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A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies

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Summary

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

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References

  1. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ferris RL, Blumenschein G, Fayette J et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867. https://doi.org/10.1056/NEJMoa1602252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus Docetaxel in advanced nonsquamous non–small-cell lung Cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reck M, Rodríguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung Cancer. N Engl J Med 375:1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  5. Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wolchok JD, Chiarion-Sileni V, Gonzalez R et al (2017) Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356. https://doi.org/10.1056/NEJMoa1709684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277–1290. https://doi.org/10.1056/NEJMoa1712126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hellmann MD, Paz-Ares L, Bernabe Caro R et al (2019) Nivolumab plus Ipilimumab in advanced non–small-cell lung Cancer. N Engl J Med 381:2020–2031. https://doi.org/10.1056/NEJMoa1910231

    Article  CAS  PubMed  Google Scholar 

  9. Antonia S, Goldberg SB, Balmanoukian A et al (2016) Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 17:299–308. https://doi.org/10.1016/S1470-2045(15)00544-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Siu LL, Even C, Mesía R et al (2019) Safety and efficacy of Durvalumab with or without Tremelimumab in patients with PD-L1–low/negative recurrent or metastatic HNSCC: the phase 2 CONDOR randomized clinical TrialDurvalumab Monotherapy and combination therapy in PD-L1–low/negative HNSCCDurvalu. JAMA Oncol 5:195–203. https://doi.org/10.1001/jamaoncol.2018.4628

    Article  PubMed  Google Scholar 

  11. Apetoh L, Ghiringhelli F, Tesniere A et al (2007) Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050

    Article  CAS  Google Scholar 

  12. Pfirschke C, Engblom C, Rickelt S et al (2016) Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44:343–354. https://doi.org/10.1016/j.immuni.2015.11.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gandhi L, Rodríguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non–small-cell lung Cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005

    Article  CAS  Google Scholar 

  14. Burtness B, Harrington KJ, Greil R et al (2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394:1915–1928. https://doi.org/10.1016/S0140-6736(19)32591-7

    Article  CAS  PubMed  Google Scholar 

  15. Ismael G, Hegg R, Muehlbauer S et al (2012) Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13:869–878. https://doi.org/10.1016/S1470-2045(12)70329-7

    Article  CAS  PubMed  Google Scholar 

  16. Launay-Vacher V (2013) An appraisal of subcutaneous trastuzumab: a new formulation meeting clinical needs. Cancer Chemother Pharmacol 72:1361–1367. https://doi.org/10.1007/s00280-013-2289-4

    Article  CAS  PubMed  Google Scholar 

  17. Pivot X, Gligorov J, Müller V et al (2013) Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol 14:962–970. https://doi.org/10.1016/S1470-2045(13)70383-8

    Article  CAS  PubMed  Google Scholar 

  18. Davies A, Merli F, Mihaljević B et al (2017) Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol 4:e272–e282. https://doi.org/10.1016/S2352-3026(17)30078-9

    Article  PubMed  Google Scholar 

  19. De Cock E, Kritikou P, Sandoval M et al (2016) Time savings with rituximab subcutaneous injection versus rituximab intravenous infusion: a time and motion study in eight countries. PLoS One 11:e0157957. https://doi.org/10.1371/journal.pone.0157957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rule S, Briones J, Smith R et al (2014) PSY89 - preference for rituximab subcutaneous (Sc) and intravenous (iv) among patients with Cd20+ non-Hodgkin’s lymphoma (Nhl) completing the Rasq measure in randomized phase iii studies Prefmab and Mabcute. Value Health 17:A537. https://doi.org/10.1016/j.jval.2014.08.1719

    Article  CAS  PubMed  Google Scholar 

  21. Radhakrishnan V, Banavali S, Gupta S et al (2019) 1209PExcellent CBR and prolonged PFS in non-squamous NSCLC with oral CA-170, an inhibitor of VISTA and PD-L1. Ann Oncol 30. https://doi.org/10.1093/annonc/mdz253.035

  22. Tang J, Shalabi A, Hubbard-Lucey VM (2017) Comprehensive analysis of the clinical immuno-oncology landscape. Ann Oncol 29:84–91. https://doi.org/10.1093/annonc/mdx755

    Article  Google Scholar 

  23. Andersson M, López-Vega JM, Petit T et al (2017) Efficacy and safety of Pertuzumab and Trastuzumab administered in a single infusion bag, followed by Vinorelbine: VELVET cohort 2 final results. Oncologist 22:1160–1168. https://doi.org/10.1634/theoncologist.2017-0079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This trial was sponsored and supported by the Canadian Clinical Trials Group. AstraZeneca Pharmaceuticals provided drug and partial funding support.

