What FDA‑approved tissue‑agnostic drugs are available, and what are their specific indications and dosing regimens?

FDA-Approved Tissue-Agnostic Drugs: Indications and Dosing

The FDA has approved eight tissue-agnostic therapies targeting specific molecular biomarkers regardless of tumor histology: pembrolizumab and dostarlimab for MSI-H/dMMR tumors, pembrolizumab for TMB-H tumors, larotrectinib and entrectinib for NTRK fusion-positive cancers, selpercatinib for RET fusion-positive tumors, dabrafenib plus trametinib for BRAFV600E-mutated tumors, and fam-trastuzumab deruxtecan for HER2-positive solid tumors. 1, 2

Immune Checkpoint Inhibitors for MSI-H/dMMR Tumors

Pembrolizumab

• Indication: Unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options 3
• Dosing: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks for adults; 2 mg/kg (up to 200 mg) IV every 3 weeks for pediatric patients 4
• Administration: Infuse over 30 minutes after dilution 4
• Key efficacy: Achieved ORR of 40% and PFS rate of 78% at 20 weeks in colorectal cancer patients with dMMR 3

Dostarlimab

• Indication: Adult patients with dMMR recurrent or advanced solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options, and who had not previously received a PD-1 or PD-L1 inhibitor 3
• Key efficacy: ORR of 42% with median duration of response of 35 months in 209 patients with dMMR solid tumors 3

Nivolumab

• Indication: Adults and children with MSI or dMMR metastatic colorectal cancer that progressed following fluoropyrimidine, oxaliplatin, and irinotecan, as single agent or in combination with ipilimumab 3

Pembrolizumab for TMB-H Tumors

• Indication: Unresectable or metastatic TMB-H (≥10 mutations/megabase) solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options 5
• Dosing: Same as MSI-H indication: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks for adults 4
• Important caveat: The TMB cut-off value remains debated in clinical practice 1

TRK Inhibitors for NTRK Fusion-Positive Tumors

Larotrectinib

• Indication: Adult and pediatric patients (≥12 years) with solid tumors harboring NTRK gene fusion without known acquired resistance mutation, that are metastatic or where surgical resection would result in severe morbidity, with no satisfactory alternatives or disease progression after treatment 3
• Key efficacy: ORR of 79% with median DOR of 35.2 months, median PFS of 28.3 months, and median OS of 44.4 months in pooled analysis of 153 patients 3
• Adverse events: Predominantly grade 1-2, most common being fatigue, increased AST/ALT, vomiting, constipation, and dizziness 3

Entrectinib

• Indication: Adult patients with metastatic or locally advanced NTRK gene fusion-positive solid tumors; also approved for ROS1-positive non-small cell lung cancer 3, 6
• Key efficacy: ORR of 57% with CR rate of 7%; response duration ≥6 months for 68% and ≥12 months for 45% of patients across 54 patients 3
• Target profile: Inhibits TRKA, TRKB, TRKC, ROS1, and ALK proteins 3, 6

Repotrectinib

• Status: Third-generation TRK inhibitor approved for NTRK fusion-positive solid tumors 3

RET Fusion-Positive Tumors

Selpercatinib

• Indication: RET fusion-positive solid tumors 1
• Mechanism: Selective RET kinase inhibitor 1

BRAFV600E-Mutated Tumors

Dabrafenib plus Trametinib

• Indication: Patients ≥6 months of age with unresectable or metastatic tumors (except colorectal cancer) carrying BRAFV600E mutation 1
• Critical exclusion: Not approved for colorectal cancer with BRAFV600E mutation due to lack of efficacy 1
• Mechanism: Dabrafenib inhibits BRAF; trametinib inhibits MEK 1

HER2-Positive Solid Tumors

Fam-Trastuzumab Deruxtecan-nxki (T-Dxd)

• Indication: HER2-positive solid tumors 1
• Most recent approval: Latest FDA tissue-agnostic approval 1

Critical Testing and Selection Considerations

When to Test

• NTRK testing: Recommended for tumor types where NTRK fusions occur with higher frequency, though frequency is <1% in most sarcomas 3
• MSI/MMR testing: Should be performed in patients with advanced solid tumors to identify candidates for immune checkpoint inhibitors 3

Patient Selection Criteria

• Patients must have progressed on prior standard therapies or have no satisfactory alternative treatment options 3
• For NTRK inhibitors, tumors must not have known acquired resistance mutations 3
• For pembrolizumab in MSI-H/dMMR, patients must not have previously received PD-1 or PD-L1 inhibitors (for some indications) 3

Common Pitfalls and Monitoring

Immune-Related Adverse Events

• Monitor for pneumonitis (dyspnea, cough, chest pain), colitis (diarrhea, abdominal pain, blood in stool), hepatitis, endocrinopathies, nephritis, and dermatologic reactions 4
• Obtain baseline and periodic monitoring of liver enzymes, creatinine, and thyroid function 4
• Immune-related adverse events can develop months after treatment completion, requiring ongoing vigilance 7, 8

Surveillance Schedule

• Clinical and laboratory evaluation every 3 months during the first year, then every 6 months thereafter 8
• Laboratory panel should include CBC, renal function, electrolytes, glycemia, coagulation studies, liver function, and TSH 8

Resistance Development

• Universal development of resistance remains a troublesome problem with both targeted and cytotoxic drugs 6
• For NTRK inhibitors, acquired resistance mutations can develop, necessitating alternative TRK inhibitors 3