Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

doi:10.3390/cancers14102355

. 2022 May 10;14(10):2355.

doi: 10.3390/cancers14102355.

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

Julie E Bauman^{1

2}, Ricklie Julian¹, Nabil F Saba³, Trisha M Wise-Draper⁴, Douglas R Adkins⁵, Paul O'Brien⁶, Mary Jo Fidler⁷, Michael K Gibson⁸, Umamaheswar Duvvuri⁹, Margo Heath-Chiozzi¹⁰, Diego Alvarado¹⁰, Richard Gedrich¹⁰, Philip Golden¹⁰, Roger B Cohen¹¹

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
² Division of Hematology/Oncology, Department of Medicine, GW Cancer Center, The George Washington University, Washington, DC 20052, USA.
³ Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
⁴ Division of Hematology/Oncology, Department of Medicine, University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, OH 45267, USA.
⁵ Division of Hematology/Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ Division of Hematology/Oncology, Department of Medicine, MUSC Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
⁷ Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
⁸ Division of Hematology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁹ Division of Head and Neck Surgery, Department of Otolaryngology, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15232, USA.
¹⁰ Celldex Therapeutics, Hampton, NJ 08827, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

PMID: 35625959
PMCID: PMC9139981
DOI: 10.3390/cancers14102355

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

Julie E Bauman et al. Cancers (Basel). 2022.

. 2022 May 10;14(10):2355.

doi: 10.3390/cancers14102355.

Authors

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
² Division of Hematology/Oncology, Department of Medicine, GW Cancer Center, The George Washington University, Washington, DC 20052, USA.
³ Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
⁴ Division of Hematology/Oncology, Department of Medicine, University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, OH 45267, USA.
⁵ Division of Hematology/Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ Division of Hematology/Oncology, Department of Medicine, MUSC Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
⁷ Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
⁸ Division of Hematology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁹ Division of Head and Neck Surgery, Department of Otolaryngology, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15232, USA.
¹⁰ Celldex Therapeutics, Hampton, NJ 08827, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

PMID: 35625959
PMCID: PMC9139981
DOI: 10.3390/cancers14102355

Abstract

In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.

Keywords: CDX-3379; EGFR; ErbB3; cetuximab; head and neck cancer.

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Conflict of interest statement

M.H.-C., D.A., R.G. and P.G. are employed by Celldex Therapeutics. The remaining authors declare no potential conflict of interest.

Figures

**Figure 2**
Progression-Free and Overall Survival.

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References

1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. - DOI - PubMed
1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7–30. doi: 10.3322/caac.21590. - DOI - PubMed
1. Sacco A.G., Cohen E.E. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol. 2015;33:3305–3313. doi: 10.1200/JCO.2015.62.0963. - DOI - PubMed
1. Grandis J.R., Melhem M.F., Gooding W.E., Day R., Holst V.A., Wagener M.M., Drenning S.D., Tweardy D.J. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J. Natl. Cancer Inst. 1998;90:824–832. doi: 10.1093/jnci/90.11.824. - DOI - PubMed
1. Ang K.K., Berkey B.A., Tu X., Zhang H.Z., Katz R., Hammond E.H., Fu K.K., Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–7356. - PubMed

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[1] Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. - DOI - PubMed

[2] Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. - DOI - PubMed

[3] Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7–30. doi: 10.3322/caac.21590. - DOI - PubMed

[4] Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7–30. doi: 10.3322/caac.21590. - DOI - PubMed

[5] Sacco A.G., Cohen E.E. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol. 2015;33:3305–3313. doi: 10.1200/JCO.2015.62.0963. - DOI - PubMed

[6] Sacco A.G., Cohen E.E. Current Treatment Options for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol. 2015;33:3305–3313. doi: 10.1200/JCO.2015.62.0963. - DOI - PubMed

[7] Grandis J.R., Melhem M.F., Gooding W.E., Day R., Holst V.A., Wagener M.M., Drenning S.D., Tweardy D.J. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J. Natl. Cancer Inst. 1998;90:824–832. doi: 10.1093/jnci/90.11.824. - DOI - PubMed

[8] Grandis J.R., Melhem M.F., Gooding W.E., Day R., Holst V.A., Wagener M.M., Drenning S.D., Tweardy D.J. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J. Natl. Cancer Inst. 1998;90:824–832. doi: 10.1093/jnci/90.11.824. - DOI - PubMed

[9] Ang K.K., Berkey B.A., Tu X., Zhang H.Z., Katz R., Hammond E.H., Fu K.K., Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–7356. - PubMed

[10] Ang K.K., Berkey B.A., Tu X., Zhang H.Z., Katz R., Hammond E.H., Fu K.K., Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–7356. - PubMed

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Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

Affiliations

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer

Authors

Affiliations

Abstract

Conflict of interest statement

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