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Authors and Affiliations

  1. Canadian Cancer Trials Group, Queen’s University, 10 Stuart Street, Kingston, ON, K7L3N6, Canada

    J. Nehra, P. Brown-Walker, I. Gauthier, D. Tu, Lesley Seymour & M. Smoragiewicz

  2. Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada

    P. A. Bradbury

  3. Department of Oncology - Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, Canada

    P. M. Ellis, R. A. Juergens & S. J. Hotte

  4. Division of Medical Oncology, BCCA Vancouver Cancer Centre, Vancouver, Canada

    J. Laskin, C. Kollmannsberger, K. Gelmon & A. V. Tinker

  5. Department of Oncology - Section of Medical Oncology, Tom Baker Cancer Centre University of Calgary, Calgary, Canada

    D. Hao

  6. Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Canada

    G. Goss & P. Wheatley-Price

  7. Clinical Pharmacology & Safety Sciences, AstraZeneca, Gaithersburg, MD, USA

    X. Song & A. Khan

Authors
  1. J. Nehra
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  2. P. A. Bradbury
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  3. P. M. Ellis
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  7. R. A. Juergens
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  8. G. Goss
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  11. K. Gelmon
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  16. X. Song
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  17. A. Khan
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  18. Lesley Seymour
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Corresponding author

Correspondence to Lesley Seymour.

Ethics declarations

Conflicts of interest

Dr. J. Nehra: No conflicts of interest.

Dr. P.A. Bradbury – Honoraria: Abbvie, Pfizer, Lilly, Merck. Advisory boards- Abbvie, BI.

Dr. P.M. Ellis- Advisory Boards: AstraZeneca, Abbvie, Takeda, Pfizer. Honoraria for speaking for: AstraZeneca, Abbvie, Pfizer, Bristol-Myers Squibb.

Dr. J. Laskin: honoraria/ad boards from Roche, BI, Takeda and AstraZeneca. My institution has received research funding from Roche, and AstraZeneca.

Dr. C. Kollmannsberger – No conflicts of interest.

Dr. D. Hao – Advisory Boards: AstraZeneca, Roche, Merck, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly.

Dr. R.A. Juergens – Advisory board, honoraria and grants: AstraZeneca, Bristol-Myers Squibb, Merck. Advisory board and honoraria: Amgen, Boehringer Ingelheim, Novartis, Roche, Pfizer, and Takeda.

Dr. G. D. Goss reports Honoraria: AstraZeneca, BMS, IO Biotech. Travel reimbursement: Boehringer Ingelheim.

Dr. P. Wheatley-Price – Advisory Boards: Takeda, Bristol-Myers Squibb, AstraZeneca, Merck, Abbvie, Roche.

Dr. S. Hotte: Astra Zeneca: Research Funding (institution); honoraria/Advisory boards.

Dr. K. Gelmon: Pharmaceutical Company Associations. Advisory Boards – AstraZeneca, Roche, Novartis, Pfizer, Oncotheryon, Nanostring, Merck, Mylan, Lilly, Genomic Health, Nanostring, BMS. Research Funding – Pfizer, Roche, AstraZeneca, Novartis, BMS. Expert Testimony - Genentech.

Dr. A.V. Tinker: No conflicts of interest.

Dr. P. Brown-Walker – No conflicts of interest.

I. Gauthier: No conflicts of interest.

Dr. D. Tu – No conflicts of interest.

Dr. X. Song – Employee of AstraZeneca and owns stock in AstraZeneca.

A. Khan: Employee of AstraZeneca and owns stock in AstraZeneca.

Dr. L. Seymour – Received funds from AstraZeneca Pharmaceuticals on behalf of CCTG to support the conduct of the trial. Owns stock in AstraZeneca.

Dr. M. Smoragiewicz – No conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Nehra, J., Bradbury, P.A., Ellis, P.M. et al. A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies. Invest New Drugs 38, 1442–1447 (2020). https://doi.org/10.1007/s10637-020-00904-7

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