Adagrasib Shows Promise in Treating KRAS G12C-Mutated GI Malignancies


In an interview with Targeted Oncology, Tanios S. Bekaii-Saab, MD, explained how adagrasib works to target KRAS mutations as well as its importance.

While some agents have indirectly affected KRAS mutations in various cancers, it was not until recently that agents specifically created to target KRAS mutations made it to testing.

One of these agents is adagrasib (MRTX849), an investigational and highly selective oral small-molecule inhibitor being examined in the treatment of patients specifically harboring the KRAS G12C mutation.

A phase 1/2 KRYSTAL-1 trial (NCT03785249) reviewed the dose escalation of adagrasib to determine the maximum-tolerated dose to be 600 mg twice a day. Throughout each phase, adagrasib showed promising clinical activity in previously treated patients with advanced or metastatic solid tumors who had a KRAS G12C mutation.

In an interview with Targeted OncologyTM following the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI), Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, explained how adagrasib works to target KRAS mutations as well as its importance.

Targeted Oncology: Can you explain the importance of KRAS as a biomarker to date? In which gastrointestinal cancer (GI) are these mutations most prevalent?

Bekaii-Saab: KRAS is one of the major drivers in cancer overall. The prevalence really depends on the disease. For example, in pancreas cancer, 90% of the mutation of KRAS is thought to be a driver. Then in colon cancer, about 45%, and in other cancers like gastric or esophageal, it's actually a small percent, less than 5%, so it really depends on the disease. One cannot overemphasize the importance of KRAS.

As I said, in the pancreas specifically, it's 90%. You start breaking those down also by subgroup, and the most common is KRAS G12D, G12V, and G12C which for GI cancers is anywhere between 2-3% of all KRAS mutations. KRAS G12C ends up being one of the rare KRAS mutations but it was the first to target.

Can you provide a brief overview of the presentation given at ASCO GI?

The phase 2 cohort that we presented at ASCO GI used a dose of adagrasib at 600 mg twice a day. The study basket included 42 patients, but I presented on the 30 patients that had GI tumors other than colon cancer, primarily pancreas cancer, biliary cancer, and other GI cancers. There were 12 patients with pancreas cancer and there were 18 patients with other GI cancers. Most of these patients had a poor performance status. The median prior therapies were 2 and ranged between 1-5. These were patients that were for the most, treated with 2 or more lines of therapies.

What was interesting is that when we looked at the response rate with pancreas cancer, it was 50% in the cohort of patients that was evaluable for response, and there was 100% disease control rate, meaning none of these patients had progression at the time of analysis. For the other GI cancers, there was 35% for the response rate, and 100% for the disease control rate. Across all the GI malignancies, there were essentially no patients who progressed and about 40% plus of the patients had a response. When you look at the pancreas, the median immediate progression free survival was 6.6 months and the patients continued on treatment with the other GI tumors, the median PFS was almost 7.9 months, and about two thirds of the patients continued on treatment.

When you look at the other GI cancers, the majority were actuall biliary tract cancer, cholangiocarcinoma, and again, there were about half of the patients who had actual responses. Interestingly, this is a relatively well tolerated agent. Most of the toxicities were grade 1 and 2, there were no grade 4 or 5. The ones that were grade 3 were primarily fatigue QT prolongation but none of them led to discontinuation.

Before adagrasib, what drugs have been used to treat patients with KRAS G12C mutations?

The whole area of targeting KRAS is recent. For the longest time, there were no agents. We only had some agents that indirectly may affect the mitogen-activated protein kinase (MAPK) pathway downstream, such as MEK inhibitors and developing drug inhibitors and others. The 2 agents that made it to first being tested, targeting KRAS, specifically KRAS G12C, are sotorasib (Lumakras) and adagrasib. Those are very specific to KRAS G12C.

Sotograsib and adagrasib were developed in parallel by two different companies, but more are being developed right now in the same space by others. This area is becoming very active for a specific agent. Sotograsib is in lung cancer and being tested in a variety of different cancers expressing G12C, from GI to ovarian. The same with adagrasib which is being developed in various malignancies, most advanced moving into lung and colorectal. The data I presented is in other GI malignancies.

What sets adagrasib apart from other KRAS inhibitors?

