A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations

A Phase II, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) for the Treatment of Unresectable and/or Metastatic Solid Tumors Harboring HER2 Activating Mutations Regardless of Tumor Histology

This is an open-label, multi-center, single arm, Phase II study to evaluate the efficacy and safety of T-DXd for the treatment of unresectable and/or metastatic solid tumors harboring specific HER2 activating mutations regardless of tumor histology. The target population are patients who have progressed following prior treatment or who have no satisfactory alternative treatment options, including approved second line therapies in the specific tumor type. Pre-specified HER2 mutations will be locally assessed using NGS tests or alternative methods. Prior HER2 targeting therapy is permitted.

Inclusion Criteria:

• Adults ≥18 years old. Other age restrictions may apply as per local regulations.
• Unresectable and/or metastatic solid tumors with pre-specified HER2 mutations (S310F, S310Y, G660D, R678Q, D769Y, D769H, V777L, Y772_A775dup / A775_G776insYVMA, L755S, G778_P780dup / P780_Y781insGSP, T862A, and V842I locally determined by NGS or a validated nucleic acid-based methodology (eg, qPCR, digital PCR) on tumor tissue, who have progressed following prior treatment or who have no satisfactory alternative treatment options.
• Prior HER2 targeted therapy is permitted.
• All patients must provide an FFPE tumor sample for retrospective central HER2 testing.
• LVEF ≥50%
• ECOG 0-1
• All patients have measurable target disease assessed by the Investigator based on RECIST v1.1

Exclusion Criteria:

• HER2 overexpressing (IHC3+ or IHC2+/ISH+) breast, gastric or gastroesophageal junction adenocarcinoma.
• HER2 mutant NSCLC.
• Medical history of myocardial infarction within 6 months before randomization/enrolment, symptomatic CHF, unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke.
• History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD cannot be ruled out by imaging at screening
• Corrected QT interval by Fridericia's formula (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.
• Lung-specific intercurrent clinically significant severe illnesses.
• History of active primary immunodeficiency, known HIV, active HBV or HCV infection
• Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
• Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
• Has spinal cord compression or clinically active central nervous system metastases.