Wells Messersmith, MD, a physician, division head, and associate director for translational research at the University of Colorado School of Medicine, discusses the potential for fam-trastuzumab deruxtecan-nxki (Enhertu) as a treatment for patients with HER2-positive colorectal cancer (CRC).

trastuzumab deruxtecan was FDA approved in January 2021

 for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma, data regarding its efficacy in patients with CRC is still early on, and the agent has not yet been approved in that patient population, Messersmith says. However, larger clinical trials should bring forth data regarding the agent that could lead to an FDA approval, he adds. 

In the phase 2 DESTINY-CRC01 trial (NCT03384940), which is examining the agent in patients with HER2-expressing metastatic CRC, patients had received at least 2 prior lines of treatment for CRC. Moreover, the trial enrolled patients who have 

 wild-type disease and central confirmation of HER2 expression, Messersmith explains. Additionally, the primary end point for this trial is objective response rate (ORR), while progression-free survival and overall survival are being examined as secondary endpoints.

Current later line options for patients with CRC, such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf), have yielded low response rates remain, Messersmith notes. While it will be important to see data from a more extensive cohort, early data have shown that trastuzumab deruxtecan elicited an ORR of 45.3%, making it a promising option for patients with CRC, Messersmith concludes. 

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Wells Messersmith, MD, discusses the potential for fam-trastuzumab deruxtecan-nxki as a treatment for patients with HER2-positive colorectal cancer. 


Dr. Messersmith on the Potential for Trastuzumab Deruxtecan in HER2+ CRC

Wells A. Messersmith, MD, co-leader of the Developmental Therapeutics Program, and director, GI Cancer Program, and professor of medicine, at the University of Colorado School of Medicine, discusses therapeutic options in metastatic colorectal cancer (mCRC) and what factors help determine the most appropriate option.

Trials exploring first- and second-line treatment strategies in mCRC have been plentiful over the past few years, Messersmith says.

In the first-line setting, bevacizumab (Avastin) has shown a benefit across patient populations. As reported in the phase III CRYSTAL trial (NCT00154102) and the phase III PRIME study (NCT00364013), EGFR inhibitors have also shown benefit in the frontline metastatic setting.

Antiangiogenesis inhibitors like ziv-aflibercept (Zaltrap) and ramucirumab (Cyramza) can also be utilized in the second-line setting.  

Determining which therapy to use in which patient depends on a variety of factors including which side the tumor is on. Notably, right-sided tumors and left-sided tumors have a different embryonic origin and must be treated differently. Moreover, microsatellite status and presence of molecular markers like 

 have to be taken into account, states Messersmith.

Wells A. Messersmith, MD, discusses therapeutic options in metastatic colorectal cancer and what factors help determine the most appropriate option.
 

Dr. Messersmith on Choosing a Treatment Option in mCRC

Wells A. Messersmith, MD, co-leader of the Developmental Therapeutics Program, and director, GI Cancer Program, and professor of medicine, at the University of Colorado School of Medicine, discusses the need for biomarkers to distinguish between VEGF inhibitors in colorectal cancer (CRC).

There is a lack of validated biomarkers for angiogenesis inhibitors in CRC, says Messersmith. There are several drugs that target VEGF, such as bevacizumab (Avastin), or PlGF, such as aflibercept (Zaltrap). Moreover, there are agents that hit VEGFR-2, such as ramucirumab (Cyramza). All these agents can be used in the second-line setting in CRC. The problem is that there are no means of predicting who is going to benefit and who is not going to benefit from these agents.

Right now, it's entirely empirical, says Messersmith. A lot of effort has gone into looking at the soluble levels of potential markers, the microvessel density, and the expression of endothelial cells. However, none of those trials ended up being positive. As such, patients are being treated with the understanding that there is likely some subset that benefits from this approach without any clarity as to who those specific patients are.

Dr. Messersmith on the Need for Biomarkers to Distinguish Between VEGF Inhibitors in CRC

Wells A. Messersmith, MD, co-leader of the Developmental Therapeutics Program, and director, GI Cancer Program, at the University of Colorado School of Medicine, discusses the rise of molecular testing in metastatic colorectal cancer (mCRC).

There has been a shift in which molecular analysis is being done for most cases, says Messersmith. However, not all tests that need to be done are done today.

When Messersmith did second opinions a couple years ago, there was nothing to reference, as tests were rarely sent for. If they were, the testing was very outdated. For example, 

. Now, both alterations should be tested for unless patients have a known 

 mutation, as they’re probably not going to present together. Back then, only codon 12 and 13 were tested for. Now it is known that codon 61 and 146 should be tested for as well. 

 or microsatellite status were also commonly ignored, adds Messersmith.

If a patient was tested a few years ago as the test may be outdated. Targets, codons, and mutations have to be tested for in order to interpret the results appropriately. Sometimes further testing is necessary to devise an appropriate treatment strategy, concludes Messersmith.

Dr. Messersmith on the Rise of Molecular Testing in mCRC

Wells A. Messersmith, MD, co-director of the Developmental Therapeutics Program, and director, GI Cancer Program, at the University of Colorado School of Medicine, discusses molecular markers to be aware of in patients with colorectal cancer (CRC).

There are several molecular markers that should be tested for, including microsatellite stability (MSS) also known as mismatch repair proficiency, says Messersmith. In this case, physicians are looking for the editing function in DNA to ensure that patients don’t have an inherited defect which manifests as Lynch syndrome. Patients with Lynch syndrome are at an increased risk of developing certain tumors. As such, it is suggested that every patient with CRC be tested for this abnormality. If found, the entire family could be treated with appropriate measures, such as screening programs, explains Messersmith.

Polymerase chain reaction-based testing is typically recommended in the case of MSS, whereas immunohistochemistry is typically used to detect mismatch repair proficiencies; both tests are used to detect inherited or acquired mismatch repair. Whether inherited or acquired, patients with these abnormalities will typically receive immunotherapy. However, these patients only comprise approximately 3% to 15% of the overall patient population, concludes Messersmith.

Wells A. Messersmith, MD

Articles

Dr. Messersmith on the Potential for Trastuzumab Deruxtecan in HER2+ CRC

Dr. Messersmith on Choosing a Treatment Option in mCRC

Dr. Messersmith on the Need for Biomarkers to Distinguish Between VEGF Inhibitors in CRC

Dr. Messersmith on the Rise of Molecular Testing in mCRC

Dr. Messersmith on Molecular Markers to be Aware of in CRC