Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review

Our plain-English summary of Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review, by J.M. Lambert, C.Q. Morris (Advances in Therapy, 2017).

The study

• Authors: J.M. Lambert, C.Q. Morris
• Journal: Advances in Therapy
• Published: 2017;34(5):1015-1035
• Type of article: Review
• Cited by: 242 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Attaching a cytotoxic "payload" to an antibody to form an antibody-drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly potent microtubule-disrupting agents, maytansinoids and auristatins, as payloads for ADCs resulted in approval of brentuximab vedotin in 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive breast cancer. Their success stimulated much research into the ADC approach, with >60 ADCs currently in clinical evaluation, mostly targeting solid tumors. Five ADCs have advanced into pivotal clinical trials for treating various solid tumors-platinum-resistant ovarian cancer, mesothelioma, triple-negative breast cancer, glioblastoma, and small cell lung cancer. The level of target expression is a key parameter in predicting the likelihood of patient benefit for all these ADCs, as well as for the approved compound, ado-trastuzumab emtansine. The development of a patient selection strategy linked to target expression on the tumor is thus critically important for identifying the population appropriate for receiving treatment.

In plain English

This review of published studies covered antibody-drug conjugates (ADCs), cancer drugs that link a cell-killing chemical to an antibody. It did not study asbestos exposure. One ADC, anetumab ravtansine, targets a molecule called mesothelin. The authors reported that mesothelin is expressed in 100% of mesothelioma cases and, in normal tissue, only in cells lining the pleura, pericardium and peritoneum. In a cited phase I study, at the 6.5 mg/kg dose there were 5 partial responses among patients with mesothelioma (31%), and 4 of the 5 lasted more than 500 days. All five were in patients given the drug as second-line treatment (10 patients; response rate 50%). A randomized pivotal trial comparing the drug with vinorelbine as second-line therapy for metastatic pleural mesothelioma began in December 2015 and finished enrollment in January 2017. The review reported no results from it. The trial required mesothelin expression above a set threshold. The authors concluded that target expression level is a key parameter in predicting the likelihood of patient benefit, but stated that it alone is not sufficient to predict anti-tumor activity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of previously published studies (no new human or animal studies)
• Who was studied: Published clinical and preclinical studies of ADCs, mostly ones targeting solid tumors. These included anetumab ravtansine, studied in patients with ovarian cancer or mesothelioma.
• Exposure: Not asbestos. The review covered ADC drugs, including anetumab ravtansine, an anti-mesothelin antibody joined to the maytansinoid DM4.
• Main results:
  • As reported by the review, mesothelin is expressed in 100% of cases of mesothelioma.
  • In normal tissue, mesothelin expression is limited to cells lining the pleura, pericardium and peritoneum.
  • In the cited phase I study, at 6.5 mg/kg there were 5 partial responses in patients with mesothelioma (31%).
  • All five mesothelioma responses were in patients given anetumab ravtansine as second-line treatment (n = 10; response rate 50%).
  • In patients with mesothelioma, 4 of the 5 responses continued for more than 500 days.
  • A randomized phase II pivotal trial comparing anetumab ravtansine with vinorelbine as second-line therapy for metastatic pleural mesothelioma was initiated in December 2015. It completed enrollment in January 2017. The review reports no results from this trial.
  • That trial required patients' mesothelin expression to exceed a predetermined threshold.
• The authors' conclusion: The authors concluded that the level of target expression is a key parameter in predicting the likelihood of patient benefit for these ADCs.
• Limitations the authors state:
  • The authors cautioned that lessons drawn from the HER2-targeted breast cancer drug may be unique to that target.
  • The authors stated that target expression alone is not sufficient to predict anti-tumor activity.

Topics

Medical terms in this study, explained in our Lexicon: Trastuzumab, HER2, Clinical Trial, Ovarian Cancer, Mesothelioma, Small Cell Lung Cancer.

Related studies

• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• Corneal Epitheliopathy Associated With Antibody-Drug Conjugates — S.V. Patel, L.A. Dalvin (2021)
• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)
• Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer — D. Mauricio, J. Harold, et al. (2021)
• Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate — M.G. Anderson, H.D. Falls, et al. (2020)
• Antibody drug conjugates in thoracic malignancies — J.M. Pacheco, D.R. Camidge (2018)

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