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

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.

Keywords: LY3023414; Mesothelioma; PI3K/mTOR inhibitor; Solid tumor.

Conflict of interest statement

M. Zauderer reports grants to their institution for research from Eli Lilly and Company, Department of Defense, NCI, Atara Biotherapeutics for research, GSK, Epizyme, Polaris, Sellas Life Sciences, BMS, Millennium/Takeda, Atara, and Curis; advisory role from Takeda, Aldeyra Therapeutics, Atara Biotherapeutics, GSK, Novocure, Aldeyra, Epizyme; personal fees from Research to Practice, Medical Learning Institute and OncLive, and non-financial support from Roche outside the submitted work.

E.W. Alley reports no conflict of interest or financial support.

J. Bendell reports research grants from Gilead, Genentech/Roche, BMS, Five Prime, Eli Lilly and Company, Merck, MedImmune, Celgene, EMD Serono, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, Abbvie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Therapeutics, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, Imclome, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle Genetics, Tepest Tx, Shattuck Labs, Synthorx, Inc., Revolution Medicines, Inc., Bicycle Therapeutics, Zymeworks, Relay Therapeutics, Atlas Medx, Scholar Rock and NGM Biopharma, other payment to institution for consulting services from BMS, Five Prime, Eli Lilly and Company, Merck, Medimmune, Celgene, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, Agios, ARMO, Ipsen, Merrimack, Oncogenex, Evelo, FORMA, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Pfizer, Seattle Genetics, Bicycle Therapeutics, Relay Therapeutis, Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2, Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Evelo, Piper Biotech, Samsung Bioepios, outside the submitted work.

E. Capelleto reports other payment for consulting services from Boehringer Ingelheim and Astrazeneca; other payments for an advisory role at MSD, outside the submitted work.

T. Bauer reports grants from Eli Lilly and Company, during the conduct of the study; grants from Daiichi Sankyo, grants from Medpacto, grants from Incyte, grants from Mirati Therapeutics, grants from MedImmune, grants from Abbvie, grants from AstraZeneca, grants from MabVax, grants from Stemline Therapeutics, grants from Merck, grants from Lilly, grants from GlaxoSmithKline, grants from Novartis, grants from Genentech, grants from Deciphera, grants from Merrimack, grants from Immunogen, grants from Millennium, grants from Phosplatin Therapeutics, grants from Calithera Biosciences, grants from Kolltan Pharmaceuticals, grants from Principa Biopharma, grants from Peleton, grants from Immunocore, grants from Roche, grants from Aileron Therapeutics, grants from Bristol-Myers Squibb, grants from Amgen, grants from Onyx, grants from Sanofi, grants from Boehringer-Ingelheim, grants from Astellas Pharma, grants from Five Prime Therapeutics, grants from Jacobio, grants from Top Alliance BioScience, grants from Janssen, grants from Clovis Oncology, grants from Takeda, grants from Karyopharm Therapeutics, grants from Foundation Medicine, grants from ARMO Biosciences, grants and other from Leap Therapeutics, grants, non-financial support and other from Ignyta, grants, non-financial support and other from Moderna Therapeutics, grants, personal fees and other from Pfizer, grants, personal fees and non-financial support from Loxo, grants, personal fees and non-financial support from Bayer, personal fees and non-financial support from Guardant Health, personal fees from Exelesis, outside the submitted work.

S. Callies, A.M. Szpurka, S. Kang, M.D. Willard are employees of Eli Lilly and Company; M.D. Willard report other payments as a stockholder for Eli Lilly and Company.

V. Wacheck reports payment as a former employee and shareholder for Eli Lilly and Company during the conduct of this study.

© 2021. The Author(s).

Figures

Fig. 1

Change in tumor size at best response

Fig. 2

Presence of genetic alterations. # Low tumor content (approximately 20% or less); * MSK IMPACT Panel /410 Genes; ** MSK IMPACT Panel /341 Genes; *** Foundation One Panel; & showed coverage of less than 100x. unknown variant/low coverage. Note: Genetic information of tumor samples with matching tumor measurements was available for 19 patients. Unique genetic alterations were detected in some tumors (n = 1 each) but are not shown for the following genes: FAT3, ZNRF3, AXIN2, INHBA, NCOR1, PTPRS, RAD51C, RYBP, SPTA1. Since different panels were utilized not all patients had been tested for mutations in the above genes