Results of S1613: HER2 Inhibitors for HER2+ CRC
I can't believe we are one month into the new year already. But, 2025 has already been a productive year. For example, primary results from our S1613 phase II trial in HER2-positive metastatic colorectal cancer have been published in the Journal of Clinical Oncology.
The study compared treatment with dual HER2 inhibitors to a standard EGFR inhibitor-based treatment in patients with previously treated, HER2-positive disease. It found that the HER2 inhibitor treatment can provide similar benefit with less toxicity.
One of the particularly intriguing findings came from an exploratory subgroup analysis that suggests greater HER2 amplification in a tumor may be associated with greater clinical benefit from HER2-inhibitor therapy as compared to EGFR-inhibitor therapy.
S1613 randomized 54 patients with RAS/BRAF wild-type metastatic disease to either a standard EGFR inhibitor-based therapy – cetuximab plus irinotecan (the CETIRI arm) – or to treatment with a pair of HER2 inhibitors – trastuzumab and pertuzumab (the TP arm).
Overall, median progression-free survival (PFS) was similar between the arms – 4.7 months on the TP arm versus 3.7 months on the CETIRI arm.
But the investigative treatment combination was better tolerated. While 12 patients on the CETIRI arm (46.1 percent) experienced Grade 3 or higher adverse events, only 6 patients on the TP arm did (23.1 percent).
Exploratory analysis found that patients whose tumors had higher levels of HER2 amplification tended to see greater clinical benefit from the dual HER2-inhibitor treatment than from the standard-of-care CETIRI treatment. For those with lower levels of HER2 amplification, the situation was reversed.
In patients whose tumors had a HER2 gene-copy number of 20 or more, those treated with TP had a median PFS of 9.9 months vs 2.9 months for those who got CETIRI. By contrast, for patients whose tumors had a HER2 gene-copy number lower than 20, median PFS was 3.0 months on TP versus 4.2 months on CETIRI.
Overall response rate differed with gene-copy number in similar fashion, with patients in the 20+ group having a higher response rate to TP than to CETIRI, while those in the less-than-20 group had a higher response rate to CETIRI than to TP.
As S1613 study chair Dr. Kanwal Raghav says in our press release on these results,
the relative benefit of these two therapies seems to depend on the level of HER2 amplification in the patient’s tumor.
And as JCO Associate Editor Dr. Andrew H. Ko concludes in the Relevance statement that annotates the article, S1613’s results highlight the importance of HER2 testing in metastatic colorectal cancer.
As I write about notable research results at the end of January, I want to ensure you we have not forgotten about the Best of SWOG! We typically hold our winter installment of this one-hour webinar at this time of year, but we’re delaying it until March this year, because of the late February deadline for submission of our grant applications to the NCI.
A final word about those grant applications …
Much has happened in the past 10 days, in terms of federal support for research. With Drs. Lara and Hershman, and with key help from our staff, we’re monitoring developments, adapting as needed, and keeping the primary goal in sight – improving the lives of people touched by cancer. Our ability to do this over the coming years depends on the success of these grant applications.
While I can’t say what will happen in the short term, I’m confident that in the longer term Congress will want cancer research to continue. Cooperative group (aka network) research has been around for more than 60 years now, and we have weathered past sea changes, government shutdowns, sequesters, budget cuts, and other storms. Through it all we have saved millions of years of human life, and we will save many more.
SWOG remains committed to our mission and our patients, and we thank you sincerely for your continued dedication to the same.
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