Topoisomerase inhibitors

Mechanism and Class Overview

• Class mechanism: Inhibit DNA topoisomerase I or II, ↑ DNA strand breaks, ↓ DNA synthesis. Topo I inhibitors are S-phase active.

Topoisomerase I Inhibitors

Irinotecan (CPT-11)

• Mechanism: Prodrug metabolized by carboxylesterase to SN-38 (active; the closed lactone form is active, and hydrolysis to the open form inactivates it). SN-38 is detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1), the same enzyme that converts indirect to direct bilirubin (reduced activity in Gilbert syndrome; absent or < 10% in Crigler-Najjar). Glucuronidation converts lipophilic SN-38 to a water-soluble form for excretion.
• Pharmacogenomics: ↓ UGT1A1 activity → ↑ toxicity (especially myelosuppression and diarrhea). Homozygous UGT1A1*28/*28 (~10% in North America; Black > White > Asian) requires a ~30% dose reduction.
• Drug interactions: Enzyme inducers (carbamazepine, rifampin, phenytoin, phenobarbital, St. John's wort) ↑ irinotecan metabolism. Pazopanib inhibits UGT1A1, reducing SN-38 glucuronidation and raising SN-38 exposure and irinotecan toxicity.
• Indications: Colorectal, pancreatic, lung, and other GI cancers.
• Diarrhea (two patterns):
  • Acute (< 24 h): cholinergic, with flushing, cramping, and sweating; treat with atropine 0.25 to 1 mg and premedicate on future cycles.
  • Delayed (> 24 h, often around the 2nd to 3rd dose): treat with high-dose loperamide and fluid/electrolyte repletion; octreotide for severe or refractory diarrhea; add a fluoroquinolone for fever, neutropenia, ileus, or suspected infection; can be life-threatening and require admission.
• Other toxicities: Myelosuppression (mainly neutropenia), nausea/vomiting, alopecia.

Liposomal irinotecan (Onivyde)

• Mechanism/PK: Irinotecan encapsulated in a pegylated liposome; the PEG coat reduces plasma-protein binding and premature elimination, designed to prolong SN-38 exposure (preclinical/PK rationale); superiority or lower systemic toxicity vs conventional irinotecan is not established, and it retains boxed-warning diarrhea and neutropenia risk. No dose adjustment for CrCl ≥ 30; same drug interactions as irinotecan. Similar toxicity profile to irinotecan (diarrhea, neutropenia); unlike pegylated liposomal doxorubicin, no hand-foot syndrome.

Topotecan (Hycamtin)

• Mechanism: Direct topo I inhibitor (not a prodrug). Renal elimination (unlike irinotecan); dose reduce in renal impairment.
• Indications: Ovarian cancer (platinum-refractory), SCLC, cervical cancer.
• Toxicities: Myelosuppression (dose-limiting, mainly neutropenia; first cycle requires ANC ≥1,500 and PLT ≥100K; retreatment per label needs ANC recovery to >1,000 (or growth factor), PLT >100K, and Hgb ≥9), fatigue, mild nausea/vomiting/diarrhea, rash, alopecia.

Topoisomerase II Inhibitors

Etoposide (VP-16)

• Mechanism: Inhibits topoisomerase II, causing DNA strand breaks (derived from the mandrake plant). Resistance from ↓ topo II expression or mutation and P170 efflux.
• Pharmacokinetics: Oral-to-IV conversion 2:1; hepatic metabolism (CYP3A4 O-demethylation) and UGT1A1 glucuronidation, plus substantial renal excretion of unchanged drug, so dose adjust for both renal and hepatic impairment (renal: 75% of dose if CrCl 15 to 50, further reduction if CrCl < 15; hepatic: reduce by 50% if t-bili 1.5 to 3 or AST > 3x ULN).
• Indications: SCLC, testicular cancer, lymphoma, leukemia (HSCT conditioning).
• Toxicities: Myelosuppression, nausea/vomiting, and hypotension during infusion (slow the infusion rate to prevent). The vehicle is polysorbate 80; routine dexamethasone premedication for hypersensitivity is not standard. Infuse slowly and monitor for infusion reactions. Etoposide phosphate has no solvent and causes fewer infusion reactions, so it is used in patients with hypersensitivity.
• Secondary AML/MLL: Etoposide causes treatment-related AML with 11q23/MLL (KMT2A) rearrangement, characteristically ~2 to 3 years after treatment (a shorter latency than the alkylator-related t-MDS/AML).

2026 update: ADC payloads and pancreatic combo

Deruxtecan (Dxd): topoisomerase I inhibitor as ADC payload

• Class: exatecan derivative (Dxd), a topo I inhibitor with high potency and membrane permeability (bystander effect). Payload of trastuzumab deruxtecan (T-DXd, Enhertu), datopotamab deruxtecan (Dato-DXd, Datroway), patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (B7-H3), raludotatug deruxtecan (CDH6).
• Deruxtecan class-effect toxicity: interstitial lung disease/pneumonitis: baseline chest CT, hold for G≥1, permanent d/c for G≥2. Neutropenia, nausea.

Sacituzumab ADC payloads (topoisomerase I inhibitors: SN-38 vs belotecan-derived)

• Sacituzumab govitecan (Trodelvy): TROP2-ADC with SN-38 payload (active metabolite of irinotecan). Mature TNBC (ASCENT; now also 1L mTNBC alone or with pembrolizumab if PD-L1 CPS ≥ 10, FDA 2026) plus HR+/HER2-negative MBC (TROPiCS-02). The urothelial accelerated approval (TROPHY-U-01) was withdrawn in 2024 after TROPiCS-04 failed to improve OS.
• Sacituzumab tirumotecan (sac-TMT, MK-2870): next-gen TROP2-ADC with belotecan-derived payload. OptiTROP-Breast01 positive in mTNBC (2024).

Liposomal irinotecan (Onivyde): NALIRIFOX in pancreatic

• NAPOLI-3 (Wainberg Lancet 2023): NALIRIFOX (liposomal irinotecan plus 5-FU/LV plus oxaliplatin) vs gem/nab-P in 1L metastatic pancreatic adenocarcinoma; mOS 11.1 vs 9.2 mo. FDA Feb 13, 2024 approval for 1L mPDAC.

Etoposide: tarlatamab for SCLC

• Etoposide plus platinum remains 1L SCLC backbone (with atezo/durva, IMpower133/CASPIAN); at relapse, tarlatamab (Imdelltra), a DLL3×CD3 bispecific, DeLLphi-301, FDA May 16, 2024 acc for platinum-treated ES-SCLC (ORR 40%); converted to full approval (label 11/2025) after DeLLphi-304 showed OS benefit vs chemotherapy (13.6 vs 8.3 mo, HR 0.60).