Skip to main content
Top
Published in:

03-01-2024 | Ovarian Cancer

Antibody-Drug Conjugates in Gynecologic Cancers

Authors: Mary Katherine Anastasio, MD, Stephanie Shuey, PharmD, Brittany A. Davidson, MD

Published in: Current Treatment Options in Oncology | Issue 1/2024

Login to get access

Opinion Statement

Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapies with the ability to selectively deliver a cytotoxic drug to a tumor cell using a monoclonal antibody linked to a cytotoxic payload. The technology of ADCs allows for tumor-specificity, improved efficacy, and decreased toxicity compared to standard chemotherapy. Common toxicities associated with ADC use include ocular, pulmonary, hematologic, and neurologic toxicities. Several ADCs have been approved by the United States Food and Drug Administration (FDA) for the management of patients with recurrent or metastatic gynecologic cancers, a population with poor outcomes and limited effective treatment options. The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.
Literature
2.
go back to reference Cancer Facts & Figures 2023. American Cancer Society, Inc. 2022. Cancer Facts & Figures 2023. American Cancer Society, Inc. 2022.
3.
go back to reference Schorge JO, et al. The effect of postsurgical therapy on stage III endometrial carcinoma. Gynecol Oncol. 1996;63(1):34–9.PubMedCrossRef Schorge JO, et al. The effect of postsurgical therapy on stage III endometrial carcinoma. Gynecol Oncol. 1996;63(1):34–9.PubMedCrossRef
4.
go back to reference Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.PubMedCrossRef Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.PubMedCrossRef
5.
go back to reference Armstrong DK, et al. Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2021;19(2):191-226. Armstrong DK, et al. Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2021;19(2):191-226.
6.
go back to reference Brooks RA, et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin. 2019;69(4):258–79.PubMedCrossRef Brooks RA, et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin. 2019;69(4):258–79.PubMedCrossRef
7.
go back to reference Marth C, et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv262. Marth C, et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv262.
8.
go back to reference Aghajanian C, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039–45.PubMedPubMedCentralCrossRef Aghajanian C, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039–45.PubMedPubMedCentralCrossRef
9.
go back to reference Burger RA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.PubMedCrossRef Burger RA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.PubMedCrossRef
10.
go back to reference Pujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8.PubMedCrossRef Pujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8.PubMedCrossRef
12.
go back to reference Gonzalez-Martin A, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391–402.PubMedCrossRef Gonzalez-Martin A, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391–402.PubMedCrossRef
13.
go back to reference Monk BJ, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40(34):3952–64.PubMedPubMedCentralCrossRef Monk BJ, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40(34):3952–64.PubMedPubMedCentralCrossRef
14.
go back to reference Moore K, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–505.PubMedCrossRef Moore K, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–505.PubMedCrossRef
16.
go back to reference Marabelle A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1–10.PubMedCrossRef Marabelle A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1–10.PubMedCrossRef
17.
go back to reference O’Malley DM, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40(7):752–61.PubMedPubMedCentralCrossRef O’Malley DM, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40(7):752–61.PubMedPubMedCentralCrossRef
19.
go back to reference Mirza MR, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145–58.PubMedCrossRef Mirza MR, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145–58.PubMedCrossRef
20.
go back to reference Colombo N, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856–67.PubMedCrossRef Colombo N, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856–67.PubMedCrossRef
21.
