Ryan B. Corcoran, MD, PhD, associate professor of medicine, Harvard Medical School, and associate professor, Cancer Center, Massachusetts General Hospital, discusses the presence of HER2 amplification in metastatic colorectal cancer (mCRC).

HER2 is amplified in about 4% of all cases of mCRC, says Corcoran. HER2 is well-known as a target in breast and gastric cancers, where it is more widely overexpressed and amplified; however, HER2 also occurs in 

Although this group of patients would typically receive EGFR-directed therapies, research has shown that those with CRC whose tumors have HER2 amplification do not respond well to EGFR antibodies. As such, rather than being a marker of resistance, HER2 has become a promising therapeutic target in CRC, says Corcoran.

Three studies have combined the anti-HER2 agent trastuzumab (Herceptin) with either pertuzumab (Perjeta), another anti-HER2 antibody, or 1 of 2 small molecule inhibitors, lapatinib (Tykerb) or tucatinib, adds Corcoran. Data from some of these studies have shown response rates ranging from 30% to 45% in this patient population with promising durability.

Although HER2 is a rare target, it is worth considering when assessing later-line therapy options for patients with CRC, concludes Corcoran.

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Ryan B. Corcoran, MD, PhD, discusses the presence of HER2 amplification in metastatic colorectal cancer.

Dr. Corcoran on Targeting HER2 Amplification in CRC

Ryan B. Corcoran, MD, PhD, associate professor of medicine, Harvard Medical School, and associate professor, Cancer Center, Massachusetts General Hospital, discusses the utility of regorafenib (Stivarga) in colorectal cancer (CRC). 

In 2012, the FDA approved regorafenib for the treatment of patients with metastatic CRC whose disease has progressed after prior therapy. The regulatory decision was based on the results of the phase III CORRECT trial, which showed that the oral multikinase inhibitor improved both progression-free survival and overall survival compared with placebo.

However, significant toxicities including fatigue, hand-foot skin reaction, diarrhea, and hypertension are associated with regorafenib, says Corcoran. 

The randomized phase II ReDOS study showed that a weekly regorafenib dose-escalation strategy, beginning at 80 mg and ending at 160 mg, led to more favorable toxicity in previously treated patients with metastatic CRC compared with the standard dose of 160 mg/day; quality-of-life parameters improved with the dose-escalation approach as well. As such, this is an appropriate and potentially optimal approach for this population, concludes Corcoran.

Ryan B. Corcoran, MD, PhD, discusses the utility of regorafenib in colorectal cancer. 
 

Dr. Corcoran on the Utility of Regorafenib in CRC

Ryan B. Corcoran, MD, PhD, associate professor of medicine, Harvard Medical School, and associate professor, Cancer Center, Massachusetts General Hospital, discusses promising combination strategies with immunotherapy in metastatic colorectal cancer (mCRC).

The bispecific antibodies, as a class, are promising, says Corcoran. Early studies have shown signals of activity with these agents, especially when they are given in combination with a checkpoint inhibitor. However, the toxicity profiles of some of these drugs have resulted in limited utility, he adds. As such, researchers are investigating how to modify these agents. Specifically, research is being focused on examining which antigens these agents are directed against and how to create elements that will allow for some degree of tumor-specific activation.

Through such efforts, the field is learning that response to therapy is not always contingent on the tumor cell, but the tumor microenvironment, says Corcoran, and more specifically, immunosuppressive cell populations. These populations are often recruited into the tumor by cytokines or chemokines produced by the tumor, concludes Corcoran.

Ryan B. Corcoran, MD, PhD, discusses promising combination strategies with immunotherapy in metastatic colorectal cancer.

Dr. Corcoran on Promising Combination Strategies With Immunotherapy in mCRC

Ryan B. Corcoran, MD, PhD, associate professor, Cancer Center, Massachusetts General Hospital, assistant professor of medicine, Harvard Medical School, discusses immunotherapy options for patients with microsatellite stable versus microsatellite instability (MSI)—high (MSI-H) colorectal cancer (CRC).  

