pf-00299804 and Head-and-Neck-Neoplasms

Patients with squamous cell carcinoma of the head and neck (SCCHN) typically present with locally advanced (LA) stage III or IV disease and are treated with combined-modality therapy with chemotherapy, radiotherapy, and surgery (if resectable). These aggressive, upfront treatment measures are often associated with substantial morbidity, and about half the patients develop locoregional or distant recurrences. Thus, new therapeutic strategies are needed that offer similar efficacy benefits with less toxicity. Current research is focused on selectively targeting signaling pathways involved in the proliferation and malignant transformation of SCCHN cells and the tumor microenvironment. For example, the ErbB receptor pathway has been implicated in the development and progression of SCCHN, and several agents targeting this pathway and downstream effectors are in various phases of clinical investigation. Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is the only currently approved targeted therapy for the treatment of LA SCCHN. Additional agents targeting EGFR and other ErbB family members, including monoclonal antibodies (eg, panitumumab, nimotuzumab) and small-molecule tyrosine kinase inhibitors (eg, erlotinib, afatinib, lapatinib) are being studied in LA SCCHN with varying results. Other treatment strategies for LA SCCHN include targeting downstream effectors of signaling and resistance mechanisms to EGFR inhibitors (eg, mammalian target of rapamycin, Src family, and Aurora kinase family). Data from ongoing and future clinical trials will continue to refine current treatment paradigms for LA SCCHN and provide new therapeutic options and potential predictive biomarkers to improve patient efficacy and safety and abrogate resistance.

Topics: Afatinib; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azepines; Carcinoma, Squamous Cell; Cetuximab; Dasatinib; ErbB Receptors; Erlotinib Hydrochloride; Head and Neck Neoplasms; Humans; Lapatinib; Molecular Targeted Therapy; Panitumumab; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Quinazolinones; Signal Transduction; Sirolimus

Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis. With the emergence of monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR), several drugs were developed and tested in HNSCC. To date, the monoclonal antibody cetuximab is the only approved therapy for curative and recurrent/metastatic patients. Other EGFR-targeting drugs either failed in the clinical trials or are still in the early phases of drug development and research.. In this article, previously published data and ongoing studies regarding dacomitinib, a second-generation irreversible TKI, for the treatment of HNSCC are presented and discussed.. The current body of evidence is not mature enough to indicate the use of dacomitinib for the treatment of HNSCC in curative or in recurrent/metastatic settings. Phase II data suggest the potential of improved outcome in selected recurrent/metastatic HNSCC based on several biomarkers, which need to be evaluated in randomized phase III trials. Meanwhile, an ongoing phase I study is investigating dacomitinib's optimal dosing combined with and without cisplatin in the curative concomitant chemoradiotherapy setting.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; ErbB Receptors; Head and Neck Neoplasms; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Protein Kinase Inhibitors; Quinazolinones; Squamous Cell Carcinoma of Head and Neck

The majority of patients with a squamous cell carcinoma of the head and neck present with locally advanced tumors. The first-line treatment of locally advanced tumor stages consists of a combined modality management. Despite these aggressive protocols, many patients develop locoregional recurrences or metastasis and place particularly high demands on the interdisciplinary treatment team. Treatment with a curative intent must be differentiated from a palliative one. In addition to prior treatment, resectability, age and performance status, patient wishes must be taken into consideration in treatment planning, especially considering that most therapies offer little to no overall survival benefit. Salvage surgery, chemo- and target therapies, and reirradiation are head and neck surgeon's and radiooncologist's weapons in the fight against these strong opponents. This review focuses on publications and meeting news from last year and reviews the current status of the clinical application of each treatment modality in recurrent or metastatic head and neck cancer.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzodioxoles; Carcinoma, Squamous Cell; Cetuximab; Combined Modality Therapy; Dasatinib; ErbB Receptors; Fluorouracil; Gefitinib; Head and Neck Neoplasms; Humans; Indoles; Neoplasm Recurrence, Local; Palliative Care; Pyrimidines; Pyrroles; Quinazolines; Quinazolinones; Salvage Therapy; Squamous Cell Carcinoma of Head and Neck; Sunitinib; Thiazoles

Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg). Cisplatin was given intravenously at 100 mg/m(2) every 3 weeks. Radiotherapy was delivered using intensity modulated radiation therapy (IMRT) to a dose of 70Gy in 35 daily fractions to the primary and nodal disease. Dose escalation was performed using a standard 3 + 3 design. Results Twelve patients with LA-SCCHN were enrolled between January 2013 and August 2014. No dose limiting toxicities (DLTs) were observed in the 15 mg and 30 mg dose levels. In the 45 mg dose level, one of four evaluable patients developed a DLT with intolerable grade 2 diarrhea requiring discontinuation of therapy. Adverse events (AEs) attributed to dacomitinib alone include diarrhea, hypertension, and acneiform and maculopapular rash. The most common non-hematological AEs include weight loss, diarrhea, dry mouth, mucositis, nausea, hypoalbuminemia, and hyponatremia. Frequency and severity of AEs did not increase with increasing dose levels of dacomitinib. All patients completed the full course of radiotherapy on schedule and the median dose of cisplatin was 200 mg/m(2), which is comparable to historical standards. Of the 10 patients evaluable for response, 1 patient relapsed with metastatic disease. Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early termination of this study.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; ErbB Receptors; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Quinazolinones; Squamous Cell Carcinoma of Head and Neck

