Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer

Abstract

Background: We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens.

Methods: This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase.

Results: The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes.

Conclusion: Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach.

Trial registration number: ClinicalTrials.gov identifier: NCT02734160.

Keywords: clinical trials as topic; immunotherapy; investigational; therapies; tumor biomarkers; tumor microenvironment.

Conflict of interest statement

Competing interests: DM has received research funding from Celgene, Incyte, and Shire, and has a consulting role with Baxter, Eli Lilly and Company, Incyte, and Shire. D-YO has received research funding from Array, AstraZeneca, Eli Lilly and Company, and Novartis, and has a consulting/advisory role with ASLAN, AstraZeneca, Bayer, Celgene, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho, and Zymeworks. AH has received travel and accommodation expenses from Eli Lilly and Company. EC has received research funding from AbbVie, Amcure, Amgen, AstraZeneca, BeiGene, BMS, Boehringer-Ingelheim, CytomX, Eli Lilly and Company, H3, Incyte, Kura, LOXO, Macrogenics, Menarini, Merck, Merck Serono, Merus, Millennium Pharmaceuticals, Nanobiotix Janssen, Nektar, Novartis, Pfizer, PharmaMar, Principia Bayer, PsiOxus Therapeutics, PUMA, Rigontec, Roche/Genentech, Sanofi, Tahio, Tesaro; has a consulting/advisory role with AbbVie, Amcure, AstraZeneca, Boehringer-Ingelheim, Celgene, Cerulean Pharma, EUSA, GLG, Guidepoint Global, Janssen-Cilag, Nanobiotix Janssen, Novartis, Pfizer, Pierre Pharma, PsiOxus Therapeutics, Roche/Genentech, Seattle Genetics, Servier; is employed by HM Hospitals Group and START; has shares in HM Hospitals Group, International Cancer Consultants, Oncoart Associated, and START; and is president and founder of NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences). AMV has participated in clinical trials funded by Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Silenseed, and Verastem. EB has received honoraria for consultancy from Corcept Therapeutics and Invitae, is on the speaker bureau for Ipsen, and his institution has received research funding from Biontech, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Helix, Mabvax, Merck, Minneamrita Therapeutics, Pharmacyclics, and Samumed. TM has received honoraria for consultancy from Baxalta, Baxter, Celgene, Genzyme, Roche, Sanofi, Shire Pharmaceuticals, Tesaro, and QED Therapeutics, and has received travel/accommodation compensation from Bayer, H3 Biomedicine, Merck, and Sanofi. VM and CZ have no conflicts of interest to disclose. YZ, IG, MM, LG, STE, and EA are employees and stock holders of Eli Lilly and Company. KAB was an employee of Eli Lilly and Company at the time this research was conducted and is a stock holder of Eli Lilly and Company and a current employee of Taiho Oncology. MCL is a current employee and stock holder of AstraZeneca. SCG was an employee of Eli Lilly and Company at the time this research was conducted and is a stock holder of Eli Lilly and Company. RG-C declares having provided scientific advice and/or received honoraria from AAA, Advanz Pharma, Amgen, Bayer, BMS, Eli Lilly and Company, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Roche, and Sanofi, and has received research support from Pfizer and BMS. Work in the unit of DM was partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant n°23719 and 5x1000 Grant n°12182, by the Italian Ministry of Health Ricerca Finalizzata 2016 GR-2016- 02361134 grant, and by the patients associations 'Nastro Viola' and 'Voglio il Massimo' donations.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Best response by patient based on change in tumor size. All treated patients with best overall response (n=33). Blue number=percentage of tumor cells at baseline with positive PD-L1 membrane staining. Dashed lines at –30% and 20% represent the thresholds for SD; neither an increase in size of more than 20% nor a decrease in size of more than 30% since the initial baseline measurement. BID, two times per day; PD, progressive disease; PD-L1, programmed death-ligand 1; PR, partial response; QD, one time per day; SD, stable disease.

Figure 2

Association between PD-L1 expression and clinical benefit. For the purpose of the biomarker analysis, any patient who had a CR, PR, or SD for ≥3 months was considered as having derived clinical benefit from study treatment. CR, complete response; NE, non-evaluable; PD, progressive disease; PD-L1, programmed death-ligand 1; PR, partial response; SD, stable disease.

Figure 3

(A) Overall survival and (B) progression-free survival in the galunisertib 150 mg BID + durvalumab 1500 mg Q4W group. BID, two times a day; Q4W, every 4 weeks.