go back to reference Lundqvist EA, Fujiwara K, Seoud M. Principles of chemotherapy. Int J Gynaecol Obstet. 2015;131(Suppl 2):S146-9.PubMed Lundqvist EA, Fujiwara K, Seoud M. Principles of chemotherapy. Int J Gynaecol Obstet. 2015;131(Suppl 2):S146-9.PubMed
22.
go back to reference Tarantino P, et al. Antibody-drug conjugates: smart chemotherapy delivery across tumor histologies. CA Cancer J Clin. 2022;72(2):165–82.PubMedCrossRef Tarantino P, et al. Antibody-drug conjugates: smart chemotherapy delivery across tumor histologies. CA Cancer J Clin. 2022;72(2):165–82.PubMedCrossRef
23.
go back to reference Calo CA, O’Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2021;21(7):875–87.PubMedCrossRef Calo CA, O’Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2021;21(7):875–87.PubMedCrossRef
24.
25.
go back to reference Damelin M, Zhong W, Myers J, Sapra P. Evolving strategies for target selection for antibody-drug conjugates. Pharm Res. 2015;32(11):3494–507.PubMedCrossRef Damelin M, Zhong W, Myers J, Sapra P. Evolving strategies for target selection for antibody-drug conjugates. Pharm Res. 2015;32(11):3494–507.PubMedCrossRef
26.
27.
go back to reference Schlothauer T, et al. Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng Des Sel. 2016;29(10):457–66.PubMedCrossRef Schlothauer T, et al. Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng Des Sel. 2016;29(10):457–66.PubMedCrossRef
28.
go back to reference Shen BQ, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30(2):184–9.PubMedCrossRef Shen BQ, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30(2):184–9.PubMedCrossRef
29.
go back to reference Zhang D, Goldberg MV, Chiu ML. Fc Engineering approaches to enhance the Agonism and effector functions of an Anti-OX40 antibody. J Biol Chem. 2016;291(53):27134–46.PubMedPubMedCentralCrossRef Zhang D, Goldberg MV, Chiu ML. Fc Engineering approaches to enhance the Agonism and effector functions of an Anti-OX40 antibody. J Biol Chem. 2016;291(53):27134–46.PubMedPubMedCentralCrossRef
30.
31.
go back to reference Chen H, Lin Z, Arnst KE, Miller DD, Li W. Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules. 2017;22(8):1281. Chen H, Lin Z, Arnst KE, Miller DD, Li W. Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules. 2017;22(8):1281.
32.
go back to reference Pahl A, Lutz C, Hechler T. Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov Today Technol. 2018;30:85–9.PubMedCrossRef Pahl A, Lutz C, Hechler T. Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov Today Technol. 2018;30:85–9.PubMedCrossRef
33.
34.
go back to reference Hamblett KJ, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70.PubMedCrossRef Hamblett KJ, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70.PubMedCrossRef
36.
go back to reference Sheyi R, de la Torre BG, Albericio F. Linkers: an assurance for controlled delivery of antibody-drug conjugate. Pharmaceutics. 2022;14(2):396. Sheyi R, de la Torre BG, Albericio F. Linkers: an assurance for controlled delivery of antibody-drug conjugate. Pharmaceutics. 2022;14(2):396.
37.
go back to reference Kovtun YV, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006;66(6):3214–21.PubMedCrossRef Kovtun YV, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006;66(6):3214–21.PubMedCrossRef
38.
go back to reference Polson AG, et al. Antibody-drug conjugates for the treatment of non-Hodgkin‘s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358–64.PubMedCrossRef Polson AG, et al. Antibody-drug conjugates for the treatment of non-Hodgkin‘s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358–64.PubMedCrossRef
39.
40.
go back to reference Masters JC, et al. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs. 2018;36(1):121–35.PubMedCrossRef Masters JC, et al. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs. 2018;36(1):121–35.PubMedCrossRef
41.
go back to reference Zhu Y, Liu K, Wang K, Zhu H. Treatment-related adverse events of antibody-drug conjugates in clinical trials: a systematic review and meta-analysis. Cancer. 2023;129(2):283–95.PubMedCrossRef Zhu Y, Liu K, Wang K, Zhu H. Treatment-related adverse events of antibody-drug conjugates in clinical trials: a systematic review and meta-analysis. Cancer. 2023;129(2):283–95.PubMedCrossRef
42.
go back to reference Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589–604.PubMedPubMedCentralCrossRef Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589–604.PubMedPubMedCentralCrossRef
