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Topoisomerase-I inhibitors jam the enzyme that untangles DNA during copying, causing double-strand breaks. As free drugs (irinotecan, topotecan) they are modest, but their analogues SN-38 and deruxtecan are the dominant antibody-drug conjugate payload class of the 2020s, active after taxane failure; cross-resistance between these ADCs is a growing problem.
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.
Stabilise the TOP1-DNA cleavage complex, causing replication-associated double-strand breaks.
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.
Daunorubicin is the anthracycline most often combined with cytarabine to bring acute myeloid leukaemia into remission; it is also part of induction for acute lymphoblastic leukaemia.
Epirubicin (Ellence) is a close relative of doxorubicin used mainly after breast cancer surgery when lymph nodes are involved, and in stomach cancer regimens; it is a little kinder to the heart.
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.
All three of the active bowel cancer chemotherapy drugs given together instead of two. It shrinks more tumours than a doublet and is chosen when shrinking the tumour is what matters, usually with bevacizumab.
Idarubicin is an anthracycline chemotherapy approved in 1990 for adult acute myeloid leukaemia, given with cytarabine in 3+7 induction and FLAG-Ida salvage and in acute promyelocytic leukaemia protocols. Randomised trials showed more complete remissions than with daunorubicin, which is why centres prefer it; heart damage, marrow suppression and extravasation injury are the class risks.
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.
Irinotecan wrapped in a fat bubble so it circulates longer. It is approved for pancreatic cancer, and in bile duct and gallbladder cancer one Korean trial found it helped as second-line treatment while a German trial did not.
Mitoxantrone is a blue chemotherapy infusion used with cytarabine for acute myeloid leukaemia and, historically, to relieve pain in advanced prostate cancer; it is also licensed for multiple sclerosis.
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 Kelun-Biotech's TROP2 ADC, approved in China in 2024 for pretreated triple-negative breast cancer and then EGFR-mutant lung cancer. Merck holds rights outside Greater China and runs the TroFuse programme of more than ten phase 3 trials across breast, lung, endometrial and cervical cancer; in the US it holds a priority voucher but no approval yet.
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.
Valrubicin (Valstar) is a chemotherapy washed into the bladder for carcinoma in situ that has not responded to BCG, in patients who cannot yet have their bladder removed.
The first-line overall survival result that made an antibody-drug conjugate the standard for PD-L1-negative or immunotherapy-ineligible metastatic triple-negative disease, and the reason the sequencing question (which TROP2 drug first, what after it) is now urgent.
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.
The first approved second-line regimen and the basis of NALIRIFOX, which NAPOLI 3 later moved to first line; it fixed the sequence (gemcitabine-based first, then liposomal irinotecan with fluorouracil) written into the 2018 ASCO guideline.
Query 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.
Shares mFOLFOXIRI Plus Bevacizumab for Organ Preservation in Locally Advanced Rectal Cancer, NeoFOL-R Trial (Perioperative Versus Adjuvnat FOLFIRINOX in Resectable Pancreatic Cancer), Adjuvant mFOLFIRINOX for High-risk Stage III Colon Cancer, mFOLFIRINOX as Adjuvent Chemotherapy in Treating Chinese Pancreatic Cancer Patients.
Shares Irinotecan-ChemoSeed in Surgically Resectable Glioblastoma, Pharmacogenomics ANDA SNP Clinical Study - Etoposide and Single Nucleotide Polymorphisms, Pharmacogenomics ANDA SNP Clinical Study - Topotecan and Single Nucleotide Polymorphisms, Retinoblastoma Phase II Expanded Access Clinical Trial.
Shares A Study to Provide Continued Access to and Assess Long-Term Safety of the Study Drug(s), Study of Trastuzumab Deruxtecan Versus Standard of Care Chemotherapy for HER2-Expressing (IHC 3+/2+) Endometrial Cancer, A Study of Dato-DXd in Chinese Patients With Advanced Non-Small Cell Lung Cancer, Triple-negative Breast Cancer and Other Solid Tumors (TROPION-PanTumor02), A Study of T-DXd as Monotherapy or in Combination With Anti-cancer Agents in Patients With Selected HER2-expressing Tumors.
Shares Perioperative Treatment in High-risk Resectable Pancreatic Cancer With NALIRIFOX, A Study to Compare the Efficacy and Safety of YL201 With Standard Chemotherapy in Patients With Metastatic Pancreatic Cancer After Failure of Gemcitabine-Based, HR070803 in Combination With Oxaliplatin, S-1 Versus NALIRIFOX as Adjuvant Therapy for Pancreatic Cancer, Intermittent or Continuous Panitumumab Plus FOLFIRI for Left Sided RAS/B-RAF Wild-type Metastatic Colorectal Cancer.
Shares A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations, A Single Arm Phase 2 Study to Evaluate Efficacy and Safety of Trastuzumab Deruxtecan for Patients With HER2 Mutant NSCLC, A Study of Dato-DXd in Chinese Patients With Advanced Non-Small Cell Lung Cancer, Triple-negative Breast Cancer and Other Solid Tumors (TROPION-PanTumor02), A Study of T-DXd as Monotherapy or in Combination With Anti-cancer Agents in Patients With Selected HER2-expressing Tumors.
Shares Study of Sacituzumab Govitecan in Participants With Metastatic Solid Tumors, Study of Sacituzumab Govitecan in Patients With Solid Tumor, A Study of Sacituzumab Govitecan Given at an Alternative Dose and Schedule in Participants With Advanced Triple-Negative Breast Cancer, Study of Sacituzumab Govitecan (SG) in Japanese Participants With Advanced Solid Tumors.
Shares Liposomal Irinotecan and Capecitabine Plus Bevacizumab as Second-line Therapy in Metastatic Colorectal Cancer, Liposomal Irinotecan With TAS102 and Bevacizumab for Patients With Metastatic Colorectal Cancer, LPM6690176 in Combination With Chemotherapy and Bevacizumab in Metastatic Colorectal Cancer Patients With RAS Mutation, AK112 Plus FOLFIRI Versus Bevacizumab Plus FOLFIRI as Second-line Treatment of MSS/pMMR Metastatic Colorectal Cancer.
Shares Adjuvant mFOLFIRINOX for High-risk Stage III Colon Cancer, Adjuvant mFOLFOXIRI vs. mFOLFOX6 in MRD Positive Stage II-III Colorectal Cancer (AFFORD), Neoadjuvant FOLFIRINOX and Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer Patients, Neoadjuvant Treatment With mFOLFOXIRI Plus Cadonilimab (AK104) Versus mFOLFOX6 in Locally Advanced Colorectal Cancer.