What is the best treatment option for a patient with HER2-positive breast cancer, comparing the Destiny Breast 5 trial to standard therapy with trastuzumab (Herceptin) plus pertuzumab (Perjeta) plus a taxane?

Trastuzumab Deruxtecan Plus Pertuzumab vs. Standard Therapy for First-Line HER2-Positive Metastatic Breast Cancer

For first-line treatment of HER2-positive metastatic breast cancer, trastuzumab deruxtecan plus pertuzumab is now superior to the previous standard of trastuzumab plus pertuzumab plus taxane, demonstrating a 44% reduction in progression risk and extending median progression-free survival by nearly 14 months (40.7 vs 26.9 months). 1

Evidence from DESTINY-Breast09 Trial

The DESTINY-Breast09 phase 3 trial directly compared these regimens in treatment-naïve HER2-positive metastatic breast cancer patients and provides the highest quality evidence for this comparison 1:

Efficacy Outcomes

• Median progression-free survival: 40.7 months with trastuzumab deruxtecan plus pertuzumab versus 26.9 months with trastuzumab plus pertuzumab plus taxane (HR 0.56; 95% CI 0.44-0.71; P<0.00001) 1
• Objective response rate: 85.1% with trastuzumab deruxtecan plus pertuzumab versus 78.6% with standard therapy 1
• Complete response rate: 15.1% versus 8.5%, respectively 1
• Median duration of response: 39.2 months versus 26.4 months 1

Safety Profile Comparison

The safety profiles were generally comparable between regimens, though with distinct toxicity patterns 1:

• Grade ≥3 adverse events: 63.5% with trastuzumab deruxtecan plus pertuzumab versus 62.3% with standard therapy 1
• Most common grade ≥3 toxicities with trastuzumab deruxtecan plus pertuzumab: neutropenia, hypokalemia, and anemia 1
• Most common grade ≥3 toxicities with standard therapy: neutropenia, leukopenia, and diarrhea 1

Critical Safety Consideration: Interstitial Lung Disease

The most important safety difference is the risk of interstitial lung disease (ILD)/pneumonitis, which occurred in 12.1% of patients receiving trastuzumab deruxtecan plus pertuzumab (including 2 fatal cases) versus 1.0% with standard therapy (all grade 1-2). 1

• Trastuzumab deruxtecan is absolutely contraindicated in patients with pre-existing interstitial lung disease 2, 3
• Active surveillance for ILD symptoms (new or worsening dyspnea, cough, fever) is mandatory throughout treatment 3
• The case fatality rate for trastuzumab deruxtecan-associated ILD ranges from 2.2% to fatal events as seen in DESTINY-Breast09 3, 1

Current Guideline Recommendations

First-Line Standard (Pre-DESTINY-Breast09)

The established first-line standard remains trastuzumab plus pertuzumab plus taxane for at least 6 cycles, followed by maintenance with trastuzumab plus pertuzumab 4:

• ASCO guidelines: Recommend trastuzumab plus pertuzumab plus taxane as first-line treatment with high evidence quality and strong recommendation strength 4
• ESMO guidelines: Recommend this combination with MCBS 1A rating (highest clinical benefit) 4
• FDA approval: Pertuzumab is approved in combination with trastuzumab and docetaxel for first-line treatment of HER2-positive metastatic breast cancer 5

Historical Efficacy Data for Standard Therapy

The CLEOPATRA trial established the original standard 4:

• Median PFS: 18.5 months with pertuzumab plus trastuzumab plus docetaxel versus 12.4 months without pertuzumab (HR 0.62; P<0.001) 4
• Median OS: 57.1 months versus 40.8 months (16.3-month improvement) 4

The PERUSE study confirmed these results across different taxane backbones 6:

• Median PFS: 20.6 months overall (19.6 months with docetaxel, 23.0 months with paclitaxel, 18.1 months with nab-paclitaxel) 6
• Overall response rate: 80% across all taxane options 6

Treatment Algorithm Based on Current Evidence

For Patients Eligible for Trastuzumab Deruxtecan

Use trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks plus pertuzumab 840 mg loading dose then 420 mg every 3 weeks as first-line therapy if:

• No history of interstitial lung disease 2, 3, 1
• No active pulmonary symptoms concerning for ILD 3
• Patient understands and accepts the 12.1% risk of ILD (including potential fatal outcomes) 1
• Access to the regimen is available (noting this represents cutting-edge evidence from 2025) 1