43.
go back to reference Kim SK, et al. Mitigation and management strategies for ocular events associated with tisotumab vedotin. Gynecol Oncol. 2022;165(2):385–92.PubMedCrossRef Kim SK, et al. Mitigation and management strategies for ocular events associated with tisotumab vedotin. Gynecol Oncol. 2022;165(2):385–92.PubMedCrossRef
44.
go back to reference • Gilbert L, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRalpha)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023;170:241-247. This phase 1b/2 study is of importance as it demonstrates the antitumor effects of mirvetuximab soravtansine in patients with platinum resistant ovarian cancer regardless of level of FRα expression. In addition, it demonstrates that the combination an antibody-drug conjugate with bevacizumab was well-tolerated. • Gilbert L, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRalpha)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023;170:241-247. This phase 1b/2 study is of importance as it demonstrates the antitumor effects of mirvetuximab soravtansine in patients with platinum resistant ovarian cancer regardless of level of FRα expression. In addition, it demonstrates that the combination an antibody-drug conjugate with bevacizumab was well-tolerated.
45.
go back to reference Heitz N, Greer SC, Halford Z. A review of tisotumab vedotin-tftv in recurrent or metastatic cervical cancer. Ann Pharmacother. 2023;57(5):585–96.PubMedCrossRef Heitz N, Greer SC, Halford Z. A review of tisotumab vedotin-tftv in recurrent or metastatic cervical cancer. Ann Pharmacother. 2023;57(5):585–96.PubMedCrossRef
47.
go back to reference Richardson D, et al. Updated results from the phase 1 expansion study of upifitamab rilsodotin (upri; xmt-1536), a napi2b-directed dolaflexin antibody drug conjugate (ADC) in ovarian cancer (076). Gynecologic Oncology. 2022;166:S48.CrossRef Richardson D, et al. Updated results from the phase 1 expansion study of upifitamab rilsodotin (upri; xmt-1536), a napi2b-directed dolaflexin antibody drug conjugate (ADC) in ovarian cancer (076). Gynecologic Oncology. 2022;166:S48.CrossRef
48.
go back to reference Kaufman B, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.PubMedCrossRef Kaufman B, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.PubMedCrossRef
49.
go back to reference Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–92.PubMedCrossRef Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–92.PubMedCrossRef
50.
go back to reference Pujade-Lauraine E, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84.PubMedCrossRef Pujade-Lauraine E, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84.PubMedCrossRef
51.
go back to reference Swisher EM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75–87.PubMedCrossRef Swisher EM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75–87.PubMedCrossRef
52.
go back to reference Chen YL, et al. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response. Mol Oncol. 2012;6(3):360–9.PubMedCrossRef Chen YL, et al. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response. Mol Oncol. 2012;6(3):360–9.PubMedCrossRef
54.
go back to reference •• Matulonis UA, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. This phase II SORAYA study is of outstanding importance as it demonstrated the antitumor effects of mirvetuximab soravtansine in patients with platinum-resistant epithelial ovarian cancer who have received up to three prior therapies including bevacizumab. The results of this study were practice-changing and led to approval of mirvetuximab for use in folate receptor alpha-positive, platinum resistant, epithelial ovarian cancer. •• Matulonis UA, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. This phase II SORAYA study is of outstanding importance as it demonstrated the antitumor effects of mirvetuximab soravtansine in patients with platinum-resistant epithelial ovarian cancer who have received up to three prior therapies including bevacizumab. The results of this study were practice-changing and led to approval of mirvetuximab for use in folate receptor alpha-positive, platinum resistant, epithelial ovarian cancer.
56.
