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Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non-small cell lung cancer patients who have progressed following chemotherapy

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Abstract

Background

IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC).

Methods

Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity.

Results

Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease ≥4 months.

Conclusions

IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC.

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Abbreviations

AE:

Adverse event

AUC0–t :

Area under the concentration–time curve from time zero to time t

CI:

Confidence interval

C max :

Maximum plasma concentration

CR:

Complete response

DLT:

Dose-limiting toxicity

ECOG:

Eastern Cooperative Oncology Group

EGFR:

Epidermal growth factor receptor

ITT:

Intention to treat

MedDRA:

Medical Dictionary for Regulatory Activities

NCI CTCAE:

National Cancer Institute Common Terminology Criteria for Adverse Events

NOS:

Not otherwise specified

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD:

Progressive disease

PFS:

Progression-free survival

PK:

Pharmacokinetic

PR:

Partial response

RECIST:

Response Evaluation Criteria In Solid Tumors

RP2D:

Recommended phase II dose

SD:

Stable disease

TEAE:

Treatment-emergent adverse event

TLR9:

Toll-like receptor 9

t max :

Time to C max

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The trial was sponsored by EMD Serono Inc., Rockland, MA, USA. The authors would like to thank the patients and their families without whom this study would not have been possible. Editorial and medical writing assistance in the preparation of this manuscript was provided by Marianne Jenal-Eyholzer, Ph.D., CMPP, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany.

Conflict of interest

Thomas E. Boyd: Consultant to Celgene; research funding by Genentech, Celgene, GSK, Onyx and Pharmacyclics. Guillaume de La Bourdonnaye: Former employee of Merck KGaA (2008–2012). David Wages: Former employee of EMD Serono. Alice S. Bexon: Previously employee of Idera Pharmaceuticals, now paid consultant to Idera Pharmaceuticals. David A. Smith, Paul Conkling, Donald A. Richards, John J. Nemunaitis, and Alain C. Mita: None.

Author information

Author notes

  1. Guillaume de La Bourdonnaye

    Present address: Philip Morris, Neuchâtel, Switzerland

  2. David Wages

    Present address: Quintiles, Durham, NC, USA

Authors and Affiliations

  1. Compass Oncology, 201 SE 136th Avenue, Vancouver, WA, 98684, USA

    David A. Smith

  2. US Oncology Research, Houston, TX, USA

    David A. Smith, Paul Conkling, Donald A. Richards & Thomas E. Boyd

  3. Virginia Oncology Associates, Norfolk, VA, USA

    Paul Conkling

  4. Texas Oncology, Tyler, TX, USA

    Donald A. Richards

  5. Mary Crowley Cancer Research Center, Dallas, TX, USA

    John J. Nemunaitis

  6. North Star Lodge Cancer Center, Yakima, WA, USA

    Thomas E. Boyd

  7. Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA

    Alain C. Mita

  8. Merck Serono International S.A., Geneva, Switzerland

    Guillaume de La Bourdonnaye

  9. EMD Serono, Rockland, MA, USA

    David Wages

  10. Bexon Clinical Consulting, on behalf of Idera Pharmaceuticals, Cambridge, MA, USA

    Alice S. Bexon

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Correspondence to David A. Smith.

Additional information

The results of this study have been published in parts in abstract form at the ECCO-ESMO 2009 multidisciplinary congress [Smith et al. (2009) Eur J Cancer 7(Suppl): abstract 9148] and at the ASCO 2012 annual meeting [Smith et al. (2012) J Clin Oncol 30(Suppl): abstract e18047].

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Smith, D.A., Conkling, P., Richards, D.A. et al. Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non-small cell lung cancer patients who have progressed following chemotherapy. Cancer Immunol Immunother 63, 787–796 (2014). https://doi.org/10.1007/s00262-014-1547-6

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  • DOI: https://doi.org/10.1007/s00262-014-1547-6

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