Liquid Biopsy Screening Protocol Aims to Identify Actionable Targets in mCRC

Kristen Ciombor, MD, MSCI

The rise of precision medicine in the metastatic colorectal cancer (mCRC) paradigm has led to more tailored treatment approaches; moreover, the goal of the ongoing COLOMATE study is to identify actionable targets to improve outcomes, said Kristen Ciombor, MD, MSCI.

For COLOMATE (NCT03765736), a phase II umbrella screening protocol, investigators are utilizing the blood-based next-generation sequencing panel Guardant360 in patients with mCRC to detect actionable molecular alterations and assess the impact of corresponding targeted therapy through its individual companion studies.

In order to be eligible for enrollment, patients with mCRC must have progressed on, been unable to receive, or had a contraindication to standard treatment with a fluoropyrimidine, oxaliplatin, irinotecan plus bevacizumab (Avastin), or anti-EGFR therapy if RAS wild-type. The study is sponsored by Academic and Community Cancer Research United (ACCRU) to screen patients with liquid biopsies in order to identify potential treatment arms.

“We have a dynamic companion trial architecture in terms of the COLOMATE screening protocol so that patients can be identified and may be able to enroll in the companion arm of the study,” said Ciombor, lead investigator of COLOMATE and an assistant professor of medicine at Vanderbilt University Medical Center.

After patients undergo a liquid biopsy, they are identified for basket trials under the umbrella protocol. These companion studies are currently available for patients with tumors that are RAS wild-type, BRAF wild-type, HER2 amplified, FGFR altered, and RAS mutated, as well as those without any known actionable alteration.

“We expect accrual to happen quickly, and we have an excellent team [calculating] the statistics and analyzing the data,” added Ciombor. “We are looking at a lot of correlatives in terms of trying to identify patterns of primary resistance or acquired resistance. We are also looking at the patients who are responding to therapy so that we can better understand why they are responding.”

In an interview with OncLive during the 2019 AACR Annual Meeting, Ciombor discussed the promise of liquid biopsies in the rapidly evolving mCRC paradigm and the potential implications of the COLOMATE trial.

OncLive: What does the current treatment landscape for patients with mCRC look like?

Ciombor: Patients with mCRC have a plethora of options available in terms of systemic therapies. However, eventually, mutations and resistance arise, and we run out of treatment options for those patients. Therefore, we are always looking for new treatments, particularly as patients have more opportunities to receive treatment over the years of their life. Lately, we have seen many advances made in the genomic space, and that is where our abstract really comes into play in terms of identifying patients who may most likely respond to therapies that are molecularly assigned.

What is the utility of liquid biopsies in mCRC?

Traditionally, in the last decade, we have done a lot of tissue-based molecular profiling. Technology has really advanced so that patients can now undergo liquid biopsies, [which are used to] identify alterations for serial monitoring of their tumors [as a way] to look for patterns of resistance. The field is moving quickly in this space, and it's nice for patients because they don't have to undergo as many tissue biopsies. It's much easier for them to have blood-based profiling. Ideally, we will also be able to monitor their tumors over time with treatments to try to identify mechanisms of resistance.

Could you expand on the hope for the widespread utility of liquid biopsies in this space?

Especially for mCRC, we have a lot of molecularly assigned therapies. If liquid biopsies can identify patients who would be most likely to respond, we might be able to find more prognostic and predictive biomarkers of response. [With those biomarkers], we can more closely tailor therapy in a targeted way.

What are some of the biomarkers that we are using now?

The traditional ones are in the RAS family: KRAS, NRAS, and HRAS. We also know that patients who have microsatellite instability-high CRC are responsive to immunotherapy. Other emerging biomarkers are now HER2 and MET amplification. We are also starting to learn that maybe FGFR is an important driver as well.

Could you provide some background on the phase II COLOMATE trial?

COLOMATE, which is a phase II umbrella screening protocol, is really trying to capitalize on the fact that we have many institutions, both academic and community partners, who see these patients every day in practice. We wanted to see if there was some way to leverage that and try to identify treatment options for patients no matter where they are.

Patients are identified through liquid biopsy and molecular profiling, and then, through the ACCRU network, the patients are identified for different basket trials under the umbrella protocol. Currently, we have several trials that are either in the activation phase or are enrolling patients. These trials include anti-HER2, EGFR rechallenge, FGFR-altered patients, and many others. We also have a big basket for patients who may not currently have any activating alterations. This will hopefully help us find additional treatment options for many patients with CRC who have already received standard therapeutics.

Are there any other ongoing, similar studies that you're particularly excited about?

There are actually several studies now, and ACCRU is leading the charge in that aspect. There are upcoming trials in pancreatic cancer looking at molecular profiling and there are other trials with biliary tract cancers. There is a lot going on in the gastrointestinal space, with trials that are either in development or initial enrollment.

How will liquid biopsies become more widespread in clinical practice?

The real benefit to liquid biopsies is that we can monitor a patient's response in real-time through cell-free DNA. We can also identify whether they are responding earlier than CT scans or other imaging modalities. We will hopefully be able to identify mechanisms of resistance and then as acquired resistance develops, we can identify, and hopefully, target those mechanisms as well.

What key messages do you want to get across from the COLOMATE trial?

It's important to know that there are many exciting studies ongoing for CRC. COLOMATE is really a novel platform design in which patients can be identified and enrolled on trials in a nice geographic distribution so that they perhaps don't have to travel as much. These patients can receive novel therapies and also contribute to the science behind therapeutics of CRC.

Ciombor K, Ou F-S, Dodge A, et al. COLOMATE: colorectal cancer and liquid biopsy screening protocol for molecularly assigned therapy. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract LB-235/14. abstractsonline.com/pp8/#!/6812/presentation/9122.