Generally, patients with CRC do not respond well to checkpoint inhibitors, says Corcoran. However, a subset of 4% to 5% of these patients with MSI-H or mismatch repair deficiency derive significant improvement from these agents, due to the high level of mutations the immune system can recognize. 

For the remaining 96% of patients, Corcoran says extensive exploration is being done with immunotherapy agents to extend the immunogenicity benefit seen in MSI-H tumors. 

Checkpoint inhibitors in combination with radiation, targeted agents, and bispecific antibodies, which engender an immune response, are currently under investigation, concludes Corcoran. 

Ryan B. Corcoran, MD, PhD, discusses immunotherapy options for patients with microsatellite stable versus microsatellite instability–high colorectal cancer.  
 

Dr. Corcoran on Immunotherapy for Microsatellite Stable/Instable CRC

Ryan B. Corcoran, MD, PhD, clinical researcher, Massachusetts General Hospital, assistant professor of medicine, Harvard Medical School, discusses the future role of liquid biopsies in gastrointestinal (GI) cancers.

The most exciting applications for liquid biopsies in this space are the ones that are on the horizon, Corcoran says. Down the road, researchers hope liquid biopsies can be used as an early-detection method. Identifying patients with early-stage disease in a more readily available fashion can potentially lead to easier curative strategies and a transformation of the way patients with GI cancers are treated.

In the nearer future, liquid biopsies have the most potential in the perioperative setting for patients with early-stage disease, specifically in the detection of subclinical residual disease. Corcoran notes that typically the only way solid tumors are cured is by surgically removing all remaining cancer cells. However, a percentage of patients will have residual disease in other sites, and this will evade detection until the cancer has recurred. Liquid biopsies are a way to locate these virtually undetectable cancer cells, and physicians can potentially eliminate the need for toxic adjuvant therapy.

Ryan B. Corcoran, MD, PhD, clinical researcher, Massachusetts General Hospital, assistant professor of medicine, Harvard Medical School, discusses the future role of liquid biopsies in gastrointestinal cancers.

Dr. Corcoran on Future of Liquid Biopsies in GI Cancers

Ryan B. Corcoran, MD, PhD, clinical researcher, Massachusetts General Hospital, assistant professor of medicine, Harvard Medical School, discusses the benefits and limitations of using liquid biopsies in gastrointestinal (GI) cancer.

One of the biggest advantages to using liquid biopsies is for genotyping purposes is that it offers the opportunity to assess the tumor genome in a minimally invasive manner, Corcoran says, and that allows researchers to observe how the tumor biology evolves throughout treatment. Another benefit of using liquid biopsy over a standard tissue biopsy in GI cancer is that is the former can better capture the tumor heterogeneity, or different tumor cells residing in different lesions, which is important because different parts of the same lesion can develop different molecular mechanisms that can be clinically relevant.

On the other hand, cell-free DNA may miss molecular alterations that could involve protein or RNA changes, Corcoran notes. Sometimes patients simply do not shed enough tumor DNA, and in those cases, results from liquid biopsy can be unrevealing, even in the presence of disease.

Ryan B. Corcoran, MD, PhD, clinical researcher, Massachusetts General Hospital, assistant professor of medicine, Harvard Medical School, discusses the benefits and limitations of liquid biopsies in gastrointestinal cancer.

Ryan B. Corcoran, MD, PhD

Articles

Dr. Corcoran on Targeting HER2 Amplification in CRC

Dr. Corcoran on the Utility of Regorafenib in CRC

Dr. Corcoran on Promising Combination Strategies With Immunotherapy in mCRC

Dr. Corcoran on Immunotherapy for Microsatellite Stable/Instable CRC

Dr. Corcoran on Future of Liquid Biopsies in GI Cancers

Dr. Corcoran on Benefits/Limitations of Liquid Biopsies in GI Cancer