In HER2+ colorectal cancer, anti-HER2 therapy may be less toxic alternative

Patients whose metastatic colorectal cancer has progressed following chemotherapy and who lack mutations in the RASand BRAF genes (RAS/BRAF wild-type) are typically treated with EGFR inhibitors. For those whose tumors also demonstrate HER2 amplification (extra copies of the HER2 gene), this therapy may be less effective.

In the SWOG S1613 clinical trial comparing this standard therapy to treatment with two HER2 inhibitors, these patients saw a similar level of clinical benefit, with lower toxicity, from the investigational treatment. An exploratory subgroup analysis also found that the greater the level of HER2 amplification in a patient’s cancer, the more pronounced was the benefit from dual anti-HER2 treatment as compared to the standard EGFR inhibitor-based treatment.

Study S1613 (NCT03365882) was supported by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), led by the SWOG Cancer Research Network, and conducted by the NIH-funded NCI National Clinical Trials Network and NCI Community Oncology Research Program. Results are published in the Journal of Clinical Oncology.

“With advent of anti-HER2 therapy in metastatic colorectal cancer, the key question for HER2-amplified RAS/BRAFwild-type tumors is who should be preferentially treated with therapy directed against HER2 vis-à-vis EGFR,” said lead author and S1613 study chair Kanwal Raghav, MD, MBBS, an associate professor with the University of Texas MD Anderson Cancer Center and an investigator with the SWOG Cancer Research Network, a clinical trials group funded by the NCI.

“While S1613 showed that anti-HER2 therapy was better tolerated and similarly efficacious to anti-EGFR therapy, the key finding is that the relative benefit of these therapies may depend on the level of HER2 amplification. Patients with higher levels of HER2 amplification appeared to benefit more from anti-HER2 therapy and less from anti-EGFR therapy, and vice-versa. This can aid refining patient selection for treatment in clinics and in further research.”

The phase 2 S1613 trial randomized 54 patients with metastatic colorectal cancer that lacked activating mutations in the RAS and BRAF genes but showed amplification (additional copies) of the HER2 gene. All patients had seen their disease get worse after previous systemic chemotherapy.

These participants were randomly assigned to treatment with either a combination of the HER2 inhibitors trastuzumab (Herceptin^®) and pertuzumab (Perjeta^®) (TP) every three weeks or a standard EGFR inhibitor-based therapy of cetuximab plus irinotecan (CETIRI) every two weeks. Treatment continued until disease progression or unacceptable toxicity.

The trial’s primary endpoint was progression-free survival (PFS, the length of time from trial randomization to disease progression or death). Median PFS did not differ between the two arms overall – 4.7 months on the TP arm versus 3.7 months on the CETIRI arm. 

Fewer patients on the investigational arm, however, experienced Grade 3 or higher adverse events (side effects). Grade 3+ adverse events occurred in six patients on the TP arm (23.1 percent) and in 12 patients on the CETIRI arm (46.1 percent).

An exploratory subgroup analysis found patients whose tumors had higher levels of HER2 amplification tended to see greater clinical benefit from the HER2-inhibitor treatment than from the standard-of-care CETIRI treatment. Among those whose tumors had a HER2 gene-copy number (GCN) of 20 or greater, median PFS was 9.9 months on TP versus 2.9 months on CETIRI. For patients with a HER2 GCN of less than 20, the opposite was observed: median PFS was 3.0 months on TP versus 4.2 months on CETIRI.

A difference based on GCN was also apparent in the overall response rate: in patients with a GCN of 20 or greater, the overall response rate on the TP arm was 57.1 percent, whereas among those with a GCN less than 20, the rate on the TP arm was 9.1 percent.

Additionally, the exploratory analysis found that those whose tumors did respond to HER2-inhibitor therapy tended to have cancers with higher HER2 GCNs. The median GCN of responders to TP therapy was 29.7, while the median GCN for non-responders was 13.2.

The authors conclude that dual-HER2 inhibition appears to be an effective non-cytotoxic therapy option for these patients and may be a preferred option for patients with a higher level of HER2 amplification.

S1613 was funded by the NIH/NCI through grants U10CA180888, U10CA180819, U10CA180820, and U10CA180868 and in part by Genentech, Inc. (a member of the Roche Group). 

In addition to Raghav, authors on the S1613 paper included Katherine A. Guthrie, PhD, SWOG Statistics & Data Management Center and Fred Hutch Cancer Center; Benjamin Tan, Jr., MD, Washington University Siteman Cancer Center; Crystal S. Denlinger, MD, Fox Chase Cancer Center; Marwan Fakih, MD, City of Hope National Medical Center; Michael J. Overman, MD, MD Anderson Cancer Center; N. Arvind Dasari, MD, MD Anderson Cancer Center; Larry R. Corum, MD, University of Kansas Cancer Center - MCA Rural MU NCORP/Olathe Health Cancer Center; Lee G. Hicks, MD, Baptist Health Cancer Research Network/Baptist Health Lexington; Mital S. Patel, MD, CORA NCORP, CommonSpirit Health Research Institute/ Cancer Center at Saint Joseph’s; Benjamin T. Esparaz, MD, Heartland Cancer Research NCORP/Cancer Care Specialists of Illinois; Syed M. Kazmi, MD, University of Texas Southwestern Medical Center/Parkland Memorial Hospital; Nitya Alluri, MD, Pacific Cancer Research Consortium NCORP/St. Luke's Cancer Institute; Sarah Colby, MS, SWOG Statistics & Data Management Center and Fred Hutch Cancer Center; Sepideh Gholami, MD, UC Davis Comprehensive Cancer Center; Philip J. Gold, MD, Swedish Cancer Institute; Elena G. Chiorean, MD, Fred Hutch Cancer Center and University of Washington School of Medicine; Scott Kopetz, MD, PhD, MD Anderson Cancer Center; Howard S. Hochster, MD, Rutgers-Cancer Institute; Philip A. Philip, MD, PhD, Wayne State University/Henry Ford Cancer Institute.
 

SWOG Cancer Research Network is part of the National Cancer Institute's National Clinical Trials Network and the NCI Community Oncology Research Program and is part of the oldest and largest publicly funded cancer research network in the nation. SWOG has more than 20,000 members in 45 states and eight other countries who design and conduct clinical trials to improve the lives of people with cancer. SWOG trials have directly led to FDA approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 3 million years of human life. Learn more at swog.org, and follow us on Twitter/X at @SWOG.

Herceptin^® (trastuzumab) and Perjeta^® (pertuzumab) are registered trademarks of Genentech, a member of the Roche Group.

Reference:
“Trastuzumab Plus Pertuzumab Versus Cetuximab Plus Irinotecan in Patients with RAS/BRAF Wild-Type, HER2-Positive, Metastatic Colorectal Cancer (S1613): A Randomized Phase II Trial.” J Clin Oncol. DOI: 10.1200/JCO-24-01710