreatic cancer?

The other important area that is probably going to be a very hot topic in the coming years will be targeting KRAS mutations. KRAS is an oncogene that is mutated in [approximately] 90% of patients with pancreatic cancer—some people say even more than 90%. But if you think 90% of patients have KRAS mutations, we can say that in most of those patients [KRAS] is a driver of the malignant process. It’s a driver of proliferation, metastasis, drug resistance, microenvironment changes, and lack of immune response. If you can target those mutations, you may be able to change the natural history of the disease.

KRAS itself as a protein has been very difficult to target. There are a number of reasons for that, but over the past few years, KRAS G12C mutations [have been explored]. Now they can be targeted. There are a couple of drugs out there that can be used in that population. Those patients will respond to the treatment and they can have a prolonged response.

So, the question is, what about the other prevalent [KRAS] mutations? The most prevalent ones are G12D, G12V, and G12R. Here comes the challenge, because drugs are being tested, but we also have to keep in mind the toxicity that goes with it, especially if you have a drug that also targets KRAS wild-type disease. However, we’re not limited to giving drugs targeting the protein or developing drugs targeting proteins. It could be that there are drugs that target the downstream signaling from KRAS, and combinations are being worked on for that. For example, ERK inhibitors with hydroxychloroquine are one example of that, which is working on autophagy.

There are also now vaccines that are being developed for KRAS mutations. There’s a lot of activity around KRAS, and that’s an area that you have to truly keep your eyes on because we think that the yield will be significant.

How do you approach treatment for patients with KRAS wild-type pancreatic cancer?

[Approximately] 10% of patients are KRAS wild-type. These patients are a different story, because 10% of patients being wild-type translates into [approximately] 6000 patients a year in pancreatic cancer in the United States. Those patients have other opportunities, because with KRAS wild-type, those patients can have other mutations that are prevalent. Now, remember simple biology. You need something to drive a cell. When you don’t have the KRAS [aberration] and the cell has become malignant, it means that there’s something else that has driven it. And we know some of those genes now. Some of those genes are targetable. Examples are HER2, BRAF, NRG1, NTRK mutations, or even microsatellite instability, which is seen more in those patients.

At the 2022 ASCO Annual Meeting, the phase 3 NOTABLE trial [NCT02395016] tested the anti-EGFR monoclonal antibody [nimotuzumab combined with gemcitabine] in patients who have KRAS wild-type pancreatic cancer. That study showed benefit with the combination in that population. If you compare that with older phase 3 trials [that evaluated] cetuximab [Erbitux] or erlotinib [Tarceva], the benefit was either marginal, like with erlotinib, or there wasn’t benefit at all, like with cetuximab. But those [trials] were done in all-comers, and all-comers [comprised] 80% to 90% of patients who had KRAS mutations.

Focusing on KRAS wild-type disease, we’re seeing some activity [with certain therapies], so that’s something. Ultimately what it means is that patients who have pancreatic cancer need to be molecularly profiled, and this includes both germline [BRCA] mutations because of the FDA-approved olaparib, and the use of cisplatin or carboplatin in those patients, which is scientifically well supported.

If you go a step further to identify patients who have KRAS wild-type disease, those patients can also be treated with targeted therapy. So, it’s very interesting. We need to do this [testing]. We need to look at BRCA1/2 mutations, but you also need to look at the KRAS mutation status, and if the KRAS status is wild-type, then you need to start digging for other potential targetable mutations in this disease.

What are some intriguing therapies under development for pancreatic cancer?

One interesting trial was the phase 3 SEQUENCE trial [NCT04229004], presented at the 2022 ASCO Annual Meeting, using sequential nab-paclitaxel [Abraxane]/gemcitabine followed by modified fluoropyrimidine, leucovorin, and oxaliplatin [mFOLFOX6] in the frontline setting. This was compared with nab-paclitaxel/gemcitabine alone, like we use in standard care. This study alternated 2 regimens. Patients were given alternate sequences in the experimental arm, and it showed that there was a benefit in terms of [progression-free survival and overall survival (OS)] in patients who got the alternate treatment regimen. It’s something that’s interesting to keep in mind.

In terms of KRAS mutations, you have 2 drugs that are active for KRAS G12C mutations. One is sotorasib [Lumakras], and the other is adagrasib [MRTX849]. Both drugs have been tested in a small number of patients and not in large, randomized trials because G12C mutations represent only 2% of mutations in pancreatic cancer. For that reason, we don’t see large trials [in that population], Nevertheless, these drugs have shown activity.

