Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy

Pancreatic adenocarcinoma is a common malignancy that remains refractory to available therapies. Gemcitabine has long been the standard, first-line agent in advanced disease. The epidermal growth factor receptor (EGFR) is a commonly expressed target in pancreatic cancer that is involved in tumor proliferation, metastasis, and induction of angiogenesis. The addition of the EGFR inhibitor erlotinib to gemcitabine has recently been demonstrated to provide a small, yet statistically significant, survival benefit in advanced disease. This has prompted further research into the applications of EGFR-targeted therapy in pancreatic cancer, albeit with disappointing results. Resistance to these therapies seems highly prevalent and has been implicated in their limited efficacy. The development of rash is associated with treatment efficacy and suggests that predictive factors may one day be identified to guide appropriate patient selection for these agents. Preclinical research has shown promise that resistance to EGFR-targeted therapies can be overcome through a variety of approaches. Application of this research in clinical trials may ultimately yield an unquestioned role for EGFR-targeted therapy in the management of this disease

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P \u3c .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN

Doubleâ blind, randomized phase 3 trial of lowâ dose 13â cis retinoic acid in the prevention of second primaries in head and neck cancer: Longâ term followâ up of a trial of the Eastern Cooperative Oncology Groupâ ACRIN Cancer Research Group (C0590)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139904/1/cncr30920.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139904/2/cncr30920_am.pd

Paclitaxel With or Without Cixutumumab as Second-Line Treatment of Metastatic Esophageal or Gastroesophageal Junction Cancer: A Randomized Phase II ECOG-ACRIN Trial

BACKGROUND: Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers. METHODS: The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated. RESULTS: Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56. CONCLUSION: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388)

Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities

Background Epidermal growth factor receptor inhibitors (EGFRI) produce various dermatologic side effects in the majority of patients, and guidelines are crucial for the prevention and treatment of these untoward events. The purpose of this panel was to develop evidence-based recommendations for EGFRI-associated dermatologic toxicities. Methods A multinational, interdisciplinary panel of experts in supportive care in cancer reviewed pertinent studies using established criteria in order to develop first-generation recommendations for EGFRI-associated dermatologic toxicities. Results Prophylactic and reactive recommendations for papulopustular (acneiform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis/fissures, and paronychia are presented, as well as general dermatologic recommendations when possible. Conclusion Prevention and management of EGFRI-related dermatologic toxicities is critical to maintain patients’ health-related quality of life and dose intensity of antineoplastic regimens. More rigorous investigation of these toxicities is warranted to improve preventive and treatment strategies

Neuregulin signaling is a mechanism of therapeutic resistance in head and neck squamous cell carcinoma

EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosur-vival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These in vitro findings were confirmed in xenograft tumor growth experiments including an approach using growth factor–supplemented Matrigel. In vivo, the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.Fil: Baro, Marta. University of Yale. School of Medicine; Estados UnidosFil: López Sambrooks, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Burtness, Barbara A.. University of Yale. School of Medicine; Estados UnidosFil: Lemmon, Mark A.. University of Yale. School of Medicine; Estados UnidosFil: Contessa, Joseph N.. University of Yale. School of Medicine; Estados Unido