MyPathway Subanalysis Backs Combination HER2-Targeting Antibodies in Colorectal Cancer

A combination of two human epidermal growth factor receptor 2 (HER2)-targeting antibodies may improve outcomes in patients with metastatic, HER2-positive colorectal cancer, but the benefit appears to be limited to KRAS wild-type tumors. The finding comes from a sub-analysis of the MyPathway basket trial, which is examining six different targeted therapies in treatment-refractory solid tumors selected for their genetic profiles.

Over a median treatment duration of 2.1 months, 18 of 57 patients (32%; 95% CI, 20%–45%) achieved an objective response with a combination of pertuzumab and trastuzumab. The median duration of response was 5.9 months, and 4 patients responded for at least 1 year. Median overall survival was 11.5 months.

When researchers examined outcomes according to KRAS mutation status, a different picture emerged. Those with wild-type KRAS fared better with treatment than those with mutant KRAS, with longer median progression-free survival (5.3 vs 1.4 months), median overall survival (14.0 vs 8.5 months), and a better objective response rate (40% vs 8%).

The results mirror the outcomes of the Heracles trial, which tested a combination of trastuzumab and the tyrosine kinase inhibitor lapatinib in KRAS wild-type, HER2-positive metastatic colorectal cancer. That study found a 30% objective response rate and a 26% partial response rate.

The two studies combine to “suggest that combination therapy against HER2 is important, but we don’t yet know which is the best combination,” Stacey Cohen, MD, assistant professor of oncology at the University of Washington and a clinician at Seattle Cancer Care Alliance, told Cancer Network. Dr. Cohen was not involved in either study.

Unfortunately, the studies also underline an existing problem in metastatic colorectal cancer, which is that there is a large population of patients that derive little benefit from targeted therapies. “With the finding that HER2-targeted therapy is most effective in the KRAS wild-type populations, that’s one more option in a group that already has EGFR [epidermal growth factor receptor] therapy, whereas the KRAS-mutant population is still suffering from a (lack) of treatment options,” said Cohen.