Topoisomerase-I inhibitors (and ADC payloads)
Topoisomerase-I inhibitors work by jamming the enzyme that untangles DNA during copying. They are weak as free drugs in many cancers, but devastating when delivered by an ADC.
Irinotecan and topotecan are modest as systemic agents. Their analogues SN-38 (sacituzumab govitecan), DXd/exatecan derivatives (T-DXd, Dato-DXd, HER3-DXd, I-DXd, R-DXd), and belotecan derivatives (sac-TMT) are the dominant ADC payload class of the 2020s: membrane-permeable for bystander killing, short half-life limiting systemic toxicity, and effective in taxane-resistant tumours. Cross-resistance between TOP1 ADCs is a growing clinical problem.
How it works
Stabilise the TOP1-DNA cleavage complex, causing replication-associated double-strand breaks.
- Bystander effect
- Active after taxanes and anthracyclines
- Cross-resistance between TOP1-payload ADCs (SLFN11 loss, TOP1 mutations)
- ILD with DXd; neutropenia and diarrhoea with SN-38
Datopotamab deruxtecan (Datroway) is the second TROP2 ADC and shares Enhertu's payload. In 2026 it became a first-line option for triple-negative breast cancer patients who cannot receive immunotherapy.
Etoposide is a chemotherapy from the mayapple plant, essential to curing testicular cancer (BEP), treating small-cell lung cancer, lymphomas, childhood sarcomas and leukaemias, and used in transplant conditioning.
FOLFIRI is the other backbone bowel-cancer chemotherapy, swapping oxaliplatin for irinotecan. Used first or second line and, since 2026, with the BRAF combination.
FOLFIRINOX is a four-drug chemotherapy combination that, in 2011, became the first treatment to meaningfully extend life in metastatic pancreatic cancer; it is now the standard before and after surgery.
Irinotecan is a topoisomerase-blocking chemotherapy central to bowel and pancreatic cancer regimens (FOLFIRI, FOLFIRINOX, NALIRIFOX) and to salvage therapy in childhood sarcomas; it carries the same warhead as the deruxtecan ADC payloads.
NALIRIFOX is a version of FOLFIRINOX using a liposome-wrapped irinotecan, approved in 2024 as a first-line option for metastatic pancreatic cancer.
Doxorubicin wrapped in a fatty bubble so it reaches tumours with less heart damage; a workhorse of relapsed ovarian cancer.
Platinum plus etoposide has been the chemotherapy backbone of small-cell lung cancer for over 40 years, and is now given with immunotherapy.
Rinatabart sesutecan is a next-generation folate-receptor ADC with a topoisomerase payload that responds in both ovarian and endometrial cancer regardless of receptor level.
The first TROP2-targeted ADC. It delivers a strong chemotherapy directly to breast and bladder cancer cells and is now a first-line option in triple-negative breast cancer.
Sacituzumab tirumotecan is a third TROP2 ADC from China, licensed to Merck for a very large global programme. It is approved in China; in the US it has a priority voucher but not yet approval.
Topotecan is the long-standing second-line chemotherapy for relapsed small-cell lung cancer, and now the comparator that new drugs must beat.
SystImmune's HER2 ADC, sharing its payload with iza-bren, now in a 1,450-patient trial to replace Kadcyla after surgery.
Trastuzumab deruxtecan (Enhertu) is the most successful ADC ever. It redefined HER2 by working in tumours with only tiny amounts of the protein, and in 2026 moved into early-stage breast cancer.
Hengrui's HER2 ADC, approved in China for lung cancer and showing Enhertu-scale results in breast cancer, part of a wave of Chinese ADCs heading for global trials.
For hormone-receptor-positive metastatic breast cancer that has already had chemotherapy, Dato-DXd controls the disease for longer with fewer severe side effects than chemotherapy, but does not help patients live longer, so it is not a standard option here. The result is a reminder that progression-free survival is a surrogate; regulators and clinicians should wait for survival data before adopting an ADC in a setting where later therapies are effective.
For fit patients with newly diagnosed metastatic pancreatic cancer, a FOLFIRINOX-type regimen is now proven to be better than gemcitabine plus nab-paclitaxel, settling a long-standing debate. The absolute gain is about two months of median survival, and the regimen is more toxic for the gut. Whether liposomal irinotecan adds anything over conventional irinotecan (standard FOLFIRINOX) has never been tested head-to-head.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
Sacituzumab govitecan is a standard second-line or later treatment for metastatic triple-negative breast cancer, roughly doubling survival compared with the chemotherapies it was tested against. Patients should expect neutropenia and diarrhoea, which are manageable with growth factor support and loperamide. Trials are now testing it earlier, in first-line combinations with pembrolizumab and after surgery for residual disease.
Latest papers
topQuery for this technology: (TITLE:"topoisomerase I inhibitor payload" OR ABSTRACT:"topoisomerase I inhibitor payload" OR TITLE:"deruxtecan" OR ABSTRACT:"deruxtecan" OR TITLE:"exatecan" OR ABSTRACT:"exatecan" OR TITLE:"SN-38 payload" OR ABSTRACT:"SN-38 payload"). Results are unfiltered search hits about Topoisomerase-I inhibitors (and ADC payloads), not a curated reading list.