Adagrasib has shown quite a bit of target inhibition and essentially a rest of growth and shrinkage in a variety of preclinical models that are driven by KRAS G12C, which really set the tone for developing this agent in clinical trials.

It is difficult to compare different agents. When you think about the KRAS protein, the KRAS protein cycles between guanine triphosphate on and guanosine diphosphate (GDP) off, and it cycles every 24 hours. Adagrasib covalently binds to KRAS G12C. It is an irreversible inhibitor, so it sticks, and you cannot just get it off. It selectively binds KRAS G12C to it's inactive GDP and keeps it in the inactive state.

Now, the next thing about adagrasib is that it's optimized for the desired properties of the KRAS G12C inhibitor. You need a longer half-life and its recycling takes about 24 hours. It sticks around through the lifetime of this resynthesis. It has those dependent decays so we understand, predictably, how the dose relates to pharmacokinetics.

Although it's not as relevant for my practice, for the brain cancer practice, it actually does have central nervous system (CNS) penetration. It goes through the blood brain barrier. With adagrasib, because of its long half-life and how it targets KRAS G12C, it enables the inhibition of KRAS dependent signaling for the complete dose interval. When you think about how it works, it maximizes the depth and duration of an entire human activity. I think it is pretty successful in terms of showing a variety of cancers so far.

What unmet need do you hope to fill if KRYSTAL-1 is a positive study?

KRYSTAL-1 is a study that's built as a phase 1, phase 1B and phase 2 study. The key criteria for entry on the study is essentially to have a KRAS G12C mutation. Phase 1 was essentially dose escalation that primarily looked at trying to determine the maximum tolerated dose, 600 mg twice a day. That ultimately went into expansion and included some rational combinations. Phase 2 was monotherapy and combination. Phase 1B for example, had an added grasp for all solid tumors and for brain metastases, since it has that CNS penetration. They looked at lung cancers, both treatment naive and those that were exposed to prior KRAS G12C.

In colon cancer, these G12C inhibitors don't appear to have much activity on their own. That is because of a feedback loop mechanism that essentially creates that adaptive resistance and activates EGFR. In colon cancer, most of the follow through development was with adagrasib and cetuximab (Erbitux), which is what's being developed right now in a large study called KRYSTAL-10, a phase 3 randomized study looking specifically at adagrasib plus cetuximab plus chemotherapy in second line colon cancer.

In pancreas cancer, they expanded from a single agent which is still ongoing but also to look at cetuximab plus. The phase 2 had a single agent in colon cancer plus cetuximab in colon cancer, then pancreas cancer plus cetuximab. The data I presented was on the other solid tumor basket. At the time, we presented with 42 patients with adagrasib, a single agent, and then there are lung cancer lung cancer cohorts, both single agents and one that includes the SDK11 mutations. There’s quite a bit of data that has been presented prior to the presentation I did at ASCO GI that included showing activity in lung cancer, colon cancer, the few patients with pancreas, ovarian, endometrial, phalangeal, you name it. Every cancer where this agent has been looked at, as long as they harbor the KRAS G12C mutation, there has been evidence of activity.

What information do you hope to obtain for the purposes of future research?

In this particular study, we continue to accrue patients with pancreatic cancer and other GI cancers based on the initial interesting activity. With other cancers as well as where there has been activity. There are developments in lung cancer specific for lung cancer, for colon cancer plus an EGFR inhibitor, for pancreas cancer a single agent plus EGFR inhibitor. The study itself is ongoing. Others have been developed based on the findings from the study, and then there's also an early access probe program for this patient population that's included in KRYSTAL-1 for those who don't have access to the study itself.

The other thing that we're excited about is that Mirati has continued the development of other KRAS inhibitors, and one of those candidate agents is a KRAS G12CD, one of the most common KRAS alterations. That's just entering into phase 1 and it's very exciting because in pancreas cancer, that is the majority of patients. If we see some of the signals that we're seeing with the G12C along with the G12D, that is going to be amazing for our pancreas cancer patients. That is going to be a game changer since we hit the plateau with chemotherapy, and that’s also true for other cancers. With colon cancer along with EGFR inhibitors, we're seeing some unique responses. I think the near future is incredibly exciting with adagrasib and similar agents that are targeting KRAS.

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