Dr. Hochster on Trastuzumab/Pertuzumab Vs Cetuximab/Irinotecan in HER2-Amplified mCRC

Howard S. Hochster, MD, distinguished professor of medicine, associate director for Clinical Research, director of Gastrointestinal Oncology, Rutgers Cancer Institute, and director of Oncology Research, RWJBarnabas Health, discusses the evaluation of trastuzumab (Herceptin) and pertuzumab (Perjeta) vs cetuximab (Erbitux) and irinotecan in HER2-amplified metastatic colorectal cancer (mCRC).

Findings from the phase 2 SWOG S1613 trial (NCT03365882) presented at the 2023 Gastrointestinal Cancers showed that trastuzumab/pertuzumab did not generate a superior progression-free survival compared with cetuximab/irinotecan. The median PFS was 4.4 months (95% CI, 1.9-7.6) among 26 patients treated with trastuzumab/pertuzumab vs 3.7 months (95% CI, 1.6-6.7) among 28 patients treated with cetuximab/irinotecan.

However, trastuzumab/pertuzumab generated an overall response rate of 31%, and rates grade 3 or high toxicities were 50% lower compared with cetuximab/irinotecan, showing the potential for trastuzumab/pertuzumab as a non-chemotherapy option for patients with RAS/BRAF wild-type, HER2-amplified mCRC, Hochster says.

This study enrolled patients with KRAS/NRAS wild-type, BRAF wild-type, HER2-amplified mCRC who received up to 2 prior lines up therapy and did not receive prior cetuximab/panitumumab (Vectibix). Enrolled patients were randomly assigned to trastuzumab plus pertuzumab or cetuximab plus irinotecan, and patients in the cetuximab/irinotecan arm were allowed to cross over following disease progression.

With trastuzumab/pertuzumab representing a potential non-chemotherapy option for patients who have this biology, it is worth testing for HER2, since there is a subset of patients who may benefit from these HER2 drugs, Hochster notes.

There is now an FDA approval for tucatinib (Tukysa) plus trastuzumab for RAS wild-type HER2-positive mCRC, based on the phase 2 MOUNTAINEER trial (NCT03043313). This approval also emphasized the importance of testing for HER2 overexpression, Hochster says.

Notably, trastuzumab/pertuzumab may provide more of benefit patients with HER2 amplification with a ratio greater than 5. Among those patients, the median PFS was 7.5 months (95% CI, 1.9-12.9) with trastuzumab/pertuzumab, compared with 3.5 months (95% CI, 1.5-6.8) for cetuximab/irinotecan. Because the patient numbers were small for this subset, the benefit for patients with a HER2 amplification ratio of more than 5 is still more of a hypothesis than a proven fact from this study, but it is important to be aware of when conducting HER2 testing, Hochster concludes.