What are the treatment options for HER2 (Human Epidermal growth factor Receptor 2)-positive metastatic colorectal cancer, specifically anti-HER2 (Human Epidermal growth factor Receptor 2) therapy?

Anti-HER2 Treatment for HER2-Positive Metastatic Colorectal Cancer

For HER2-positive metastatic colorectal cancer that has progressed after standard chemotherapy, dual HER2 blockade with trastuzumab plus tucatinib is the preferred first-line anti-HER2 regimen, with trastuzumab deruxtecan reserved for subsequent lines after progression on other HER2-targeted therapies. 1, 2

Patient Selection and Testing Requirements

• HER2 testing should be performed after failure of standard fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens to identify candidates for anti-HER2 therapy 1
• HER2 positivity is defined by either HER2 overexpression (IHC 3+ or IHC 2+ with positive ISH) or gene amplification detected by next-generation sequencing 1, 3
• Anti-HER2 therapy is optionally recommended in third-line or beyond, particularly in RAS wild-type tumors (ESMO Level III, C; ESCAT II-B) 1
• HER2 amplification occurs in approximately 5-6% of RAS wild-type metastatic colorectal cancer patients 3, 4

First-Line Anti-HER2 Therapy Options

Trastuzumab Plus Tucatinib (Preferred)

• FDA-approved combination: tucatinib 300 mg orally twice daily plus trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg IV every 21 days 2
• This regimen achieved an objective response rate of 38% (95% CI: 28-49%) with median duration of response of 12.4 months in the MOUNTAINEER trial 2
• 81% of responders maintained response for ≥6 months, and 34% for ≥12 months 2
• Treatment continues until disease progression or unacceptable toxicity 2

Trastuzumab Plus Pertuzumab (Alternative)

• Combination regimen: pertuzumab 840 mg IV loading dose, then 420 mg IV every 3 weeks plus trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg IV every 3 weeks 1
• Achieved 32% objective response rate (95% CI: 20-45%) in heavily pretreated patients in the MyPathway trial 5
• Disease control rate of 50-54% with acceptable toxicity profile 1, 5
• Recommended by NCCN and CSCO guidelines as a standard option 1

Trastuzumab Plus Lapatinib (Alternative)

• Dual HER2/EGFR blockade: trastuzumab plus lapatinib achieved 30% objective response rate (95% CI: 14-50%) in the HERACLES trial 1
• 22% of patients experienced grade 3 adverse events, primarily fatigue, rash, and increased bilirubin 1
• This was the original regimen demonstrating proof-of-concept for HER2 targeting in colorectal cancer 1

Second-Line Anti-HER2 Therapy After Progression

Trastuzumab Deruxtecan (Preferred for Second-Line)

• Reserve trastuzumab deruxtecan for use after progression on other HER2-targeted regimens due to increased risk of high-grade toxicities, particularly interstitial lung disease 3
• Showed promising efficacy in the DESTINY-CRC01 trial for patients with HER2 overexpression/amplification who failed standard treatment 1
• May have activity even in RAS-mutated, HER2-positive disease unlike signal transduction inhibitors 3

Critical Treatment Considerations

RAS Mutational Status Impact

• HER2-targeted therapies that inhibit signal transduction (trastuzumab plus pertuzumab, trastuzumab plus lapatinib, trastuzumab plus tucatinib) have limited activity in RAS-mutated tumors 3
• Trastuzumab deruxtecan, as an antibody-drug conjugate, may retain some efficacy in RAS-mutated, HER2-positive disease 3
• Anti-HER2 therapy is particularly recommended for RAS wild-type, HER2-positive patients 1

Timing in Treatment Algorithm

• Standard first-line treatment remains chemotherapy plus bevacizumab or anti-EGFR therapy (for RAS wild-type left-sided tumors) 3
• Anti-HER2 therapy should be considered in subsequent lines after progression on standard chemotherapy 1
• For patients not appropriate for intensive therapy, anti-HER2 regimens may be considered in first-line 1

Monitoring and Toxicity Management

• Most common adverse events with trastuzumab plus tucatinib include diarrhea (33%), fatigue (32%), and nausea (30%) 5
• Grade 3-4 adverse events occur in approximately 37% of patients, most commonly hypokalemia and abdominal pain 5
• Cardiac function monitoring is essential with all trastuzumab-based regimens due to potential cardiotoxicity 6

Common Pitfalls to Avoid

• Do not use anti-HER2 therapy without confirmed HER2 amplification/overexpression by validated testing methods 1
• Avoid switching between anti-EGFR antibodies if one fails; this is not recommended 1
• Do not expect significant benefit from signal transduction-inhibiting HER2 therapies in RAS-mutated disease 3
• Testing should be performed at qualified institutions using standardized methods (IHC, ISH, or NGS) 1

Emerging Evidence and Future Directions

• Pertuzumab plus trastuzumab emtansine (T-DM1) showed only 9.7% response rate in HERACLES-B trial, not meeting its primary endpoint, though disease control was 67.7% 7
• The optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies remains under investigation 3
• Patients should be encouraged to participate in clinical trials of novel anti-HER2 antibody-drug conjugates when available 1