go back to reference •• Moore KN, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. J Clin Oncol. 2023;41(17_suppl):LBA5507–LBA5507. While the final results from this study have not yet been published, the initial results report of the phase III MIRASOL study are of outstanding importance. This study confirms mirvetuximab as the first treatment to demonstrate both progression-free and overall survival in platinum-resistant ovarian cancer compared to investigator’s choice chemotherapy. These results will likely result in changes to standard of care treatment for patients with FR alpha-positive platinum resistant ovarian cancer. •• Moore KN, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. J Clin Oncol. 2023;41(17_suppl):LBA5507–LBA5507. While the final results from this study have not yet been published, the initial results report of the phase III MIRASOL study are of outstanding importance. This study confirms mirvetuximab as the first treatment to demonstrate both progression-free and overall survival in platinum-resistant ovarian cancer compared to investigator’s choice chemotherapy. These results will likely result in changes to standard of care treatment for patients with FR alpha-positive platinum resistant ovarian cancer.
57.
go back to reference O’Malley DM, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRalpha)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379–85.PubMedCrossRef O’Malley DM, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRalpha)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379–85.PubMedCrossRef
58.
go back to reference Naumann RW, et al. Phase 1 dose-escalation study of STRO-002, an antifolate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced, progressive platinum-resistant/refractory epithelial ovarian cancer (EOC). J Clin Oncol. 2021;39(15_suppl): 5550–5550. Naumann RW, et al. Phase 1 dose-escalation study of STRO-002, an antifolate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced, progressive platinum-resistant/refractory epithelial ovarian cancer (EOC). J Clin Oncol. 2021;39(15_suppl): 5550–5550.
59.
go back to reference Naumann RW, et al. STRO-002-GM2: A phase 1, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody-drug conjugate (ADC), in combination with bevacizumab in patients with advanced epithelial ovarian cancer (EOC, including fallopian tube or primary peritoneal cancers). J Clin Oncol. 2022;40(16_suppl):TPS5622–TPS5622. Naumann RW, et al. STRO-002-GM2: A phase 1, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody-drug conjugate (ADC), in combination with bevacizumab in patients with advanced epithelial ovarian cancer (EOC, including fallopian tube or primary peritoneal cancers). J Clin Oncol. 2022;40(16_suppl):TPS5622–TPS5622.
60.
go back to reference Shimizu T, et al. First-in-human phase 1 study of MORAb-202, an antibody-drug conjugate comprising farletuzumab linked to eribulin mesylate, in patients with folate receptor-α-positive advanced solid tumors. Clin Cancer Res. 2021;27(14):3905–15.PubMedCrossRef Shimizu T, et al. First-in-human phase 1 study of MORAb-202, an antibody-drug conjugate comprising farletuzumab linked to eribulin mesylate, in patients with folate receptor-α-positive advanced solid tumors. Clin Cancer Res. 2021;27(14):3905–15.PubMedCrossRef
61.
go back to reference Armstrong DK, et al. Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer. Gynecol Oncol. 2013;129(3):452–8.PubMedCrossRef Armstrong DK, et al. Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer. Gynecol Oncol. 2013;129(3):452–8.PubMedCrossRef
62.
go back to reference Vergote I, et al. A randomized, double-blind, placebo-controlled, phase iii study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J Clin Oncol. 2016;34(19):2271–8.PubMedCrossRef Vergote I, et al. A randomized, double-blind, placebo-controlled, phase iii study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J Clin Oncol. 2016;34(19):2271–8.PubMedCrossRef
63.
go back to reference Levan K, et al. Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b. BMC Cancer. 2017;17(1):303.PubMedPubMedCentralCrossRef Levan K, et al. Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b. BMC Cancer. 2017;17(1):303.PubMedPubMedCentralCrossRef
64.
