John L. Hays, MD, PhD, assistant professor, Department of Internal Medicine, The Ohio State University, member, Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center – James, discusses unmet needs for patients with colorectal cancer (CRC) and future directions for research in this disease.

The optimal way to integrate surgery, radiation, and systemic therapy for patients with CRC has yet to be identified, signaling an unmet need in this disease. Hays says. Although data support the use of upfront chemotherapy or systemic therapy in patients with oligometastatic CRC, many patients with CRC will receive several treatment modalities throughout their disease. These may includetargeted therapies, local therapies such as surgery and radiation, and pseudo-local therapies such as Yttrium-90 treatment or hepatic arterial fusion pumps for patients with liver disease, Hays explains. The roles of each of these treatment options within the overall context of the CRC armamentarium remain unknown and should be defined in the future, Hays notes.

Although sequencing parameters are unclear, the unprecedented variety of approaches for CRC management provides patients with several effective treatment options, Hays emphasizes. However, further research should focus on translating the best options and sequences into clinical practice, according to Hays.

The development of immunotherapy may also benefit patients with CRC, Hays says. For instance, patients with mismatch repair–deficient (dMMR) disease have responded well to treatment with immune checkpoint inhibitors, Hays explains. A phase 2 trial (NCT04165772) evaluated the efficacy of the PD-1 inhibitor dostarlimab-gxly (Jemperli) in patients with stage II or III dMMR rectal cancer. In this trial, all 12 patients (100%; 95% CI, 74%-100%) who completed dostarlimab treatment and underwent 6 or more months of follow-up achieved a clinical complete response.

However, the efficacy of immune checkpoint inhibition appears to be localized to patients with dMMR CRC and is not effective in most patients with mismatch repair–proficient (pMMR) disease, Hays emphasizes. Future research should investigate optimal strategies for harnessing the immune system to target tumor cells in the large population of patients with pMMR CRC. The use of cellular therapies or targeted therapies in combination with immunotherapy may be one such approach, Hays concludes.

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John L. Hays, MD, PhD, discusses unmet needs for patients with colorectal cancer and future directions for research in this disease.

Dr Hays on Unmet Needs in CRC

John L. Hays, MD, PhD, assistant professor, Department of Internal Medicine, The Ohio State University, member, Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center–James, discusses advances in treating patients with HER2-positive colorectal cancer (CRC).

® State of the Science Summit™, Hays discussed targeted therapies in CRC. In the past, treatments such as FOLFOX, FOLFOXIRI, bevacizumab (Avastin), as well as EGFR inhibitors were commonly used, Hays begins. These regimens represented standard treatment approaches for about 10 years in this patient population. However, in recent years, there has been an increased understanding of the molecular aspects of CRC and how treatment can be targeted to certain gene alterations such as HER2 to improve outcomes in populations that have historically had poor prognosis, Hays expands.

Despite these advances, such alterations are found in the minority of patients with CRC, Hays continues. HER2 for example is overexpressed in only about 5% of patients with CRC, Hays adds. These patients can respond well to various types of inhibition of the HER2 gene or protein. In addition, these advancements are broadening the treatment landscape beyond chemotherapy regimens like FOLFOX and FOLFIRI to include targeted therapies such as trastuzumab (Herceptin) and fam-trastuzumab deruxtecan-nxki (Enhertu), Hays notes.

Moving forward, investigators are focused on developing more effective targeted therapies, so patients with actionable alterations can receive chemotherapy-free approaches that lead to further improved outcomes, Hays concludes.

John L. Hays, MD, PhD, discusses advances in treating patients with HER2-positive colorectal cancer.

Dr Hays on Treating Patients With HER2+ CRC

John L. Hays, MD, PhD, assistant professor, the Department of Internal Medicine, the Ohio State University, member, the Translational Therapeutics Program, the Ohio State University Comprehensive Cancer Center - James Cancer Hospital, discusses the importance of clinical trials in colorectal cancer (CRC).

A key to advancing the treatment space in CRC is understanding how to deliver more effective treatment to patients in the frontline setting with the hope of curing more of them, Hays says. The emergence of HER2-targeted therapies for patients with CRC has shown that more tailored treatments can be delivered to different patients, and investigating more surgical and adjuvant strategies could lead to more cures, Hays explains.

For example, single-agent dostarlimab-gxly (Jemperli) elicited a clinical complete response rate of 100% with no evidence of residual tumor among 14 patients with stage II/III mismatch repair–deficient locally advanced rectal cancer treated on a phase 2 trial (NCT04165772), Hays adds.

Just as HER2-targeted agents have been developed, it will be important to further understand actionable targets in CRC and how targeted agents can represent better treatments options for patients in the recurrent setting, Hays concludes.

John L. Hays, MD, PhD, discusses the importance of clinical trials in colorectal cancer.


Dr. Hays on the Importance of Clinical Trials in CRC

John L. Hays, MD, PhD, an assistant professor in the Department of Internal Medicine at The Ohio State University and a member of the Translational Therapeutics Program at the Ohio State University Comprehensive Cancer Center - James Cancer Hospital, discusses expanding treatment options for HER2-positive colorectal cancer (CRC).

Targeting HER2 has evolved from the days when trastuzumab (Herceptin) was the only targeted agent, Hays says. The treatment paradigm now includes antibodies that target the extracellular domain, antibody-drug conjugates, and small-molecule inhibitors, Hays says. However, evaluation regarding whether to use these treatments as single agents or in combination is still ongoing, Hays notes.

For example, small-molecule inhibitors, such as tucatinib (Tukysa), could target patients with HER2-positive disease who are not as responsive to trastuzumab alone, Hays explains. The phase 2 MOUNTAINEER trial (NCT03043313) is exploring trastuzumab plus tucatinib in patients with HER2-positive metastatic CRC, Hays concludes.

John L. Hays, MD, PhD, discusses expanding treatment options for HER2-positive colorectal cancer.


Dr. Hays on Treatment Options in HER2-Positive CRC

John L. Hays, MD, PhD, assistant professor, Department of Internal Medicine, The Ohio State University, member, the Translational Therapeutics Program, the Ohio State University Comprehensive Cancer Center - James Cancer Hospital, discusses the importance of genetic testing in colorectal cancer (CRC).

The treatment landscape of colon cancer has evolved over the past few years, with the emergence of treatments beyond standard chemotherapy, Hays says. There are several defined molecular subtypes and mutations within colon cancer, and testing for them can lead to different treatment algorithms for patients as they undergo therapy for metastatic CRC, Hays continues.

Instead of treating every patient at a surface level, it is important to treat a patient’s tumor at a molecular level because that will provide a better chance at survival and good quality of life, Hays concludes. 

John L. Hays, MD, PhD, discusses the importance of genetic testing in colorectal cancer. 


John L. Hays, MD, PhD

Articles

Dr Hays on Unmet Needs in CRC

Dr Hays on Treating Patients With HER2+ CRC

Dr. Hays on the Importance of Clinical Trials in CRC

Dr. Hays on Treatment Options in HER2-Positive CRC

Dr. Hays on the Importance of Genetic Testing in Colorectal Cancer