Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma

Our plain-English summary of Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma, by M.G. Zauderer, E.W. Alley, J. Bendell, et al (Investigational New Drugs, 2021).

The study

• Authors: M.G. Zauderer, E.W. Alley, J. Bendell, E. Capelletto, T.M. Bauer, S. Callies, A.M. Szpurka, S. Kang, M.D. Willard, V. Wacheck, A.M. Varghese
• Journal: Investigational New Drugs
• Published: 2021;39(4):1081-1088
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BACKGROUND LY3023414 is a selective, ATP competitive inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK. A Phase 1 dose escalation, 200 mg twice daily (BID) of LY3023414 was the determined recommended phase 2 dose (RP2D). We report the antitumor activity and safety of LY3023414 monotherapy in patients with advanced mesothelioma.METHODS Patients enrolled had advanced malignant pleural or peritoneal mesothelioma with measurable disease, ECOG PS 0-1, were refractory or ineligible to receive standard therapies. Patients received LY3023414 200 mg BID. This dose expansion cohort is intended to evaluate preliminary antitumor activity of LY3023414 by overall response rate. Safety, tolerability and pharmacokinetics were assessed. Biomarkers associated with treatment response was an exploratory endpoint. RESULTS Forty-two patients received LY3023414 for a median duration of 11.2 weeks (range: 1.1-53.0). One patient had a confirmed partial response (PR) (ORR 2.4%). Three patients had an unconfirmed PR. Seventeen patients had stable disease (SD) (DCR 43%). Most common adverse events (AEs) included fatigue (43%), nausea (43%), decreased appetite (38%), vomiting (33%), and diarrhea (29%). AEs were mostly mild or moderate. Grade ≥ 3 AEs were reported for 21% of patients with fatigue as the most frequent event (10%). Alterations of BAP1 were identified in 11/19 patients as the most common molecular aberration, followed by SETD2 and NF2 alterations. No obvious pattern of genetic changes/mutations in single genes or pathways was associated with anti-tumor activity. CONCLUSION LY3023414 monotherapy (200 mg BID) demonstrated an acceptable and manageable safety profile with limited single-agent activity in patients with advanced mesothelioma. ClinicalTrials.gov identifier: NCT01655225; Date of registration: 19 July 2012.

© 2021. The Author(s).

In plain English

This article reported the mesothelioma group of a phase 1, multicenter, open-label, nonrandomized trial of LY3023414, an experimental drug that blocks the PI3K/mTOR pathway. It studied a treatment, not asbestos exposure. Forty-two patients with advanced malignant pleural or peritoneal mesothelioma took 200 mg twice daily, for a median of 11.2 weeks. One patient had a confirmed partial response lasting 7.4 months (response rate 2.4%). Three had unconfirmed partial responses, and 17 had stable disease, for a disease control rate of 43%. Thirteen patients could not be assessed. Median progression-free survival was 2.83 months (95% confidence interval 2.53 to 3.98). Side effects possibly caused by the drug affected 40 of 42 patients, most often fatigue and nausea (43% each). Nine patients (21%) had drug-related effects of grade 3 or higher. Among 19 patients with genetic data, BAP1 alterations were most common (11 patients), and no genetic pattern was clearly linked to response. The authors concluded the drug had an acceptable safety profile with limited single-agent activity. They said the small number of tissue samples limited the genetic analysis.

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: Phase 1, multicenter, nonrandomized, open-label drug trial; this report covers the mesothelioma expansion cohort (Part B)
• Who was studied: 42 patients with advanced or metastatic malignant pleural or peritoneal mesothelioma (ECOG performance status 0 or 1, measurable disease, no previous PI3K/mTOR inhibitor therapy); median age 69, 74% male; 41 (98%) had prior systemic therapy
• Exposure: Treatment with LY3023414 (a PI3K/mTOR inhibitor) 200 mg twice daily as a single drug; median treatment duration 11.2 weeks (range 1.1 to 53.0). Asbestos exposure was not studied.
• Main results:
  • Of the 42 treated patients, one had a confirmed partial response lasting 7.4 months (overall response rate 2.4%); three had unconfirmed partial responses
  • 17 patients (41%) had stable disease as best response; disease control rate 43%
  • 13 patients (31%) could not be evaluated for tumor response because follow-up tumor assessment was missing
  • Median progression-free survival for enrolled patients was 2.83 months (95% CI 2.53 to 3.98)
  • 40 of 42 patients (95%) had at least one adverse event possibly related to the drug; most frequent were fatigue (43%), nausea (43%), decreased appetite (38%), vomiting (33%), diarrhea (29%) and rash (19%)
  • Grade 3 or higher treatment-related adverse events occurred in 9 patients (21%), including fatigue (4 patients) and rash (3 patients); no grade 5 treatment-related events
  • Three patients (7%) stopped treatment because of adverse events
  • Among 19 patients with genetic data, BAP1 alterations were most common (11 patients), followed by SETD2 and NF2 (5 patients each)
  • No obvious pattern of genetic alterations was associated with anti-tumor activity
• The authors' conclusion: The authors concluded that LY3023414 at 200 mg twice daily had an acceptable safety profile with limited single-agent activity in unselected patients with advanced mesothelioma, and that predictive biomarkers appear to be needed for further development
• Limitations the authors state:
  • Few patients had tumor tissue and matching tumor assessments, so no correlation between biomarkers and response could be identified
  • PTEN status was not measured by both protein and DNA methods, which the authors said could explain the lower rate of PTEN loss than in earlier studies

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Peritoneal Mesothelioma, Biomarker, BAP1.

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• Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107) — T. Jahan, L. Gu, et al. (2012)

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