Where Do ADCs Fit Into the Treatment Paradigm for Patients With NSCLC?



1. Marks S, Naidoo J. Antibody drug conjugates in non-small cell lung cancer: an emerging therapeutic approach. Lung Cancer. 2022;163:59-68. doi:10.1016/j.lungcan.2021.11.016

2. Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35(4):e00225. doi:10.1042/BSR20150089

3. Enhertu. Prescribing information. Daiichi Sankyo; 2022. Accessed December 5, 2022. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true

4. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097-5108. doi:10.1158/1078-0432.CCR-15-2822

5. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

6. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Investigators. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431

7. Datopotamab deruxtecan-based combinations show promising clinical activity in patients with advanced non-small cell lung cancer. Press release. AstraZeneca. August 9, 2022. Accessed December 9, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/datopotamab-deruxtecan-based-combinations-show-promising-clinical-activity-in-patients.html

8. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329-2340. doi:10.1158/1535-7163.MCT-21-0206

9. Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496-22512. doi:10.18632/oncotarget.4318

10. Krop I, Juric D, Shimizu T, et al. Abstract GS1-05: datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: results from the phase 1 TROPION-PanTumor01 study. Cancer Res. 2022;82(suppl 4):GS1-05. doi:10.1158/1538-7445.SABCS21-GS1-05

11. Trodelvy. Prescribing information. Gilead Sciences; 2022. Accessed December 5, 2022. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.pdf

12. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov. 2022;12(1):74-89. doi:10.1158/2159-8290.CD-21-0715

13. Patritumab deruxtecan granted U.S. FDA breakthrough therapy designation in patients with metastatic EGFR-mutated non-small cell lung cancer. Press release. Daiichi Sankyo. December 23, 2021. Accessed December 9, 2022. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202112/20211223_E1.pdf

14. Gazzah A, Bedard PL, Hierro C, et al. Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study. Ann Oncol. 2022;33(4):416-425. doi:10.1016/j.annonc.2021.12.012

15. Wang J, Anderson MG, Oleksijew A, et al. ABBV-399, a c-Met antibody-drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res. 2017;23(4):992-1000. doi:10.1158/1078-0432.CCR-16-1568

16. Strickler JH, Weekes CD, Nemunaitis J, et al. First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, in patients with advanced solid tumors. J Clin Oncol. 2018;36(33):3298-3306. doi:10.1200/JCO.2018.78.7697

17. Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules. 2020;25(20):4764. doi:10.3390/molecules25204764

18. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93. doi:10.1038/s41392-022-00947-7

19. de Taeye SW, Bentlage AEH, Mebius MM, et al. FcγR binding and ADCC activity of human IgG allotypes. Front Immunol. 2020;11:740. doi:10.3389/fimmu.2020.00740

20. Aoyama M, Tada M, Yokoo H, Demizu Y, Ishii-Watabe A. Fcγ receptor-dependent internalization and off-target cytotoxicity of antibody-drug conjugate aggregates. Pharm Res. 2022;39(1):89-103. doi:10.1007/s11095-021-03158-x

21. Nolting B. Linker technologies for antibody-drug conjugates. Methods Mol Biol. 2013;1045:71-100. doi:10.1007/978-1-62703-541-5_5

22. Kellogg BA, Garrett L, Kovtun Y, et al. Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage. Bioconjug Chem. 2011;22(4):717-727. doi:10.1021/bc100480a

23. Starodub AN, Ocean AJ, Shah MA, et al. First-in-human trial of a novel anti-Trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res. 2015;21(17):3870-3878. doi:10.1158/1078-0432.CCR-14-3321

24. Masters JC, Nickens DJ, Xuan D, Shazer RL, Amantea M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs. 2018;36(1):121-135. doi:10.1007/s10637-017-0520-6

25. Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata 1,2. J Am Chem Soc. 1966;88(16):3888-3890. doi:10.1021/ja00968a057

26. Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem. 1985;260(27):14873-14878. doi:10.1016/S0021-9258(17)38654-4

