A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer

Sukhmani K Padda, Karen L Reckamp, Marianna Koczywas, Joel W Neal, Jun Kawashima, Shengchun Kong, Daniel B Huang, Mark Kowalski, Heather A Wakelee, Sukhmani K Padda, Karen L Reckamp, Marianna Koczywas, Joel W Neal, Jun Kawashima, Shengchun Kong, Daniel B Huang, Mark Kowalski, Heather A Wakelee

Abstract

Introduction: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC).

Methods: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK).

Results: Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib.

Conclusions: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS.

Gov identifier: NCT02206763.

Keywords: EGFR; Erlotinib; JAK1/2; Lung cancer; TBK1.

Conflict of interest statement

Jun Kawashima reports previous employment and stock with Gilead Sciences, Inc. Shengchun Kong reports previous employment and stock with Gilead Sciences, Inc. Mark Kowalski reports previous employment with Gilead Sciences, Inc. Joel W. Neal reports honoraria from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI PeerView CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, and MJH Life Sciences CME; he reports consulting fees for AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly, Calithera Biosciences, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, and Natera; he reports receiving research funding through his institution from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen, and AbbVie; and he receives royalties from Up To Date. Sukhmani K. Padda received research funding through her institution from EpicentRx, Forty Seven Inc., Bayer, and Boehringer Ingelheim; she has participated in advisory boards and received fees from AstraZeneca, AbbVie, Blueprint Medicines, G1 Therapeutics, Janssen Pharmaceuticals, and Pfizer. Karen L. Reckamp reports grant funding through her institution from AbbVie, Acea, Adaptimmune, Boehringer Ingelheim, Bristol Meyers Squibb, Calithera, Daiichi Sankyo, Elevation Oncology, Genentech, GlaxoSmithKline, Guardant, Janssen, Loxo Oncology, Molecular Partners, Seattle Genetics, Spectrum, Takeda Pharmaceuticals, Xcovery, and Zeno; she reports receiving consulting fees from Calithera, Euclises, Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, Daiichi Sankyo, EMD Serono, Genentech, Guardant, Janssen, Eli Lilly, Merck KGaA, Precision Health, Seattle Genetics, Takeda Pharmaceuticals, and Tesaro. Heather A. Wakelee reports receiving grant funding through her institution from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, Bristol Myers Squibb, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead Sciences, Inc., Merck, Novartis, Pharmacyclics, Seattle Genetics, Xcovery, Eli Lilly, and Pfizer; she reports honoraria from Novartis and AstraZeneca; she participated in and received advisory board fees from AstraZeneca, Xcovery, Janssen, Daiichi Sankyo, Blueprint, Mirati, Helsinn, and participated in advisory boards for which she did not receive fees from Merck, Takeda Pharmaceuticals, and Genentech/Roche. Marianna Koczywas and Daniel B. Huang have stated that they have no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Best percentage change from baseline in tumor size by dose level (N = 11). aPatient with best overall response of progressive disease