go back to reference • Gerber DE, et al. Phase Ia study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin DNIB0600A in patients with non-small cell lung cancer and platinum-resistant ovarian cancer. Clin Cancer Res. 2020;26(2):364–372. This phase I trial of lifastuzumab vedotin in patients with platinum-resistant ovarian cancer is of importance as it identified NaPi2b as a target of interest and demonstrated encouraging antitumor activity with an acceptable safety profile. • Gerber DE, et al. Phase Ia study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin DNIB0600A in patients with non-small cell lung cancer and platinum-resistant ovarian cancer. Clin Cancer Res. 2020;26(2):364–372. This phase I trial of lifastuzumab vedotin in patients with platinum-resistant ovarian cancer is of importance as it identified NaPi2b as a target of interest and demonstrated encouraging antitumor activity with an acceptable safety profile.
65.
go back to reference • Moore KN, et al. Phase 1b study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2020;158(3):631–639. This phase 1b study of lifastuzumab vedotin is also of importance as it demonstrated efficacy in a different patient population, specifically those with recurrent platinum-sensitive ovarian cancer. In addition, this study is important as it evaluates the use of combination therapy with lifastuzumab and carboplatin with or without bevacizumab. • Moore KN, et al. Phase 1b study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2020;158(3):631–639. This phase 1b study of lifastuzumab vedotin is also of importance as it demonstrated efficacy in a different patient population, specifically those with recurrent platinum-sensitive ovarian cancer. In addition, this study is important as it evaluates the use of combination therapy with lifastuzumab and carboplatin with or without bevacizumab.
66.
go back to reference Yurkovetskiy AV, et al. Dolaflexin: a novel antibody-drug conjugate platform featuring high drug loading and a controlled bystander effect. Mol Cancer Ther. 2021;20(5):885–95.PubMedCrossRef Yurkovetskiy AV, et al. Dolaflexin: a novel antibody-drug conjugate platform featuring high drug loading and a controlled bystander effect. Mol Cancer Ther. 2021;20(5):885–95.PubMedCrossRef
68.
go back to reference Harter P, et al. UP-NEXT (GOG-3049/ENGOT-Ov71-NSGO-CTU): A study of upitifamab rilsodotin (UpRi), a NaPi2b-directed antibody drug conjugate (ADC), in platinum-sensitive recurrent ovarian cancer. J Clin Oncol. 2023;41(16_suppl):TPS5614–TPS5614. Harter P, et al. UP-NEXT (GOG-3049/ENGOT-Ov71-NSGO-CTU): A study of upitifamab rilsodotin (UpRi), a NaPi2b-directed antibody drug conjugate (ADC), in platinum-sensitive recurrent ovarian cancer. J Clin Oncol. 2023;41(16_suppl):TPS5614–TPS5614.
70.
go back to reference Hassan R, Kreitman RJ, Pastan I, Willingham MC. Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol. 2005;13(3):243–7.PubMedCrossRef Hassan R, Kreitman RJ, Pastan I, Willingham MC. Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol. 2005;13(3):243–7.PubMedCrossRef
71.
go back to reference Lheureux S, et al. A randomized phase II study of bevacizumab and weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant or refractory ovarian cancer NCI trial#10150. J Clin Oncol. 2022;40(16_suppl):5514–5514. Lheureux S, et al. A randomized phase II study of bevacizumab and weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant or refractory ovarian cancer NCI trial#10150. J Clin Oncol. 2022;40(16_suppl):5514–5514.
72.
go back to reference •• Nishikawa T, et al. Trastuzumab deruxtecan for human epidermal growth factor receptor 2-expressing advanced or recurrent uterine carcinosarcoma (NCCH1615): the STATICE trial. J Clin Oncol. 2023;41(15):2789–2799. This phase II STATICE trial is of outstanding importance as it demonstrates the efficacy of trastuzumab deruxtecan for HER2-expressing advanced or recurrent uterine carcinosarcoma regardless of HER2 status. There are currently no FDA-approved ADCs for use in uterine cancer, and identifying treatments for advanced or recurrent uterine cancer is of utmost importance. •• Nishikawa T, et al. Trastuzumab deruxtecan for human epidermal growth factor receptor 2-expressing advanced or recurrent uterine carcinosarcoma (NCCH1615): the STATICE trial. J Clin Oncol. 2023;41(15):2789–2799. This phase II STATICE trial is of outstanding importance as it demonstrates the efficacy of trastuzumab deruxtecan for HER2-expressing advanced or recurrent uterine carcinosarcoma regardless of HER2 status. There are currently no FDA-approved ADCs for use in uterine cancer, and identifying treatments for advanced or recurrent uterine cancer is of utmost importance.
