Exploring Advancements in Targeting KRAS in Cholangiocarcinoma

In an interview with CancerNetwork® about the 2026 Chicago Cholangiocarcinoma Symposium, Chih-Yi “Andy” Liao, MD, discussed the core message of his presentation on targeting KRAS in cholangiocarcinoma, why KRAS has been slower to gain traction in this disease than FGFR2 and IDH1, and how the distribution of KRAS mutations in biliary tract cancer shapes drug development. He reviewed early clinical data for KRAS G12C and G12D inhibitors, outlined a practical molecular testing approach for community oncologists, and described how his program coordinates multidisciplinary care. Liao also discussed the challenge of early detection, the key messages he wants the broader oncology community to take from the symposium, and his perspective on the recent FDA approval of lirafugratinib in previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma.¹

Liao is an associate professor of Medicine, associate director of Gastrointestinal Oncology, and co-director of the Neuroendocrine Tumor program at University of Chicago School of Medicine. He works within the multidisciplinary liver tumor program alongside colleagues in hepatology, transplant surgery, and interventional radiology.

CancerNetwork: You spoke at the 2026 Chicago Cholangiocarcinoma Symposium about targeting KRAS in cholangiocarcinoma. What was the core theme of your presentation?

Liao: Thank you for having me. It definitely is a very exciting time to be giving this talk. The key takeaway message is that targeting KRAS for cholangiocarcinoma is now a reality. For more than 40 years since the KRAS gene was discovered, we haven’t found a way to target it until now, and we’ve seen some preliminary data on KRAS inhibitors for cholangiocarcinoma that look very promising. Of course, we’re awaiting further clinical trial results. We also explored other strategies beyond small molecule inhibitors, such as autophagy inhibition, T-cell engagers, T-cell receptor–based T-cell therapies, and even cancer vaccines. The key takeaway is that KRAS targeting is here, and we are very excited for this new era and looking forward to what the clinical trials will show for patients with cholangiocarcinoma.

Most of the attention, historically, in cholangiocarcinoma has been on targets such as FGFR2 and IDH1. Why has KRAS been slower to move in this disease?

It’s mainly because, for the longest time, we didn’t have any KRAS inhibitors that were successful in the field. It wasn’t until 2021 that the very first KRAS inhibitor, sotorasib [Lumakras], was approved in lung cancer.² Since then, the field has learned many lessons from the first-generation KRAS G12C inhibitors to design next-generation molecules. Most of these have focused on other diseases such as lung cancer, pancreatic cancer, or colon cancer, where KRAS mutations are perhaps more prevalent or more relevant to practice. It wasn’t until relatively recently, in the past few years, that it caught on in cholangiocarcinoma.

The KRAS landscape in biliary tract cancer skews toward G12D and G12V rather than the G12C that drove early KRAS inhibitor approvals. What are the implications for cholangiocarcinoma specifically? Are multiselective RAS(ON) inhibitors a realistic near-term option for these patients?

KRAS mutations come in different forms. For patients with biliary tract cancer who have a KRAS mutation, the most prevalent one is KRAS G12D. Of patients who have a KRAS mutation, 41% have the G12D mutation, and 23% have the G12V mutation. KRAS G12C is only 6% of KRAS-mutant biliary tract cancers, and 30% of patients have a different KRAS mutation. Now, KRAS G12C inhibitors were the first to come to market because that was the one we discovered how to target first. There has definitely been a lot of exciting phase 2 data. For example, adagrasib [Krazati], a KRAS G12C inhibitor, is now listed in the NCCN guidelines as a treatment to consider for patients with cholangiocarcinoma whose tumors have the KRAS G12C mutation. That’s based on the KRYSTAL-1 study [NCT03785249], which showed a response rate of 41.7%, which is pretty impressive for second-line therapy in cholangiocarcinoma.³ However, if you look at all biliary tract cancers, only 1% of them have the KRAS G12C mutation. How do we target these other, more common mutations such as G12D? Now, we finally have some data in cholangiocarcinoma with small molecule inhibitors for KRAS G12D.

As for your question about the multi-selective RAS(ON) inhibitors, KRAS inhibitors come in many different forms. You can have mutant-selective KRAS inhibitors, for example G12C inhibitors, which can target the OFF state or the ON state. You can have pan-KRAS inhibitors, which can target any KRAS mutation. Then, you have these tri-complex inhibitors that target RAS in the ON state. They can either be selective for a single mutation, or they can be multi-RAS inhibitors, for example targeting KRAS, HRAS, and NRAS. One example of this type of drug is daraxonrasib [Rasonque], which has recently generated a lot of excitement, as it was approved for pancreatic cancer and totally revolutionized the treatment landscape for that disease. It’s the most common question I get nowadays, including in the past few weeks.

