Current readings: Window-of-opportunity trials for thoracic malignancies

Our plain-English summary of Current readings: Window-of-opportunity trials for thoracic malignancies, by A.S. Tsao (Seminars in Thoracic and Cardiovascular Surgery, 2014).

The study

• Author: A.S. Tsao
• Journal: Seminars in Thoracic and Cardiovascular Surgery
• Published: 2014;26(4):323-30
• Type of article: Review
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Recent major advances in metastatic non-small cell lung cancer have occurred with the identification of molecular biomarker targets and administration of novel agents with resulting improvement in clinical outcomes. In the early-stage setting, personalized therapy with novel agents and molecular profiling are being incorporated into neoadjuvant "window-of-opportunity" trials. These important studies enable biomarker research and an expedited analysis of the efficacy of the targeted agent. However, there are significant limitations to window-of-opportunity trials. The aim of this article is to review the current window-of-opportunity trials of neoadjuvant targeted agents for thoracic malignancies, discuss the benefits and limitations of these trials, and propose more optimal alternative trial end points. Neoadjuvant trials of resectable non-small cell lung cancer and mesothelioma that are ongoing or under development and relevant to thoracic surgeons are also discussed. The success of these trials will depend on a collaborative multidisciplinary effort, especially from the field of thoracic surgery.

Copyright © 2014 Elsevier Inc. All rights reserved.

In plain English

This article was a review, not a new study, and did not examine asbestos. The author summarized three "window-of-opportunity" trials in which patients with operable early-stage non-small cell lung cancer took a targeted drug briefly before surgery. In one (Lara-Guerra and colleagues), gefitinib produced a partial response in 11% of 35 evaluable patients; only a sensitizing EGFR mutation predicted response. In another (Rizvi and colleagues), 17 of 21 patients whose tumors shrank by at least 25% on WHO bidimensional measurements after 21 days of gefitinib had an EGFR mutation. In a third (Altorki and colleagues), 30 of 35 patients (86%) given pazopanib had some tumor-volume reduction. For malignant pleural mesothelioma, the author described an MD Anderson dasatinib trial without giving results, a planned trial of chemotherapy with or without MPDL3280A, and a study by Mansfield and colleagues. That study reported PD-L1 expression in 40% of 224 archived mesothelioma tumors, which was associated with worse survival. The author concluded that these trials have a role in studying early-stage lung cancer and mesothelioma but may not benefit patients without an actionable mutation.

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: Narrative review ("Current Readings" commentary) of three published window-of-opportunity trials, plus a description of ongoing and planned neoadjuvant trials
• Who was studied: Patients in the reviewed and planned trials: people with resectable (operable) non-small cell lung cancer and resectable malignant pleural mesothelioma. The review itself enrolled no patients.
• Exposure: No asbestos or fiber exposure was studied. The subject was short courses of targeted drugs given before surgery: gefitinib, pazopanib, dasatinib, afatinib, nintedanib, and the PD-L1 inhibitor MPDL3280A.
• Main results:
  • Reviewed trial by Lara-Guerra et al (stage I NSCLC, gefitinib up to 28 days): among 35 evaluable patients, 11% had a partial response, 81% stable disease and 8% progression. Only a sensitizing EGFR mutation predicted a partial response.
  • Reviewed trial by Rizvi et al (50 patients, stage I-II NSCLC, gefitinib up to 21 days): 21 patients had tumor shrinkage of at least 25% by WHO bidimensional measurements after 21 days of gefitinib, and 17 of these 21 responding patients had an EGFR mutation. None of the 5 patients with a KRAS mutation had a radiographic response.
  • Reviewed trial by Altorki et al (35 patients, stage I-II NSCLC, pazopanib): 30 patients (86%) had some tumor-volume reduction, and 2 (6%) had a reduction of at least 50%.
  • The author described a neoadjuvant dasatinib trial at MD Anderson for resectable malignant pleural mesothelioma whose primary end point was modulation of p-SrcTyr419 in tumor cells. No results of this trial were given.
  • The author described a planned Southwest Oncology Group trial for resectable epithelioid or biphasic malignant pleural mesothelioma, randomizing patients to cisplatin-pemetrexed with or without the PD-L1 inhibitor MPDL3280A.
  • Cited study by Mansfield et al: in a retrospective analysis of archived malignant pleural mesothelioma tumor tissue (n = 224), 40% showed PD-L1 expression. This expression was associated with greater disease burden and worse survival (6 vs 14 months, P less than 0.0001).
• The authors' conclusion: The author concluded that window-of-opportunity studies with targeted agents have a role in advancing the study of early-stage NSCLC and mesothelioma. The author added that these trials may not benefit the patient unless the patient has an actionable mutation and the benefit from the agent is large, so larger, more general neoadjuvant trials are also needed.

Topics

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

Medical terms in this study, explained in our Lexicon: Non-Small Cell Lung Cancer, Biomarker, Molecular Profiling, Mesothelioma, Thoracic Surgery.

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