The goals of this study were to investigate the clinical activity, safety, and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN).. Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16(INK4A) expression by IHC, and investigation of their relationship with clinical outcomes.. Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months [95% confidence interval (CI), 2.9-5.0] and 6.6 months (95% CI, 5.4-10.3). Adverse events were mostly grade 1-2. Mutations in the PI3K pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 vs. 4.9 months without mutations, P = 0.013; 2.8 vs. 9.9 months with low expression, P = 0.004). Those harboring PI3K pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 vs. 12.5 months lacking PI3K pathway mutations and with low inflammatory cytokine expression, P = 0.005).. Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Carcinoma, Squamous Cell; Cluster Analysis; Female; Gene Dosage; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Protein Kinase Inhibitors; Quinazolinones; Retreatment; Risk Factors; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome

Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided).. Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test.. Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr.. Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33-44 % decrease in AUC (all p <0.05) (Jänne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Enteral Nutrition; ErbB Receptors; Female; Gastrostomy; Head and Neck Neoplasms; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Quinazolinones; Squamous Cell Carcinoma of Head and Neck

An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck (RM-SCCHN).. Eligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate.. Sixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 [12.7%, 95% confidence interval (CI) 5.6% to 23.5%] achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs.. Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Diarrhea; ErbB Receptors; Female; Head and Neck Neoplasms; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Quinazolinones; Treatment Outcome

Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients. Therefore, validated predictive biomarkers are required to identify patients most likely to benefit from this therapeutic option. To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA. Platinum-based chemotherapy elevated the mutation rates of SCCHN compared to chemotherapy-naïve SCCHNs. Cisplatin-treated SCCHN genomes uniquely exhibited a novel mutational signature characterized by C:G to A:T transversions at CCR sequence contexts that may have arisen due to error-prone translesional synthesis. Somatic mutations in REV3L, the gene encoding the catalytic subunit of DNA polymerase ζ involved in translesional synthesis, are significantly enriched in a subset of patients who derived extended clinical benefit to dacomitinib (P = 0.04). Functional assays showed that loss-of-function of REV3L dramatically enhanced the sensitivity of SCCHN cells to dacomitinib by the loss of both translesion synthesis and homologous recombination pathways. Our data suggest that the 'platinum' mutational signature and inactivation of REV3L may inform treatment options in patients of recurrent SCCHN.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cisplatin; DNA Mutational Analysis; DNA-Binding Proteins; DNA-Directed DNA Polymerase; Drug Resistance, Neoplasm; Exome; Gene Silencing; Head and Neck Neoplasms; High-Throughput Nucleotide Sequencing; Humans; Mutation; Quinazolinones; Recombinational DNA Repair; RNA Interference; RNA, Small Interfering; Squamous Cell Carcinoma of Head and Neck

The purpose of the present study was to explore the antiproliferative effect of BYL719, a specific inhibitor for phosphatidylinositol 3-kinase (PI3K) p110α, in human head and neck cancer cell lines, as a single agent or in combination with the irreversible EGFR tyrosine kinase inhibitor, dacomitinib.. Six head and neck cancer cell lines consisting of two PIK3CA mutant cell lines, SNU-1076 and Detroit562, and four PIK3CA wild-type cell lines, SNU-1066, SNU-1041, FaDu and SCC25, were analyzed.. The PIK3CA-mutant cell lines were more sensitive to BYL719 than the PIK3CA wild-type cell lines. Following BYL719 treatment, all PIK3CA wild-type cell lines, except for the SNU-1066 cell line, exhibited higher IC50 values compared to the PIK3CA mutant cell lines. Administration of BYL719 induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependant manner. Furthermore, the administration of BYL719 reduced the level of p-mTOR, p-AKT and p-S6 expression indicating the down-regulation of downstream signaling.. BYL719, a PI3K alpha selective blocker, could be a promising factor in the treatment of head and neck cancer either as a single agent or in combination with dacomitinib.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Drug Synergism; Head and Neck Neoplasms; Humans; Phosphoinositide-3 Kinase Inhibitors; Quinazolinones; Thiazoles

Epidermal growth factor receptor (EGFR) is over-expressed in nearly all cases of squamous cell carcinoma of the head and neck (SCCHN), and is an important driver of disease progression. EGFR targeted therapies have demonstrated clinical benefit for SCCHN treatment. In this report, we investigated the pre-clinical efficacy of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, both alone and in combination with ionizing radiation (IR), a primary curative modality for SCCHN. One normal oral epithelial (NOE) and three SCCHN (FaDu, UT-SCC-8, UT-SCC-42a) cell lines were used to conduct cell viability, clonogenic survival, cell cycle, and immunoblotting assays in vitro, using increasing doses of Dacomitinib (10-500 nM), both with and without IR (2-4 Gy). The FaDu xenograft model was utilized for tumor growth delay assays in vivo, and immunohistochemical analyses were conducted on extracted tumors. A dose-dependent reduction in cell viability and clonogenic survival after Dacomitinib treatment was observed in all three SCCHN models. Treatment led to a significant reduction in EGFR signalling, with a subsequent decrease in phosphorylation of downstream targets such as ERK, AKT, and mTOR. In vivo, Dacomitinib treatment delayed tumor growth, while decreasing phospho-EGFR and Ki-67 immunoexpression. These effects were further enhanced when combined with IR, both in vitro and in vivo. The preclinical data support the further evaluations of Dacomitinib combined with IR for the future management of patients with SCCHN.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Drug Evaluation, Preclinical; ErbB Receptors; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Inbred BALB C; Phosphorylation; Quinazolinones; Real-Time Polymerase Chain Reaction; Signal Transduction; Squamous Cell Carcinoma of Head and Neck

Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC), and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases), to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Proliferation; Cetuximab; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Head and Neck Neoplasms; Humans; In Situ Hybridization, Fluorescence; Mutation; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Quinazolines; Quinazolinones; ras Proteins; Signal Transduction; Tumor Cells, Cultured