What are some of the most relevant KRAS agents in cholangiocarcinoma?

Right now, we don’t have a lot of data, but there are some early-phase trials that have read out. For example, the KRYSTAL-1 study of adagrasib that we talked about had a response rate of 41.7%, which is very promising. Another is divarasib. There is a phase 1/2 study that was presented at [the 2025 European Society of Medical Oncology (ESMO) Congress]; for patients with biliary tract cancer, the response rate was 23%, and [median] progression-free survival was 7.2 months.⁴ Another is calderasib [MK-1084], based on the phase 1 KANDLELIT-001 study [NCT05067283], which was also presented at ESMO last year and showed a response rate of 64% for cholangiocarcinoma.⁵ These are all KRAS G12C inhibitors, and KRAS G12C is really the minority. Only a minority of patients with biliary tract cancer have this mutation.

KRAS G12D is the most common KRAS mutation that we see in biliary tract cancer, and it was only very recently, at [the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting] a few months ago, that we got the first clinical trial data, from a phase 1/2 study [NCT06500676] conducted in China, for a drug called GFH375, which is being developed in the US as VS-7375.⁶ This is a KRAS G12D ON/OFF inhibitor. We learned preliminary phase 1/2 data. They treated 20 patients in this cohort, and the response rate was 40%, including 1 patient with a complete response, and the median progression-free survival was 6.2 months. These are very exciting data that tell us these KRAS inhibitors can definitely work in cholangiocarcinoma, but the clinical trials are just getting started, so we encourage all our patients to participate in these trials.

Cholangiocarcinoma has become a dense setting for targets. For a community oncologist who sees only a few patients with cholangiocarcinoma a year, what does a practical molecular testing approach look like?

I can’t emphasize enough that every patient with cholangiocarcinoma should have molecular profiling. I usually get it as soon as I meet the patient, ideally from tissue, but it’s sometimes hard to get tissue, and if that’s the case, using ctDNA approaches may also be reasonable. That’s because about 40% of patients with biliary tract cancer will have tumors with targetable alterations, including all these genes we talk about: FGFR, IDH1, BRAF, TRK, and HER2, and now KRAS is targetable too. It’s important not to miss this because this could be a great potential treatment option for our patients.

Where is multidisciplinary coordination most important in cholangiocarcinoma, where does it break down most frequently, and how does your program address that?

Here at the University of Chicago, we have a multidisciplinary liver tumor program. That’s a joint venture between us in medical oncology, but also hepatology, transplant surgery, and interventional radiology. Every Monday afternoon, we have clinic together, so we physically go in and see the patients together. It’s a very crowded room for the patients, but it’s great because it’s 1-stop shopping, rather than referring a patient to 3 different specialists. That can cause a lot of back and forth, but it can also delay the patient’s care, and we don’t want that, especially in cholangiocarcinoma, which is a fast-moving cancer. We want to expedite treatment as much as possible. We also have a multidisciplinary tumor board on Thursday. Usually, in advance of the Monday clinic visit, we will have discussed the patient’s case at the tumor board, so that on Monday, we come up with a cohesive plan to tell the patient. That’s important for cholangiocarcinoma—this multidisciplinary collaboration. There are definitely roles for systemic therapy, but also roles for locoregional therapies such as liver-directed therapy and surgical approaches such as resection and liver transplant. During the conference, we had a multidisciplinary tumor board, which simulates what we do behind the scenes for these patients, where all of us get together to discuss the patient’s case and discuss how best to approach their treatment.

Cholangiocarcinoma is hard to diagnose early on. What does a realistic early detection future look like, and is there anything in the research pipeline that gives you optimism?

Unfortunately, like you said, we don’t have a reliable screening test, like colonoscopy for colon cancer or mammograms for breast cancer. We don’t have that for cholangiocarcinoma, and oftentimes, by the time patients develop symptoms and get diagnosed, their cancer is already advanced, so we wish we had a better tool for early detection.

What does the broader oncology community, including clinicians who aren’t GI specialists or don’t see many patients with cholangiocarcinoma, need to understand about where this disease stands today and when to refer?

For the broader oncology community, there are 2 main take-home messages. One is that treating this disease really requires a multidisciplinary approach. We and other places that have these multidisciplinary programs are all here to help and collaborate with our community oncology partners. Refer patients to us as early as possible so we can see if there are multidisciplinary options, for example, if locoregional therapies like surgery, transplant, or liver-directed therapy would benefit these patients in addition to systemic therapy. The second message is that molecular profiling is super important. Everyone with cholangiocarcinoma needs to have one.

