For patients with HER2-overexpressed or -amplified breast or gastric cancer, treatment with HER2-targeting agents is standard of care. HER2 amplification/overexpression in metastatic colorectal cancer (mCRC) is rare (approximately 2% to 6% of patients). This low frequency of HER2 alterations has constrained investigations of HER2-targeted therapies in mCRC. However, based on the activity of HER2-targeted combinations in preclinical studies, the phase II HERACLES clinical study evaluated the combination of trastuzumab and the HER2-targeted tyrosine kinase inhibitor (TKI) lapatinib, demonstrating an objective response rate (ORR) of 30% in heavily pretreated HER2-positive, KRAS exon wildtype mCRC. Recently, in HER2-positive breast cancer, another HER2-targeted combination, trastuzumab plus pertuzumab in combination with chemotherapy, became a standard first-line therapy based on substantial progression-free survival (PFS) and overall survival (OS) improvement.
The efficacy and safety of trastuzumab and pertuzumab has now been evaluated in one cohort of 57 heavily pretreated patients with HER2-amplified mCRC as part of the ongoing, phase II, multiple basket MyPathway study. At a median follow-up of 7.3 months, the study met its primary endpoint with an ORR of 32%. This included 17 patients with a partial response (30%) and 1 patient with a complete response (2%). Of interest, none of the eight patients with HER2 amplification without overexpression achieved a response. The median duration of response was 5.9 months, and 4 patients had responses ongoing for 12 months or longer. The median PFS and OS were 2.9 months and 11.5 months, respectively.
Exploratory analysis found a relationship between KRAS mutation status and outcomes. Among patients with wildtype KRAS tumors, the PFS and OS were 5.3 months and 14.0 months, while those with KRAS-mutated tumors had worse outcomes (PFS 1.4 months; OS 8.5 months). Similarly, patients with right-sided colon tumors were less likely to respond to treatment and had shortened PFS and OS.
The combination of pertuzumab and trastuzumab was well tolerated and toxicities were consistent with the known safety profile of these agents. The most common treatment-related adverse events (TRAEs) of any grade were diarrhea (33%), fatigue (32%), and nausea (30%). Grade 3/4 TRAEs occurred in 37% of patients, and serious TRAEs occurred in 18% of patients.
The authors highlighted the importance of molecular testing in mCRC and concluded that the combination of pertuzumab and trastuzumab represents a potential treatment option for heavily pretreated patients with HER2-amplified mCRC. However, the low activity in patients with KRAS mutations indicate that both HER2 and KRAS status should be considered in treatment decision making.