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

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.