Antibody drug conjugates in thoracic malignancies

Our plain-English summary of Antibody drug conjugates in thoracic malignancies, by J.M. Pacheco, D.R. Camidge (Lung Cancer, 2018).

The study

• Authors: J.M. Pacheco, D.R. Camidge
• Journal: Lung Cancer
• Published: 2018;124:260-269
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Antibody drug conjugates (ADCs) have the potential to alter the efficacy: toxicity ratio of cytotoxic therapy utilizing surface markers on cancer cells as antibody targets to preferentially deliver toxic payloads to tumor cells while limiting systemic toxicity. Multiple ADCs, differing in their antibody targets, cytotoxic payloads and linker molecules are currently being evaluated in non-small-cell lung cancer, small-cell lung cancer and malignant pleural mesothelioma. Here we review the available data in thoracic malignancies and the potential issues influencing the efficacy and toxicity of these approaches.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This article was a review, not a new study. The authors searched PubMed, meeting abstracts and clinicaltrials.gov for trials of antibody drug conjugates (drugs joining an antibody to a cell-killing chemical) in non-small-cell lung cancer, small-cell lung cancer and malignant pleural mesothelioma. The article does not discuss asbestos. For mesothelioma, they summarized a randomized phase 2 trial of second-line treatment in patients whose tumors overexpressed mesothelin: 166 received anetumab ravtansine and 82 received vinorelbine. Response rates were 8% and 6%. Median progression-free survival was 4.3 and 4.5 months, not significantly different. An interim analysis suggested no difference in median overall survival (10.1 versus 11.6 months). A phase I study had reported a 31% response rate in 16 mesothelioma patients. In 25 patients with CD30-positive pleural mesothelioma, brentuximab vedotin had a 10% response rate. The authors wrote that the mesothelioma trial did not suggest a benefit of anetumab ravtansine over vinorelbine. They noted that no such drug was licensed for a chest cancer, called the overall data intriguing, and said cross-trial comparisons were difficult.

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 published and presented clinical trial data
• Who was studied: Clinical trials of antibody drug conjugates in patients with non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM). The sources were PubMed without date limits, major meeting abstracts since 2015, and clinicaltrials.gov. Trials without efficacy data specific to a thoracic malignancy were excluded.
• Exposure: No asbestos exposure was studied. The treatments reviewed were antibody drug conjugates, each made of an antibody, a linker and a cytotoxic payload. Examples include sacituzumab govitecan, trastuzumab emtansine, telisotuzumab vedotin, rovalpituzumab tesirine, anetumab ravtansine and brentuximab vedotin.
• Main results:
  • A reviewed randomized phase 2 trial compared anetumab ravtansine with vinorelbine as second-line treatment of MPM overexpressing mesothelin, defined as at least 30% of tumor cells staining 2+ or 3+ by IHC.
  • In that trial, the overall response rate was 8% with anetumab ravtansine (166 patients) and 6% with vinorelbine (82 patients).
  • In the same trial, median progression-free survival was 4.3 months with anetumab ravtansine and 4.5 months with vinorelbine, which was not significantly different (HR 1.215, p = 0.859).
  • In the same trial, an interim analysis suggested no difference in median overall survival: 10.1 months with anetumab ravtansine and 11.6 months with vinorelbine (p = 0.721).
  • In the same trial, grade 3-4 treatment-emergent adverse events occurred in 47% of patients on anetumab ravtansine and 72% of patients on vinorelbine.
  • A reviewed phase I study reported a 31% overall response rate with anetumab ravtansine in MPM. Four of its 5 responders had a partial response lasting more than 600 days.
  • Table 1 lists 16 MPM patients in that phase I study.
  • In 25 patients with CD30-positive MPM (median of 2 prior therapies), brentuximab vedotin gave an overall response rate of 10%.
  • The review cited data that mesothelin, the target of anetumab ravtansine, was expressed in 95% of 261 epithelioid mesothelioma specimens and was not expressed in 25 examined sarcomatoid cases.
  • In a reviewed study of 54 previously treated NSCLC patients given sacituzumab govitecan (IMMU-132), the overall response rate was 19%.
  • In the reviewed phase 2 TRINITY trial of rovalpituzumab tesirine in 339 DLL-3 positive SCLC patients, the overall response rate was 12% for all patients and 14% for those with high DLL-3 expression.
• The authors' conclusion: The authors concluded that, although no antibody drug conjugate is licensed for a thoracic malignancy, the available trial data are intriguing. For MPM, they concluded that a large phase 2 trial did not suggest a benefit of anetumab ravtansine over vinorelbine, with both drugs showing few responses.
• Limitations the authors state:
  • The authors stated that comparisons across trials are difficult because different trials used different methods to measure target expression.
  • The authors stated that a head-to-head trial is needed before an antibody drug conjugate could be judged the preferred second-line treatment in NSCLC.
  • The authors stated that resistance mechanisms to these drugs are unclear.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Pleural Mesothelioma.

Related studies

• Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review — J.M. Lambert, C.Q. Morris (2017)
• 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)
• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)
• Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate — M.G. Anderson, H.D. Falls, et al. (2020)
• Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer — D. Mauricio, J. Harold, et al. (2021)
• Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC — F. Facchinetti, A. Marabelle, et al. (2016)

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