TY - JOUR
T1 - Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer
AU - Bauman, Julie E.
AU - Saba, Nabil F.
AU - Roe, Denise
AU - Bauman, Jessica R.
AU - Kaczmar, John
AU - Bhatia, Aarti
AU - Muzaffar, Jameel
AU - Julian, Ricklie
AU - Wang, Steven
AU - Bearelly, Shethal
AU - Baker, Audrey
AU - Steuer, Conor
AU - Giri, Anshu
AU - Burtness, Barbara
AU - Centuori, Sara
AU - Caulin, Carlos
AU - Klein, Robert
AU - Saboda, Kathylynn
AU - Obara, Stefanie
AU - Chung, Christine H.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - PURPOSEPrimary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance.PATIENTS AND METHODSThis multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used.RESULTSFrom 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months; P =.04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (P =.03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%; P =.02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (P interaction =.02).CONCLUSIONThe ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.
AB - PURPOSEPrimary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance.PATIENTS AND METHODSThis multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used.RESULTSFrom 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months; P =.04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (P =.03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%; P =.02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (P interaction =.02).CONCLUSIONThe ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.
KW - Antibodies, Monoclonal/therapeutic use
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Bayes Theorem
KW - Cetuximab
KW - Head and Neck Neoplasms/drug therapy
KW - Humans
KW - Neoplasm Recurrence, Local/pathology
KW - Squamous Cell Carcinoma of Head and Neck/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85166362527&partnerID=8YFLogxK
U2 - 10.1200/JCO.22.01994
DO - 10.1200/JCO.22.01994
M3 - Article
C2 - 36977289
AN - SCOPUS:85166362527
SN - 0732-183X
VL - 41
SP - 3851
EP - 3862
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 22
ER -