The question now becomes, do we have any other good KRAS-targeting drugs or even pan-KRAS–targeting agents? In terms of other classes of drugs that can work around KRAS, one would be SHIP2 inhibitors, and another would be SOS1 inhibitors. There is a lot of activity going on there, in addition to what I mentioned earlier regarding vaccines. In the New England Journal of Medicine, there was an article about a T-cell receptor gene therapy targeting neoantigen. It was not a large trial. It was one patient, but there were very interesting signals. So hopefully these things will be going forward.

We talked about KRAS mutations and wild-type mutations. [The NOTABLE trial] was done when we were not using much of the combination of gemcitabine/nab-paclitaxel, so [the trial] was done when it was probably mostly single-agent gemcitabine. And that’s the reason why the combination was as such. And in NOTABLE, which compared placebo or nimotuzumab plus gemcitabine, the combination showed benefit, and the median OS improved from 8.5 months for gemcitabine alone to 10.9 months for the combination. I don’t know what’s going to happen to this drug, but we have an active agent that we can think about.

What other mutations could serve as potential targets?

Rare mutations can be seen in patients with KRAS wild-type disease, [including] NRG1 mutations. There was the phase 1/2 eNRGy trial [NCT02912949] by Alison Schram, MD, from Memorial Sloan Kettering Cancer Center, in patients with the NRG1-mutated [solid tumors] using a drug called zenocutuzumab. It showed activity in patients with advanced disease who were previously treated.

P53 mutations and tumor suppressor gene mutations are quite common in pancreatic cancer. They’re probably the second [most common] mutations after KRAS mutations. But tumor suppressor gene mutations are notoriously difficult to target. There was a study—it wasn’t only in pancreatic cancer—using a drug called PC14586, which is a small molecule, and there are some interesting signals there in patients with pancreatic cancer, which is worth also keeping in mind. If this really holds true, then that’s going to be a major breakthrough in this disease.

As I mentioned earlier, molecular profiling, whether it’s somatic, germline, or both, has to be considered in every newly diagnosed patient with pancreatic cancer. Even in localized disease, there is at least 1 ongoing trial looking at the addition of olaparib in the adjuvant setting in patients who have received adjuvant treatment for 6 months, patients who have BRCA1/2 or PALB2 mutations. Treatment is becoming more personalized, but unfortunately, we’re way behind non–small cell lung cancer, which went fast ahead of us, but we’re getting there.

Are there any other noteworthy agents emerging in pancreatic cancer?

S-1 is a drug that has gone through initial testing in a pilot phase 2 trial, and it was interesting. [It] facilitates the delivery of chemotherapy into the tumor. This drug is now being tested in a randomized trial outside of the United States and there’s a proposed trial to happen in the United States.

Finally, there is a target for claudin18.2 [CLDN18.2], and maybe you’ve heard about this more in clinical trials for patients with gastric cancer. CLDN18.2 is overexpressed in around 15% to 20% of patients with pancreatic cancer, and there are studies trying to target it. There’s a drug called zolbetuximab [IMAB362] that’s being tested in addition to chemotherapy. And there are also other strategies, such as CAR T cells using CLDN18.2 and other approaches.

What do these developments and emerging therapies mean for the future of pancreatic cancer?

There are emerging strategies to target KRAS mutations, which for decades has been a challenge in treating this disease, and gradually, we’re coming into drugs and strategies that we hope are going to be successful. KRAS wild-type patients represent a group of patients who may have other targeted mutations, but at this time, they can also possibly be targeted by an anti-EGFR strategy that has failed in the past. In the past, we did not differentiate between KRAS wild-type or mutations, but now if we can look at care for patients with KRAS wild-type disease alone, then we can probably benefit them by giving anti-EGFR treatment, which is similar to what we do in colon cancer. We don’t give anti-EGFR treatment in patients who have KRAS mutations. They are only for patients with KRAS wild-type disease, so maybe you can do the same thing in pancreatic cancer and see some benefit.

There’s work being done on the microenvironment in the form of a number of strategies, looking at enhancing the immune response targeting CLDN18.2 or using a drug like S-1 to help other drugs to go along and be delivered to the tumor cells. Delivery to tumor cells is also a challenge because the microenvironment being as dense, as fibrotic, and as hypovascular as it is, is a challenge for delivering drugs to the microenvironment.

Reference

1. Philip PA. New treatment options in pancreatic cancer. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancer; June 29, 2022-July 2, 2022; Barcelona, Spain.