For Patients Ineligible for Trastuzumab Deruxtecan

Use trastuzumab plus pertuzumab plus taxane (docetaxel or paclitaxel preferred) for at least 6 cycles, followed by maintenance trastuzumab plus pertuzumab if: 4

• Pre-existing interstitial lung disease is present 2, 3
• Patient declines trastuzumab deruxtecan after informed discussion of ILD risk 1
• Trastuzumab deruxtecan is not available or accessible 4

Taxane Selection for Standard Therapy

When using the standard trastuzumab plus pertuzumab plus taxane regimen 4, 6:

• Docetaxel: First choice per FDA approval and CLEOPATRA trial data 4, 5
• Paclitaxel: Valid alternative with similar PFS (23.0 vs 19.6 months with docetaxel), more peripheral neuropathy (31% vs 16%) but less febrile neutropenia (1% vs 11%) and mucositis (14% vs 25%) 6
• Nab-paclitaxel: Acceptable option with slightly lower PFS (18.1 months) 6

Special Population: HR-Positive/HER2-Positive Disease

For patients with hormone receptor-positive and HER2-positive disease 4, 7:

• After completing chemotherapy: Add endocrine therapy to maintenance trastuzumab plus pertuzumab (MCBS 1A) 4, 7
• If chemotherapy contraindicated: Consider trastuzumab plus pertuzumab plus endocrine therapy without chemotherapy for highly selected patients with minimal disease burden and strong ER/PgR expression 7

Common Pitfalls and How to Avoid Them

Pitfall 1: Using Trastuzumab Deruxtecan in Patients with ILD History

Never administer trastuzumab deruxtecan to patients with any history of interstitial lung disease—this is an absolute contraindication. 2, 3 The 12.1% incidence of ILD with trastuzumab deruxtecan plus pertuzumab includes fatal cases, and pre-existing ILD dramatically increases this risk 1.

Pitfall 2: Stopping HER2-Targeted Therapy When Chemotherapy Ends

Continue trastuzumab plus pertuzumab (or trastuzumab deruxtecan plus pertuzumab) as maintenance therapy after completing chemotherapy until disease progression or unacceptable toxicity. 4, 2 Multiple studies demonstrate benefit from continuing HER2 blockade beyond chemotherapy completion 2.

Pitfall 3: Inadequate ILD Monitoring with Trastuzumab Deruxtecan

Establish a systematic surveillance protocol for ILD symptoms (dyspnea, cough, fever) at every visit, with low threshold for chest imaging if symptoms develop. 3 The 2.2% case fatality rate for trastuzumab deruxtecan-associated ILD requires vigilant monitoring 3.

Pitfall 4: Treating Recent Adjuvant Therapy Recurrence as First-Line

Patients who recur within 6-12 months of completing adjuvant trastuzumab plus pertuzumab should be treated according to second-line recommendations, not first-line. 4 However, patients who recur within 12 months of adjuvant trastuzumab alone (without pertuzumab) may receive first-line therapy 4.

Nuances in Evidence Interpretation

Strength of DESTINY-Breast09 Data

The DESTINY-Breast09 trial represents the single highest quality and most recent evidence for first-line HER2-positive metastatic breast cancer treatment 1. The magnitude of benefit (13.8-month PFS improvement, 44% risk reduction) substantially exceeds the historical benefit of adding pertuzumab to trastuzumab plus taxane (6.1-month PFS improvement in CLEOPATRA) 4, 1.

Guideline Lag Behind Evidence

Current ESMO and ASCO guidelines predate the DESTINY-Breast09 results and therefore recommend trastuzumab plus pertuzumab plus taxane as the standard first-line approach 4. The 2025 DESTINY-Breast09 publication will likely prompt guideline updates to incorporate trastuzumab deruxtecan plus pertuzumab as the preferred first-line option for eligible patients 1.

Chemotherapy-Free Regimen Advantage

Unlike the standard regimen requiring taxane chemotherapy, trastuzumab deruxtecan plus pertuzumab eliminates the need for separate cytotoxic chemotherapy while achieving superior outcomes. 1 This represents a paradigm shift toward antibody-drug conjugate-based therapy that may improve quality of life by avoiding taxane-associated toxicities (alopecia, neuropathy, mucositis) 6, 1.