Trastuzumab Combo Appears Effective, Tolerable in RAS/BRAF+ HER2+ CRC

Trastuzumab/pertuzumab elicited similar efficacy and fewer high-grade AEs vs cetuximab/irinotecan in RAS/BRAF wild-type, HER2–positive metastatic CRC.

Trastuzumab (Herceptin) in combination with pertuzumab (Perjeta) may offer a more favorable safety profile than cetuximab (Erbitux) in combination with irinotecan (Camptosar) in treating patients with RAS/BRAF wild-type, HER2–positive metastatic colorectal cancer (CRC), according to a manuscript of the phase 2 S1613 trial (NCT03365882) published in the Journal of Clinical Oncology.¹

Of note, safety evaluable patients treated in the trastuzumab combination arm (TP; n = 26) reported lower incidence of grade 3 or higher adverse events (AEs; 23.1%) than in the cetuximab combination arm (CETIRI; n = 26; 46.2%). Of note, treatment with CETIRI was associated with greater grade 3 or higher incidence of acneiform rash (12% vs 0%), maculopapular rash (8% vs 4%), diarrhea (8% vs 0%), fatigue (8% vs 0%), and gastrointestinal (GI) disorders (8% vs 0%).

Investigators found that efficacy between the 2 regimens were similar, with no significant progression-free survival (PFS) differences observed between arms (HR, 0.79; 95% CI, 0.43-1.45; P = .44). Median PFS was 4.7 months (95% CI, 1.9-7.6) in the TP arm and 3.7 months (95% CI, 1.6-6.7) in the CETIRI arm, and 6-month PFS rates were 38.5% and 37.0%, respectively.

Additionally, a nominal overall survival (OS) benefit was observed in the TP arm, but it did not reach statistical significance. Median OS was not reached (95% CI, 19.4-not reached [NR]) with TP vs 24.7 months (95% CI, 15.2-33.8) in patients treated with CETIRI, with respective 2-year OS rates of 67.1% and 56.7% (HR, 0.56; 95% CI, 0.25-1.29; P = .17).

“[D]ual-HER2 inhibition appears to be a well-tolerated, efficacious, parenteral, and noncytotoxic treatment of patients with RAS/BRAF [wild-type], HER2-positive [metastatic] CRC,” Kanwal Pratap Singh Raghav, MD, MBBS, associate professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, wrote in the publication with study coinvestigators.¹ “Conceivably, our data strongly support that patients with a higher level of HER2 amplifications should be preferably treated with dual anti-HER2 therapy over anti-EGFR antibody-based therapy, where TP appears to provide greater clinical benefit relative to CETIRI.”

Patients 18 years and older with metastatic or locally advanced colon or rectal adenocarcinoma without activating mutations in exons 2, 3, and 4 of KRAS/NRAS genes or exon 15 of the BRAF gene were randomly assigned 1:1 to receive either trastuzumab plus pertuzumab or cetuximab plus irinotecan until disease progression or unacceptable toxicity. Patients in the CETIRI arm could cross over to receive TP (cTP) upon disease progression if meeting eligibility criteria.

Those treated in the TP arm received loading doses of 8 mg/kg of trastuzumab and 840 mg of pertuzumab followed by 6 mg/kg of trastuzumab and 420 mg of pertuzumab every 3 weeks. In the CETIRI arm, 500 mg/m² of cetuximab and 180 mg/m² of irinotecan were administered every 2 weeks.

In the TP (n = 26) and CETIRI (n = 27) cohorts, the median ages were 56.2 (range, 32.1-83.8) and 59.1 (range 38.9-75.2), most patients were White (73% vs 78%), and all patients had an ECOG performance status of 0 or 1. Most patients in each arm did not have prior irinotecan treatment (58% vs 52%) and had a HER2/CEP17 ratio (HCR) of greater than 5 (73% vs 74%); a greater percentage in the TP arm had a HER2 gene copy number of 20 or greater (54% vs 41%).

The primary end point of the study was PFS. Prespecified secondary end points included objective response rate, 2-year OS, and grade 3 or higher AE incidence.²

Additional efficacy analysis revealed a numerical ORR benefit with TP vs CETIRI (34.6% vs 28.0%; P = .62) and a higher disease control rate (73.1% vs 60.0%; P = .28). Furthermore, biomarker analysis revealed that higher levels of HER2 amplification were associated with a longer median PFS in the TP vs CETIRI arm––7.5 months (95% CI, 1.9-12.9) vs 3.5 months (95% CI, 1.5-6.8), respectively. By contrast, patients with low HCR saw a greater PFS benefit with CETIRI––2.8 months (95% CI, 1.2-4.4) with TP vs 6.6 months (95% CI, 1.1-12.5) with CETIRI.

References

1. Raghav KPS, Guthrie KA, Tan B, et al. 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. Published online January 6, 2025. doi:10.1200/JCO-24-01710
2. S1613, trastuzumab and pertuzumab or cetuximab and irinotecan hydrochloride in treating patients with locally advanced or metastatic HER2/​Neu amplified colorectal cancer that cannot be removed by surgery. ClinicalTrials.gov. Updated January 14, 2025. Accessed January 21, 2025. https://tinyurl.com/bddw54cv