73.
go back to reference •• Meric-Bernstam F, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(17_suppl): LBA3000–LBA3000. While the final results are not published, interim results from the DESTINY-PanTumor02 trial are of outstanding importance. Trastuzumab deruxtecan demonstrated efficacy in cervical, endometrial, and ovarian cancer, emphasing the importance of targeting HER2 expressing gynecologic cancers. •• Meric-Bernstam F, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(17_suppl): LBA3000–LBA3000. While the final results are not published, interim results from the DESTINY-PanTumor02 trial are of outstanding importance. Trastuzumab deruxtecan demonstrated efficacy in cervical, endometrial, and ovarian cancer, emphasing the importance of targeting HER2 expressing gynecologic cancers.
74.
go back to reference Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist Updat. 2014;17(4–6):89–95.PubMedCrossRef Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist Updat. 2014;17(4–6):89–95.PubMedCrossRef
75.
go back to reference Moore KN, et al. Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in patients with solid tumors. Cancer. 2017;123(16):3080–7.PubMedCrossRef Moore KN, et al. Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in patients with solid tumors. Cancer. 2017;123(16):3080–7.PubMedCrossRef
76.
go back to reference Varughese J, et al. Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Cancer. 2011;117(14):3163–72.PubMedCrossRef Varughese J, et al. Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Cancer. 2011;117(14):3163–72.PubMedCrossRef
77.
go back to reference Goldenberg DM, et al. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496–512.PubMedPubMedCentralCrossRef Goldenberg DM, et al. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496–512.PubMedPubMedCentralCrossRef
78.
go back to reference Bardia A, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746–56.PubMedCrossRef Bardia A, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746–56.PubMedCrossRef
79.
go back to reference Francoeur AA, Liao CI, Caesar MA, Chan A, Kapp DS, Cohen JG, Salani R, Chan JK. The increasing incidence of stage IV cervical cancer in the USA: what factors are related?. Int J Gynecol Cancer. 2022;32(9). Francoeur AA, Liao CI, Caesar MA, Chan A, Kapp DS, Cohen JG, Salani R, Chan JK. The increasing incidence of stage IV cervical cancer in the USA: what factors are related?.  Int J Gynecol Cancer. 2022;32(9).
80.
go back to reference Liao CI, et al. Trends in human papillomavirus-associated cancers, demographic characteristics, and vaccinations in the US, 2001–2017. JAMA Netw Open. 2022;5(3): e222530.PubMedPubMedCentralCrossRef Liao CI, et al. Trends in human papillomavirus-associated cancers, demographic characteristics, and vaccinations in the US, 2001–2017. JAMA Netw Open. 2022;5(3): e222530.PubMedPubMedCentralCrossRef
81.
82.
go back to reference •• Coleman RL, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021. 22(5):609–619. This phase II study of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer is of outstanding importance as it demonstrated durable antitumor activity with a manageable safety profile. Patients with recurrent or metastatic cervical cancer have very poor prognoses, and effective treatment options in this population are crucial. The results of this study led to FDA-approval of tisotumab vedotin for recurrent or metastatic cervical cancer with progression on or after chemotherapy. •• Coleman RL, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021. 22(5):609–619. This phase II study of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer is of outstanding importance as it demonstrated durable antitumor activity with a manageable safety profile. Patients with recurrent or metastatic cervical cancer have very poor prognoses, and effective treatment options in this population are crucial. The results of this study led to FDA-approval of tisotumab vedotin for recurrent or metastatic cervical cancer with progression on or after chemotherapy.
83.
