SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM)

Our plain-English summary of SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM), by S.H. Ou, J. Moon, L.L. Garland, et al (Journal of Thoracic Oncology, 2015).

The study

• Authors: S.H. Ou, J. Moon, L.L. Garland, P.C. Mack, J.R. Testa, A.S. Tsao, A.J. Wozniak, D.R. Gandara
• Journal: Journal of Thoracic Oncology
• Published: 2015;10(2):387-91
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: The PI3K/Akt/mammalian target of rapamycin pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mammalian target of rapamycin inhibitor, in patients with unresectable MPM.

Methods: MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression-free survival (PFS) by RECIST 1.1.

Results: A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate was 2% [95% confidence interval (CI): 0-12%] by RECIST 1.1 and 0% (0-10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17-41%) by RECIST 1.1, and 27% (95% CI: 16-39%) by modified RECIST. The median PFS was 2.8 months (95% CI: 1.8-3.4) by RECIST 1.1. The median overall survival was 6.3 months (95% CI: 4.0-8.0). There was no difference in PFS among patients who received one or two prior chemotherapy regimens (p = 0.74). There was no difference in overall survival between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3 to 4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%).

Conclusion: Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.

In plain English

This was a phase II trial of everolimus in people with advanced malignant pleural mesothelioma whose disease had progressed after platinum-based chemotherapy. Everolimus is a drug taken by mouth that blocks a cell-growth signal called mTOR. The article does not discuss asbestos exposure. Sixty-one patients enrolled between December 2008 and September 2010, and 59 could be evaluated. They took 10 mg of everolimus daily until their disease worsened or side effects became unacceptable. The main measure was the share of patients alive without disease progression at 4 months, which was 29% (95% CI: 17–41%). One of 45 patients with measurable disease had a confirmed partial response, lasting 7 months. Median progression-free survival was 2.8 months (95% CI: 1.8–3.4) by RECIST 1.1, and median overall survival was 6.3 months (95% CI: 4.8–8.0). The most common side effects were fatigue (59%), high blood triglycerides (44%) and anemia (42%). One death from shortness of breath was judged possibly drug-related, and eleven patients stopped early because of side effects. The authors concluded that single-agent everolimus lacks sufficient clinical activity in advanced MPM to warrant further study.

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: Single-drug phase II clinical trial using a two-stage design, run through Southwest Oncology Group (SWOG) member sites
• Who was studied: Patients with unresectable malignant pleural mesothelioma who had received one or two prior systemic regimens, at least one of them platinum-based. 61 were enrolled between December 1, 2008 and September 15, 2010, and 59 were evaluable. Median age was 67.0, and 45 of 59 were male.
• Exposure: No asbestos exposure was studied. The intervention was the drug everolimus (RAD001), 10 mg taken by mouth once daily.
• Main results:
  • 4-month progression-free survival was 29% (95% CI: 17–41%) by RECIST 1.1 and 27% (95% CI: 16–39%) by modified RECIST, among evaluable patients
  • A one-sided test against the null hypothesis of a 30% 4-month progression-free survival gave p = 0.59
  • Among 45 patients with measurable disease by RECIST 1.1, one had a confirmed partial response (ORR 2%, 95% CI: 0–12%), lasting 7 months
  • Another 24 of these 45 patients (53%) had stable disease by RECIST 1.1, a disease control rate of 55% (95% CI: 40–70%)
  • Of 36 patients evaluable by modified RECIST, none responded and 20 had stable disease, a disease control rate of 56% (95% CI: 38–72%)
  • Median progression-free survival was 2.8 months (95% CI: 1.8–3.4 months) by RECIST 1.1
  • Median overall survival for all 59 evaluable patients was 6.3 months (95% CI: 4.8–8.0 months)
  • Progression-free survival did not differ between patients with one versus two prior regimens (p = 0.74)
  • Median overall survival was 6 months (95% CI: 4.7–9.1) for epithelioid histology and 7.6 months (95% CI: 3.4–8.1) for nonepithelioid histologies. The difference was not statistically significant (p = 0.47).
  • The most common side effects were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%) and anorexia (32%)
  • The most common grade 3–5 side effects were fatigue (10%), anemia (7%) and lung infection (7%)
  • One death from dyspnea was judged possibly related to the drug, and eleven patients stopped treatment early because of adverse events
• The authors' conclusion: The authors concluded that everolimus has limited clinical activity in advanced MPM and that single-agent mTOR inhibition lacks sufficient clinical activity to warrant further study
• Limitations the authors state:
  • The authors did not test patients' samples for inactivation of Merlin/NF2, a possible marker of sensitivity to everolimus

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: Pleural Mesothelioma, Unresectable, Chemotherapy, Progression-Free Survival, confidence interval, Modified RECIST (mRECIST), Median Overall Survival, Overall Survival.

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• Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma — M.G. Zauderer, E.W. Alley, et al. (2021)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509 — L.L. Garland, K. Chansky, et al. (2011)
• EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells — H.I. Onen, A. Yilmaz, et al. (2015)
• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)

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