27. Li W, Veale KH, Qiu Q, et al. Synthesis and evaluation of camptothecin antibody-drug conjugates. ACS Med Chem Lett. 2019;10(10):1386-1392. doi:10.1021/acsmedchemlett.9b00301

28. Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70:369-413. doi:10.1146/annurev.biochem.70.1.369

29. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554

30. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9007. doi:10.1200/JCO.2021.39.15_suppl.9007

31. Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255(2):232-240. doi:10.1016/j.canlet.2007.04.010

32. Kubo K, Azuma A, Kanazawa M, et al; Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig. 2013;51(4):260-277. doi:10.1016/j.resinv.2013.09.001

33. Levy B, Leventakos K, Lou Y, et al. P47.04 TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab and platinum-based chemotherapy in advanced NSCLC. J Thoracic Oncol. 2021;16(10):S1097-S1098. doi:10.1016/j.jtho.2021.08.497

34. Strop P, Tran TT, Dorywalska M, et al. RN927C, a Site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther. 2016;15(11):2698-2708. doi:10.1158/1535-7163.MCT-16-0431

35. Camptosar. Prescribing information. Pfizer; 2022. Accessed December 5, 2022. https://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=533

36. Wu C, Zhang Y, Yang D, et al. Novel SN38 derivative-based liposome as anticancer prodrug: an in vitro and in vivo study. Int J Nanomedicine. 2018;14:75-85. doi:10.2147/IJN.S187906

37. Bardia A, Mayer IA, Diamond JR, et al. Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol. 2017;35(19):2141-2148. doi:10.1200/JCO.2016.70.8297

38. Singh H, Leyton VJ. Abstract P062: The CL2A-SN38 linker-payload system conjugated to trastuzumab results in improved cellular cytotoxicity over time relative to T-DM1. Mol Cancer Ther. 2021;20(suppl 12):P062. doi:10.1158/1535-7163.TARG-21-P062

39. Garassino MC, Reznick D, Liu SY, et al. EVOKE-01: a phase 3 study of sacituzumab govitecan (SG) versus docetaxel in patients with non–small cell lung cancer (NSCLC) progressing on or after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2022;40(suppl 16):TPS1949. doi:10.1200/JCO.2022.40.16_suppl.TPS9149

40. Garon EB, Liu SV, Owen SP, et al. EVOKE-02: a phase 2 study of sacituzumab govitecan (SG) plus pembrolizumab (pembro) with or without platinum chemotherapy in first-line metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl 16):TPS9146. doi:10.1200/JCO.2022.40.16_suppl.TPS9146

41. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213

42. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

43. Pettit GR, Kamano Y, Herald CL, et al. The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. J Am Chem Soc. 1987;109(22):6883-6885. doi:10.1021/ja00256a070

44. Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol. 2012;30(7):631-637. doi:10.1038/nbt.2289

45. Wang Y, Liu L, Fan S, et al. Antibody-drug conjugate using ionized cys-linker-MMAE as the potent payload shows optimal therapeutic safety. Cancers (Basel). 2020;12(3):744. doi:10.3390/cancers12030744

46. Bai R, Pettit GR, Hamel E. Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol. 1990;39(12):1941-1949. doi:10.1016/0006-2952(90)90613-p

47. Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE. Structural basis of microtubule destabilization by potent auristatin anti-mitotics. PLoS One. 2016;11(8):e0160890. doi:10.1371/journal.pone.0160890

48. Camidge DR, Bar J, Horinoushi H, et al. Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl 16):9016. doi:10.1200/JCO.2022.40.16_suppl.9016

49. Mahalingaiah PK, Ciurlionis R, Durbin KR, et al. Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol Ther. 2019;200:110-125. doi:10.1016/j.pharmthera.2019.04.008

50. Kupchan SM, Komoda Y, Branfman AR, et al. The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides. J Org Chem. 1977;42(14):2349-2357. doi:10.1021/jo00434a001

51. Oroudjev E, Lopus M, Wilson L, et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther. 2010;9(10):2700-2713. doi:10.1158/1535-7163.MCT-10-0645

52. Lopus M, Oroudjev E, Wilson L, et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010;9(10):2689-2699. doi:10.1158/1535-7163.MCT-10-0644

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