References

    1. Maemondo M, Inoue A, Kobayashi K, The North-East Japan Study Group et al. Gefitinib or chemotherapy for non−small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–2388. doi: 10.1016/S1470-2045(11)70393-X.
    1. Rosell R, Carcereny E, Gervais R, Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–246. doi: 10.1016/S1470-2045(11)70393-X.
    1. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. doi: 10.1200/JCO.2012.44.2806.
    1. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1454–1466. doi: 10.1016/S1470-2045(17)30608-3.
    1. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41–50. doi: 10.1056/NEJMoa1913662.
    1. Mok TS, Wu Y-L, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–640. doi: 10.1056/NEJMoa1612674.
    1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–2247. doi: 10.1158/1078-0432.CCR-12-2246.
    1. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75RA26. doi: 10.1126/scitranslmed.3002003.
    1. Papadimitrakopoulou VA, Wu Y, Han J, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Presented at: ESMO 2018 Congress; October 19-23, 2018; Munich, Germany. Abstract 5121
    1. Ramalingam SS, Cheng Y, Zhou C, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at: ESMO 2018 Congress; October 19-23, 2018; Munich, Germany. Abstract 865
    1. Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–248. doi: 10.1038/nrclinonc.2018.8.
    1. Wang Y, van Boxel-Dezaire AHH, Cheon HJ, Yang J, Stark GR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci USA. 2013;110:16975–16980. doi: 10.1073/pnas.131582110.
    1. Chang Q, Bournazou E, Sansone P, et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia. 2013;15:848–862. doi: 10.1593/neo.13706.
    1. Gao SP, Mark KG, Leslie K, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117:3846–3856. doi: 10.1172/JCI31871.
    1. Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor, AZD1480, potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16:487–497. doi: 10.1016/j.ccr.2009.10.015.
    1. Haura EB, Zheng Z, Song L, Cantor A, Bepler G. Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res. 2005;11:8288–8294. doi: 10.1158/1078-0432.CCR-05-0827.
    1. Greulich H, Chen TH, Feng W, et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2005;2:e313. doi: 10.1371/journal.pmed.0020313.
    1. Kim DM, Kim MJ, Moon J-H, et al. Inhibition of JAK1/2 can overcome EGFR-TKI resistance in human NSCLC. Biochem Biophys Res Commun. 2020;527:305–310. doi: 10.1016/j.bbrc.2020.04.095.
    1. Lee HJ, Zhuang G, Cao Y, Du P, Kim H-J, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014;26:207–221. doi: 10.1016/j.ccr.2014.05.019.
    1. Murakami T, Takigawa N, Ninomiya T, et al. Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. Lung Cancer. 2014;83:30–36. doi: 10.1016/j.lungcan.2013.10.011.
    1. Looyenga BD, Hutchings D, Cherni I, Kingsley C, Weiss GJ, MacKeigan JP. STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. PLoS ONE. 2012;7:e30820. doi: 10.1371/journal.pone.0030820.
    1. Harada D, Takigawa N, Ochi N, et al. JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. Cancer Sci. 2012;103:1795–1802. doi: 10.1111/j.1349-7006.2012.020363.x.
    1. Su Q, Banks E, Bebernitz G, et al. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a potent and selective Janus kinase 1 inhibitor. J Med Chem. 2020;63:4517–4527. doi: 10.1021/acs.jmedchem.9b01392.
    1. Chen H, Bebernitz G, Bell K, et al. Abstract 4046: Targeting JAK/STAT adaptive mechanism with JAK1 inhibitor azd4205 reduces residual disease and prolongs benefit of osimertinib. Cancer Res. 2017;77:4046. doi: 10.1158/7445.AM2017-4046.
    1. Stubbs MC, Wen X, Xue C-B, et al. Abstract 2938: In vivo assessment of the combination of the JAK1 selective inhibitor itacitinib with first- and second-generation EGFR inhibitors in models of non-small cell lung cancer. Cancer Res. 2019;78:2938. doi: 10.1158/1538-7445.AM2018-2938.
    1. Kim SM, Kwon OJ, Hong YK, et al. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther. 2012;11:2254–2264. doi: 10.1158/1535-7163.MCT-12-0311.
    1. Song L, Rawal B, Nemeth JA, Haura EB. JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol Cancer Ther. 2011;10:481–494. doi: 10.1158/1535-7163.mct-10-0502.
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Tarceva (erlotinib) tablets for oral use. Prescribing Information; Genentech, South San Francisco, CA (2016). Available at:
    1. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5:e73–e81. doi: 10.1016/s2352-3026(17)30237-5.
    1. Mesa RA, Kiladjian J-J, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35:3844–3850. doi: 10.1200/jco.2017.73.4418.
    1. Verstovsek S, Courby S, Griesshammer M, et al. A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia. Leuk Res. 2017;60:11–17. doi: 10.1016/j.leukres.2017.05.002.
    1. Wu Y-L, Zhou C, Liam C-K, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26:1883–1889. doi: 10.1093/annonc/mdv270.
    1. Zhou C, Wu Y-L, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–742. doi: 10.1016/s1470-2045(11)70184-x.
    1. Barbie DA, Spira A, Kelly K, et al. Phase 1B study of momelotinib combined with trametinib in metastatic, Kirsten rat sarcoma viral oncogene homolog-mutated non-small-cell lung cancer after platinum-based chemotherapy treatment failure. Clin Lung Cancer. 2018;19:e853–e859. doi: 10.1016/j.cllc.2018.07.004.
    1. Xin Y, Kawashima J, Weng W, Kwan E, Tarnowski T, Silverman JA. Pharmacokinetics and safety of momelotinib in subjects with hepatic or renal impairment. J Clin Pharmacol. 2018;58:522–532. doi: 10.1002/jcph.1050.
    1. Gupta V, Mesa RA, Deininger MWN, et al. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017;102:94–102. doi: 10.3324/haematol.2016.148924.
    1. Ng K, Hendifar A, Starodub A, et al. Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. Invest New Drugs. 2019;37:159–165. doi: 10.1007/s10637-018-0650-5.
    1. Tan WK, Tan ARY, Sivanandam P, et al. In vitro inhibition of human aldehyde oxidase activity by clinically relevant concentrations of gefitinib and erlotinib: comparison with select metabolites, molecular docking analysis, and impact on hepatic metabolism of zaleplon and methotrexate. J Pharmacol Exp Ther. 2020;374:295–307. doi: 10.1124/jpet.120.265249.
    1. Zheng J, Xin Y, Zhang J, et al. Pharmacokinetics and disposition of momelotinib revealed a disproportionate human metabolite-resolution for clinical development. Drug Metab Dispos. 2018;46:237–247. doi: 10.1124/dmd.117.078899.
    1. Gao SP, Chang Q, Mao N, et al. JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal. 2016;9:33. doi: 10.1126/scisignal.aac8460.
    1. Park JS, Hong MH, Chun YJ, Kim HR, Cho CB. A phase Ib study of the combination of afatinib and ruxolitinib in EGFR mutant NSCLC with progression on EGFR-TKIs. Lung Cancer. 2019;134:46–51. doi: 10.1016/j.lungcan.2019.05.030.
    1. Yu HA, Perez L, Chang Q, et al. A phase 1/2 trial of ruxolitinib and erlotinib in patients with EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib. J Thorac Oncol. 2017;12:102–109. doi: 10.1016/j.jtho.2016.08.140.
    1. Zhu Z, Aref AR, Cohoon TJ, et al. Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 2014;4:452–465. doi: 10.1158/-13-0646.
    1. Gong K, Guo G, Gerber DE, et al. TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Invest. 2018;128:2500–2518. doi: 10.1172/jci96148.
    1. Blakely CM, Pazarentzos E, Olivas V, et al. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 2015;11:98–110. doi: 10.1016/j.celrep.2015.03.012.

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