Now that the symposium is over, what other presentations from your colleagues did you find interesting, and are there any topics you think will gain more momentum in this disease’s care?

I think some of the interesting ones include [Ethan Ludmir, MD’s] presentation on the role of radiation. He presented a lot of useful data, and we have many different locoregional therapy options for these patients, so knowing the data behind them really helps us with treating our patients. Same with [Robert Lewandowski, MD’s] talk on interventional radiology and what they can offer. [Joseph Franses, MD, PhD], also gave us an update on the new systemic therapy approvals in 2026 for cholangiocarcinoma, which is always very exciting.

The FDA recently approved lirafugratinib, the third FGFR2 inhibitor in cholangiocarcinoma. What are your thoughts on the agent?

We were part of the clinical trial that led to the approval... so we’re super excited to have yet another FDA approval for cholangiocarcinoma. That’s always a win for our patients, and now we have 3 FDA-approved FGFR inhibitors on the market. We can look at each of the individual trials and the data separately. We can’t compare them head to head because they’re different patient populations, and these drugs are all slightly different. But all of them show efficacy for [FGFR2 fusion-positive] cholangiocarcinoma, so I think they all have a place in our clinical practice and in our research. We’ve learned a lot more since the first FGFR inhibitors came out about how tumors become resistant to FGFR inhibitors. One of the mechanisms is that they can acquire additional mutations called gatekeeper mutations in the FGFR2 molecule, and so some of these next-generation drugs, like lirafugratinib, were designed with this in mind to overcome some of these resistance mutations.

If a patient comes to you with this indication, previously treated, what are you giving first among pemigatinib (Pemazyre), futibatinib (Lytgobi), and lirafugratinib? Do you have a ranking or a sense of when you would give one over another?

In terms of efficacy, before lirafugratinib was approved, the progression-free and overall survival numbers for futibatinib technically looked a little better than the phase 2 FIGHT-202 study [NCT02924376] with pemigatinib. A lot of oncologists I’ve seen are using futibatinib first. But I’ve also seen the other camp, where they use pemigatinib first, because futibatinib has potential activity to overcome some of these resistance mutations for tumors that have progressed on other FGFR inhibitors. Oncologists always like to have a backup plan, right? I’ve seen oncologists use pemigatinib first and futibatinib second because it may be active after pemigatinib.

Lirafugratinib is kind of the same situation, where it was designed with this in mind to overcome these resistance mutations, so perhaps after progression, let’s say on pemigatinib, it would still be active. These data were presented previously at ASCO. I could potentially see using pemigatinib first and, upon progression, using lirafugratinib.

Now, [in terms of] adverse effects, these drugs are also slightly different. They all cause FGFR2-class adverse effects, like hyperphosphatemia, [ocular] toxicity, [nail] toxicity, and things like that, but the degree is different. From my patients’ personal, subjective experiences, lirafugratinib is probably the hardest to tolerate, but that’s just what former patients have told me. It’s always a balance between the benefits and the toxicities.

References

1. FDA approves lirafugratinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. News release. FDA. September 23, 2026. Accessed September 28, 2026. https://tinyurl.com/mst6kcav
2. FDA approves LUMAKRAS™ (Sotorasib), the first and only targeted treatment For patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. News release. Amgen. May 28, 2021. Accessed September 28, 2026. https://tinyurl.com/5pntr6b7
3. Pant S, Yaeger R, Spira AI, KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082
4. Krebs MG, Lee C-H, Ami EB, et al. Single-agent divarasib experience in patients with KRAS G12C-positive pancreatic adenocarcinoma (panc), cholangiocarcinoma (cholangio), and other solid tumors. Ann Oncol. 2025;36(suppl 2):S569-S570. doi:10.1016/j.annonc.2025.08.1496
5. Simonelli M, Rojas CI, Dziadziuszko R, et al. MK-1084 monotherapy in participants (Pts) with KRAS G12C–mutated advanced solid tumors: activity and safety in the phase I KANDLELIT-001 study. Ann Oncol. 2025;36(suppl 2):S568-S569. doi:10.1016/j.annonc.2025.08.1495
6. Zhu L, Deng Y, Zong H, et al. Preliminary efficacy of GFH375 in patients with advanced cholangiocarcinoma or colorectal cancer harboring KRAS G12D mutation. J Clin Oncol. 2026;44(suppl 16):3008. doi:10.1200/JCO.2026.44.16_suppl.3008