go back to reference •• Vergote I, et al. Tisotumab Vedotin in combination with carboplatin, pembrolizumab, or bevacizumab in recurrent or metastatic cervical cancer: results from the innovaTV 205/GOG-3024/ENGOT-cx8 study. J Clin Oncol. 2023:JCO2300720. These recently published results from the innovaTV205/GOG-3024/ENGOT-cx8 study are of outstanding importance. This phase Ib/II study of tisotumab vedotin in combination with carboplatin, pembrolizumab, or bevacizumab in patients with recurrent or metastatic cervical cancer. As previously stated, patients with recurrent or metastatic cervical cancer have poor prognoses, and effective treatment options are needed. All combinations demonstrated antitumor activity with manageable safety profiles. •• Vergote I, et al. Tisotumab Vedotin in combination with carboplatin, pembrolizumab, or bevacizumab in recurrent or metastatic cervical cancer: results from the innovaTV 205/GOG-3024/ENGOT-cx8 study. J Clin Oncol. 2023:JCO2300720. These recently published results from the innovaTV205/GOG-3024/ENGOT-cx8 study are of outstanding importance. This phase Ib/II study of tisotumab vedotin in combination with carboplatin, pembrolizumab, or bevacizumab in patients with recurrent or metastatic cervical cancer. As previously stated, patients with recurrent or metastatic cervical cancer have poor prognoses, and effective treatment options are needed. All combinations demonstrated antitumor activity with manageable safety profiles.
84.
go back to reference Seagen and Genmab announce TIVDAK® (tisotumab vedotin-tftv) improved overall survival in patients with recurrent or metastatic cervical cancer compared with chemotherapy alone. News release. Seagen Inc. and Genmab A/S. 2023. bit.ly/3r60gnB. Accessed 4 Sep 2023. Seagen and Genmab announce TIVDAK® (tisotumab vedotin-tftv) improved overall survival in patients with recurrent or metastatic cervical cancer compared with chemotherapy alone. News release. Seagen Inc. and Genmab A/S. 2023. bit.​ly/​3r60gnB. Accessed 4 Sep 2023.
86.
go back to reference Sakai H, et al. HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. Breast Cancer. 2018;25(5):605–13.PubMedCrossRef Sakai H, et al. HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. Breast Cancer. 2018;25(5):605–13.PubMedCrossRef
87.
go back to reference Hunter FW, et al. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer. 2020;122(5):603–12.PubMedCrossRef Hunter FW, et al. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer. 2020;122(5):603–12.PubMedCrossRef
88.
go back to reference Loganzo F, Sung M, Gerber HP. Mechanisms of resistance to antibody-drug conjugates. Mol Cancer Ther. 2016;15(12):2825–34.PubMedCrossRef Loganzo F, Sung M, Gerber HP. Mechanisms of resistance to antibody-drug conjugates. Mol Cancer Ther. 2016;15(12):2825–34.PubMedCrossRef
89.
go back to reference Loganzo F, et al. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther. 2015;14(4):952–63.PubMedCrossRef Loganzo F, et al. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther. 2015;14(4):952–63.PubMedCrossRef
90.
go back to reference Sung M, et al. Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1). Mol Cancer Ther. 2018;17(1):243–53.PubMedCrossRef Sung M, et al. Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1). Mol Cancer Ther. 2018;17(1):243–53.PubMedCrossRef
Metadata
Title
Antibody-Drug Conjugates in Gynecologic Cancers
Authors
Mary Katherine Anastasio, MD
Stephanie Shuey, PharmD
Brittany A. Davidson, MD
Publication date
03-01-2024

ASH 2024 Annual Meeting Coverage

inMIND supports tafasitamab addition in follicular lymphoma

Combining tafasitamab with lenalidomide and rituximab significantly improves progression-free survival for patients with relapsed or refractory follicular lymphoma.

Featuring the official presentation video

Read more
SPONSORED

Recent advances in the use of CAR T-cell therapies in relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma

In this webinar, Professor Martin Dreyling and an esteemed international panel of CAR T-cell therapy experts discuss the latest data on the safety, efficacy, and clinical impact of CAR T-cell therapies in the treatment of r/r DLBCL and r/r FL.

Please note, this webinar is not intended for healthcare professionals based in the US and UK.

Sponsored by:
  • Novartis Pharma AG
Chaired by: Prof. Martin Dreyling
Developed by: Springer Healthcare
Watch now