NGS and ctDNA Testing Guide Treatment Selection and Sequencing in mCRC

Cathy Eng, MD, FACP, FASCO

In an interview with OncLive® regarding her presentation at the 42nd Annual Chemotherapy Foundation Symposium (CFS) Symposium, Cathy Eng, MD, FACP, FASCO, shared insights on biomarker testing and sequencing strategies for patients with colorectal cancer (CRC); delved into clinically relevant data from the phase 3 CheckMate-8HW (NCT04008030) and MOUNTAINEER-03 (NCT05253651) trials; and explained how results from next-generation sequencing (NGS) and circulating tumor DNA (ctDNA) assays can inform treatment decisions for her patients with CRC.

“The most important take home point for any patient with metastatic disease is that you definitely need molecular sequencing completed,” Eng explained. “NGS is recommended as standard of care as soon as [the patient is] diagnosed. This way, we can identify basically any potential molecular markers that may have an impact on treatment and the sequence of therapy.”

Eng serves as the David H. Johnson Endowed Chair in Surgical and Medical Oncology, a professor of medicine, Hematology and Oncology, the director for Strategic Relations, the co-director of Gastrointestinal (GI) Oncology, co-leader of the GI Cancer Research Program, and the director of the Young Adult Cancers Program at the at Vanerbilt-Ingram Cancer Center in Nashville, Tennessee.

OncLive: What clinical trials in the CRC landscape did you discuss in your presentation and how do these data influence clinical practice?

Eng: My talk was largely focused on the microsatellite instability–high patient population in the metastatic setting. We know pembrolizumab [Keytruda] is currently FDA approved [for these patients], but there [has been] some recent data with the combination of nivolumab [Opdivo] and ipilimumab [Yervoy] demonstrating superiority over chemotherapy for newly diagnosed, mismatch repair–deficient patients with CRC. This [regimen] has showed an improvement in progression-free survival vs systemic chemotherapy. We do not have the data for nivolumab plus ipilimumab vs nivolumab alone. Everyone is waiting for those data.

I also highlighted some trials evaluating the role of immunotherapy in the neoadjuvant setting of locally advanced CRC and rectal cancer. [This includes] updated results [with] dostarlimab-gxly [Jemperli], with longer-term follow-up still demonstrating a 100% clinical response; these data [are being validated] in the ongoing phase 2 study [NCT04165772].

There were some very interesting data [presented during] the 2024 ESMO Congress investigating the combination of nivolumab and ipilimumab for T3/T4 or node-positive patients [with early-stage colorectal cancer in the CheckMate-8HW trial] We also assessed the role of LAG3 in combination regimens for patients with early-stage colon carcinoma. An impressive clinical pathologic complete response and overall major pathologic response [was reported]. That is very, very interesting. An ongoing study is evaluating the role of dostarlimab in early-stage dMMR colon carcinoma.

I highlighted updates from the phase 2 MOUNTAINEER trial [NCT03043313] to remind everybody that the phase 3 MOUNTAINEER-03 trial is open for those patients who have HER2-positive, newly diagnosed metastatic CRC. The role of fam-trastuzumab deruxtecan-nxki [Enhertu], which is an antibody-drug conjugate [ADC], was largely tested in patients who had been previously treated with HER2 therapy in the past. This gives us the option of using this ADC. [T-DXd] just received an agnostic approval in April of this year. [However], interstitial lung disease is still an issue for our patient population, and we have to be cognizant of that.

Last but not least, I touched upon sequencing, which is a question I always get in the refractory setting. Which combination or drug do I prefer? Do I use regorafenib [Stivarga]? Do I use trifluridine and tipiracil [Lonsurf] plus bevacizumab [Avastin], or do I use fruquintinib [Fruzaqla], which also was just FDA approved in November 2023.

It's important to have a discussion with the patient [about] potential adverse effects [AEs] associated [with these agents], because they each have different AEs. At the end of the day, all our patients, if they're doing very well and their performance status and laboratory tests are within normal limits, are going to end up receiving the majority of those drugs anyway.

Overall, I don't necessarily think one [agent] is superior to the other, but they have different AEs, [which I] keep in mind.

In which patient populations have you found treatment with T-DXd to be most beneficial or appropriate since the agent’s tumor agnostic approval?

I've used T-DXd for patients who previously received HER2-targeted therapy. They may have received tucatinib [Tukysa] and trastuzumab [Herceptin] already. That's the way the [phase 2 DESTINY-PanTumor02 (NCT04482309)] was designed; it allowed patients to have prior [exposure to] HER2-targeted drugs, and I think that's the most appropriate patient population to use it in.

I am also going to start using [T-DXd] for a patient with a HER2 mutation, which is not very common [in CRC] by any means, but T-DXd [could provide] additional benefit.

What role do you see for ctDNA testing in the management of colorectal cancer, and how might its application evolve with ongoing research and trials?

ctDNA testing is of great interest in multiple malignancies. It probably has the greatest history of being evaluated in CRC, largely in the metastatic setting. There are several ongoing trials looking at including ctDNA as part of their correlative work. Whether or not we're going to allow it to serve as a primary end point moving forward [is uncertain]. I don't think the FDA is there yet. We would like to see them consider that moving forward.

There is a lot to do with ctDNA that can benefit the patient. In a setting where the patients had a liver resection or a metastatic resection, there are ongoing trials in stage III CRC, but the science continues to evolve. That's where we have to be very careful, because by the time we design and complete a clinical trial, several years have passed. We need to make sure our platform is the most appropriate platform.

It's important to keep in mind that ctDNA is detected more easily in patients with liver metastasis vs a patient with lung metastasis or peritoneal metastasis. The site of the metastatic location and size of the site of involvement [affects] whether ctDNA will be detected.

ctDNA is an additional tool that I utilize in my practice. [I do] not [utilize it] for all my early-stage patients, but I will use it for some, especially those who don't go onto a clinical trial, though I do encourage clinical trial participation.

The [observational] GALAXY study [UMIN000039205] from the Japanese group has provided us with some very interesting information [on the prognostic value of ctDNA]. Their most recent paper looked at the role of ctDNA following liver resection and whether adjuvant therapy is warranted. There is a lot more information [we need] to collect, but it's reasonable to consider [ctDNA] as one of our tools when we’re evaluating patients and considering next options.

What is the importance of NGS for patients with colorectal cancer?

NGS is critical for all our patients. If a patient has not had NGS completed already, it needs [to happen as soon as possible], because it helps us make decisions about whether they could go on a clinical trial. It helps us make decisions about sequencing. It helps us to provide them with the best information possible regarding their prognosis and overall outcome.