I'll author rigorous eligibility criteria grounded in precedent and the specific safety liabilities of this drug class. Let me pull the relevant reference data first.

Phase 3 Eligibility Criteria — Anti-HER2 Deruxtecan-Class ADC in Previously-Treated HER2+ Metastatic Breast Cancer

Design intent. The two defining liabilities — interstitial lung disease (ILD)/pneumonitis (potentially fatal, the class-defining risk) and left-ventricular dysfunction — drive a layered safety strategy: hard exclusions for the truly high-risk, but graded/relaxable thresholds and active surveillance (rather than blanket bans) elsewhere, so a real-world pretreated metastatic population can still enroll. Notes flag every place I deliberately loosened a criterion to protect feasibility.

Inclusion Criteria

1. Histologically/cytologically confirmed breast cancer that is unresectable or metastatic.

2. HER2-positive by IHC 3+, or IHC 2+ with ISH amplification, on the most recent evaluable tumor sample (central confirmation required; archival tissue acceptable if no fresh biopsy feasible). Per DESTINY-Breast03 precedent.

3. Disease progression on ≥1 prior HER2-directed regimen in the metastatic setting (e.g., trastuzumab + taxane ± pertuzumab, or T-DM1), or recurrence during/within 6 months of (neo)adjuvant HER2-directed therapy. Set line of therapy to the development position; second-line is the standard precedent.

4. Measurable disease per RECIST v1.1 (non-measurable, bone-only disease permitted only if the development plan and statistical analysis support it).

5. ECOG performance status 0–1.

6. Adequate organ function within ~7–14 days of first dose:
   - ANC ≥ 1.5 × 10⁹/L
   - Platelets ≥ 100 × 10⁹/L
   - Hemoglobin ≥ 9.0 g/dL (transfusion-independent ≥ 14 days)
   - Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN with documented Gilbert's or hepatic metastases)
   - AST/ALT ≤ 3 × ULN (≤ 5 × ULN if liver metastases present)
   - CrCl ≥ 50 mL/min (Cockcroft-Gault)
   - Albumin ≥ 2.8 g/dL

7. Cardiac function — LVEF ≥ 50% by ECHO or MUGA at screening (institutional LLN if higher). Floor at 50% rather than a higher value to avoid excluding the many patients with prior anthracycline/trastuzumab exposure who have mild asymptomatic decline.

8. QTc (Fridericia) ≤ 470 ms (women) / ≤ 450 ms (men) on screening ECG.

9. Baseline chest CT (with the screening tumor assessment) reviewed and free of ILD/pneumonitis or clinically significant pulmonary inflammatory findings. This is an enabling criterion — a clean baseline CT is the anchor for the on-study ILD surveillance program.

10. Age ≥ 18; life expectancy ≥ 12 weeks; recovery to ≤ Grade 1 (or baseline) from prior-therapy toxicities (excluding alopecia, stable neuropathy).

11. Negative pregnancy test and agreement to highly effective contraception (WOCBP); standard consent/compliance.

Exclusion Criteria

Pulmonary / ILD (the hard line — class-defining, potentially fatal)

1. Any history of (treated or untreated) non-infectious ILD/pneumonitis, drug-induced pneumonitis, organizing pneumonia, or pulmonary fibrosis, OR active ILD/pneumonitis at screening. Non-negotiable hard exclusion — the deruxtecan-class ILD signal can be fatal and prior ILD is the dominant risk factor.

2. Suspected ILD that cannot be ruled out on baseline imaging (equivocal findings must be adjudicated before enrollment).

3. Clinically significant pulmonary disease — e.g., requiring supplemental oxygen, severe/uncontrolled COPD or asthma, or resting SpO₂ < 92% on room air. Note: well-controlled COPD/asthma is NOT excluded — only oxygen-dependent or unstable disease, to avoid over-excluding an older comorbid population.

4. Lung-specific factors raising ILD risk at investigator discretion: prior thoracic radiation pneumonitis, or current need for chronic high-dose pulmonary-toxic concomitant medication.

Cardiac

5. Baseline LVEF < 50% or below institutional LLN.

6. Symptomatic congestive heart failure (NYHA Class II–IV) or prior CHF with documented LVEF < 40%.

7. Clinically significant cardiac disease: MI or unstable angina within 6 months, uncontrolled arrhythmia, uncontrolled hypertension, or congenital long-QT syndrome.

8. Troponin elevation above ULN at screening without a non-cardiac explanation (optional, recommended where the cardiac signal warrants closer triage).

CNS

9. Untreated or symptomatic CNS metastases. Patients with treated, stable, asymptomatic brain metastases — off steadily-tapered/low-dose corticosteroids (≤ 10 mg prednisone-equivalent) for ≥ 2 weeks and radiologically stable ≥ 2–4 weeks — ARE eligible. Excluding all brain mets would make a pretreated HER2+ population, where CNS disease is common, hard to enroll.

Prior therapy / washout

10. Prior treatment with any deruxtecan-class agent (or the same exatecan-derivative payload), or prior intolerance/discontinuation for toxicity of any topoisomerase-I-payload ADC.

11. Inadequate washout: anticancer therapy, major surgery, or radiotherapy within the protocol-defined interval (typically ~3–4 weeks, or 5 half-lives for targeted agents) before first dose.

12. Live vaccine within 30 days of first dose.

Concomitant medications / interactions

13. Chronic strong CYP3A4 inhibitors or inducers that cannot be discontinued/substituted before dosing. Deruxtecan payload is CYP3A4-metabolized — strong inhibitors raise payload exposure and ILD/myelosuppression risk. Frame as substitutable, not an absolute ban.

14. Concurrent use of other pneumotoxic agents where avoidable (investigator discretion).

General

15. Active, uncontrolled infection (including known active HBV/HCV; HIV permitted if well-controlled per current inclusive-trial norms); second malignancy requiring active therapy; uncontrolled intercurrent illness; pregnancy/lactation; hypersensitivity to study-drug components.

Embedded On-Study Safety Architecture (protocol body, not eligibility — but the reason the criteria above can be tolerant)

These surveillance commitments are what permit the eligibility floors to stay enrollable:

• ILD program: baseline + scheduled chest CT; mandatory prompt work-up (HRCT, pulmonology consult, ± PFTs/SpO₂) of any new respiratory symptom (cough, dyspnea, fever); pre-specified dose-interruption/discontinuation and corticosteroid rules even for Grade 1 (asymptomatic) ILD. Patient and investigator ILD education.
• Cardiac program: serial LVEF (ECHO/MUGA) every ~9–12 weeks with protocol-defined hold/discontinue rules for asymptomatic LVEF decline or symptomatic dysfunction.
• Hematologic: CBC before each cycle with standard dose-modification table.

Feasibility vs. Safety — Key Trade-off Decisions

Net effect: the only truly hard, no-exception gate is the ILD history/baseline-pulmonary line — appropriate because it is the lethal class signal. Everywhere else, risk is managed through floors plus active monitoring rather than exclusion, keeping a representative pretreated HER2+ metastatic population enrollable.

These criteria are a precedent-grounded teaching/authoring draft. Exact thresholds, washout windows, line-of-therapy, CNS steroid limits, and cardiac/ILD management algorithms must be finalized against the Investigator's Brochure, regulatory feedback, and the specific statistical/operational plan before use.