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A phase i study of ixazomib and erlotinib in patients with advanced solid tumors

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Summary

Background. Preclinical studies have shown that the combined inhibition of EGFR and NF-kB pathways to target the RalB/TBK1 pathway led to synergistic antitumor activity. Based on this rationale, we conducted a Phase I dose-escalation study combining the EGFR inhibitor erlotinib with the NF-kB inhibitor ixazomib in advanced solid tumors. Patients and methods. Patients with advanced solid tumors were eligible. The bayesian optimal interval phase I dose escalation design was used to establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Results. Nineteen patients with a range of solid tumors were enrolled. The most common treatment-related adverse events of any grade were diarrhea (42.1%, 8/19), followed by rash (36.8%, 7/19) and nausea (21.1%, 4/19). The combination RP2D for oral ixazomib was 4.0 mg on days 1, 8, and 15 of a 28-day cycle, with oral erlotinib 150 mg daily. While no patient achieved RECIST v1.1 objective responses, 3 patients with advanced sarcoma experienced durable RECIST v1.1 stable disease ≥ 6 months (8.4, 10.6, and 15.7 months) and the best response was -13% decrease in clear cell sarcoma. Conclusions. The combination of erlotinib and ixazomib was safe and well tolerated among patients with advanced cancer, with preliminary signals of antitumor activity in patients with advanced sarcoma.

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Data availability

Data are available upon reasonable request.

References

  1. Yoshida T, Zhang G, Haura EB (2010) Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer. Biochem Pharmacol 80:613–623

    Article  CAS  Google Scholar 

  2. Soria JC, Ohe Y, Vansteenkiste J et al (2018) Osimertinib in untreated egfr-mutated advanced non-small-cell lung cancer. N Engl J Med 378:113–125

    Article  CAS  Google Scholar 

  3. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132

    Article  CAS  Google Scholar 

  4. Kobayashi S, Boggon TJ, Dayaram T et al (2005) Egfr mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    Article  CAS  Google Scholar 

  5. Wu YL, Tsuboi M, He J et al (2020) Osimertinib in resected egfr-mutated non-small-cell lung cancer. N Engl J Med 383:1711–1723

    Article  CAS  Google Scholar 

  6. Janne PA, Yang JC, Kim DW et al (2015) Azd9291 in egfr inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689–1699

    Article  Google Scholar 

  7. Zhou W, Ercan D, Chen L et al (2009) Novel mutant-selective egfr kinase inhibitors against egfr t790m. Nature 462:1070–1074

    Article  CAS  Google Scholar 

  8. Mok TS, Wu YL, Ahn MJ et al (2017) Osimertinib or platinum-pemetrexed in egfr t790m-positive lung cancer. N Engl J Med 376:629–640

    Article  CAS  Google Scholar 

  9. Sequist LV, Han JY, Ahn MJ et al (2020) Osimertinib plus savolitinib in patients with egfr mutation-positive, met-amplified, non-small-cell lung cancer after progression on egfr tyrosine kinase inhibitors: Interim results from a multicentre, open-label, phase 1b study. Lancet Oncol 21:373–386

    Article  CAS  Google Scholar 

  10. Reckamp KL, Frankel PH, Ruel N et al (2019) Phase ii trial of cabozantinib plus erlotinib in patients with advanced epidermal growth factor receptor (egfr)-mutant non-small cell lung cancer with progressive disease on epidermal growth factor receptor tyrosine kinase inhibitor therapy: A california cancer consortium phase ii trial (nci 9303). Front Oncol 9:132

    Article  Google Scholar 

  11. Hong DS, LoRusso P, Hamid O et al (2019) Phase i study of amg 337, a highly selective small-molecule met inhibitor, in patients with advanced solid tumors. Clin Cancer Res 25:2403–2413

    Article  CAS  Google Scholar 

  12. Seguin L, Kato S, Franovic A et al (2014) An integrin beta(3)-kras-ralb complex drives tumour stemness and resistance to egfr inhibition. Nat Cell Biol 16:457–468

    Article  CAS  Google Scholar 

  13. Bivona TG, Hieronymus H, Parker J et al (2011) Fas and nf-kappab signalling modulate dependence of lung cancers on mutant egfr. Nature 471:523–526

    Article  CAS  Google Scholar 

  14. Vrabel D, Pour L, Sevcikova S (2019) The impact of nf-kappab signaling on pathogenesis and current treatment strategies in multiple myeloma. Blood Rev 34:56–66

    Article  CAS  Google Scholar 

  15. Liu S, Yuan Y (2015) Bayesian optimal interval designs for phase i clinical trials. Journal of the Royal Statistical Society: Series C: Applied Statistics 507–523.

  16. Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer 45:228–247.

  17. Kato S, Kim KH, Lim HJ et al (2020) Real-world data from a molecular tumor board demonstrates improved outcomes with a precision n-of-one strategy. Nat Commun 11:4965

    Article  CAS  Google Scholar 

  18. Sicklick JK, Kato S, Okamura R et al (2019) Molecular profiling of cancer patients enables personalized combination therapy: The i-predict study. Nat Med 25:744–750

    Article  CAS  Google Scholar 

  19. Rodon J, Soria JC, Berger R et al (2019) Genomic and transcriptomic profiling expands precision cancer medicine: The winther trial. Nat Med 25:751–758

    Article  CAS  Google Scholar 

  20. Schwaederle M, Zhao M, Lee JJ et al (2015) Impact of precision medicine in diverse cancers: A meta-analysis of phase ii clinical trials. J Clin Oncol 33:3817–3825

    Article  CAS  Google Scholar 

  21. Hong DS, DuBois SG, Kummar S et al (2020) Larotrectinib in patients with trk fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21:531–540

    Article  CAS  Google Scholar 

  22. Hong DS, Fakih MG, Strickler JH et al (2020) Kras(g12c) inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207–1217

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Amadeo Biter for the editorial input.

Funding

Funded by Takeda Pharmaceutical.

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Authors and Affiliations

  1. Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA

    Shumei Kato

  2. Department of Internal Medicine, University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Jacob J. Adashek

  3. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Vivek Subbiah, Siqing Fu, Mianen Sun, Ly Nguyen, Elsa J. Brown, Timothy A. Yap, Daniel D. Karp, Sarina A. Piha-Paul & David S. Hong

Authors
  1. Shumei Kato
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  2. Jacob J. Adashek
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  3. Vivek Subbiah
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  4. Siqing Fu
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  5. Mianen Sun
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  6. Ly Nguyen
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  7. Elsa J. Brown
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  8. Timothy A. Yap
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  9. Daniel D. Karp
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  10. Sarina A. Piha-Paul
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  11. David S. Hong
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Contributions

Conception and design: SK, DSH. Financial support: DSH. Administrative support: MS, LN, EJB. Collection and assembly of data: MS, LN, EJB. Data analysis and interpretation: SK, DSH. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Shumei Kato.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Institutional Review Board.

All participants signed an informed consent document approved by the Institutional Review Board prior to study entry.

Consent for publication

All authors consented to publication.

Competing interests

Dr. Shumei Kato serves as consultant for Foundation Medicine and CureMatch; receives speaker’s fees; serves on the advisory board for Pfizer; and receives research funding from ACT Genomics, Sysmex, Konica Minolta, and OmniSeq.

Dr. Sarina A. Piha-Paul receives Clinical Trial Research Support/Grant Funding through the institution from the following sources:

AbbVie, Inc.; ABM Therapeutics, Inc.; Acepodia, Inc; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma, Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Daiichi Sankyo; Eli Lilly; ENB Therapeutics; Five Prime Therapeutics; F-Star Therapeutics; Gene Quantum; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Silverback Therapeutics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; NCI/NIH; P30CA016672 – Core Grant (CCSG Shared Resources).

Dr. David S. Hong has following disclosures:

Research/Grant Funding: AbbVie, Adaptimmune, Adlai Nortye, Amgen, Astra-Zeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, EMD Serono, Erasca, Fate Therapeutics, Genentech, Genmab, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, LOXO, Merck, MedImmune, Millenium, Mirati, miRNA, Molecular Templates, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics, Verstatem, VM Oncology.

Travel, Accommodations, Expenses: AACR, Amgen, ASCO, Astra Zeneca, Bayer, Celgene, Eli Lilly, Genentech, Genmab, GlaxoSmithKline, Janssen, LOXO, miRNA, Pfizer, Philips, SITC, Takeda.

Consulting, Speaker or Advisory Role: Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Boxer Capital, COG, Ecor1, Genentech, GLG, Group H, Guidepoint, HCW Precision, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, WebMD.

Other ownership interests: Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc (Advisor).

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Brief summary

Ixazomib and erlotinib against advanced cancer

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Kato, S., Adashek, J.J., Subbiah, V. et al. A phase i study of ixazomib and erlotinib in patients with advanced solid tumors. Invest New Drugs 40, 99–105 (2022). https://doi.org/10.1007/s10637-021-01153-y

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  • DOI: https://doi.org/10.1007/s10637-021-01153-y

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