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author:("gulnik, Mark")
1.  Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial 
The lancet oncology  2013;14(4):371-382.
Summary
Background
Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.
Methods
We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.
Findings
Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).
Interpretation
The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.
Funding
National Cancer Institute and Cycle for Survival Fund, Memorial Sloan-Kettering Cancer Center.
doi:10.1016/S1470-2045(13)70049-4
PMCID: PMC3766955  PMID: 23477833
2.  Targeted treatment of head and neck squamous-cell carcinoma: potential of lapatinib 
OncoTargets and therapy  2014;7:245-251.
Squamous-cell cancer of the head and neck is a heterogeneous malignancy with treatment predicated on a multimodality therapy involving surgery, chemotherapy, and radiation. However, this approach results in durable responses in only a subset of patients, and is associated with significant toxicity. In advanced disease, multi-agent platinum-based chemotherapy produces only modest improvements in survival. Increased insight into tumor biology has demonstrated several critical oncogenic pathways offering prospects for targeted therapy that may improve upon the existing treatment strategies. The epidermal growth factor receptor is one such target, and directed therapy with the monoclonal antibody cetuximab has been extensively studied. Lapatinib is an oral agent that targets multiple transmembrane receptors within the epidermal growth factor receptor family, and offers a promising new approach to treatment. This paper reviews the rationale for and clinical activity of lapatinib in squamous-cell cancer of the head and neck.
doi:10.2147/OTT.S46933
PMCID: PMC3928467  PMID: 24611017
epidermal growth factor receptor; targeted therapy; oral cavity; pharynx; larynx
3.  Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC 
OncoTargets and therapy  2013;6:135-143.
The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.
doi:10.2147/OTT.S23165
PMCID: PMC3594037  PMID: 23493883
afatinib; EGFR; irreversible EGFR inhibitor; EGPR-TKIs; LUX lung; resistance mutation; targeted therapy
4.  New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN) 
Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN.
doi:10.1007/s12032-012-0159-2
PMCID: PMC3466428  PMID: 22252310
Epidermal growth factor receptor (EGFR); Monoclonal antibody; Tyrosine kinase inhibitor; Resistance; Squamous cell carcinoma of the head and neck
5.  A Phase II Study of Pazopanib in Patients with Recurrent or Metastatic Invasive Breast Carcinoma: A Trial of the Princess Margaret Hospital Phase II Consortium 
The Oncologist  2010;15(8):810-818.
Reported are the results of a multicenter, open-label, single-arm, phase II trial to evaluate the safety and efficacy of pazopanib in human epidermal growth factor receptor 2 nonoverexpressing recurrent breast cancer or metastatic breast cancer patients.
Purpose.
Angiogenesis is an important hallmark of breast cancer growth and progression. Pazopanib, an oral small molecule inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and KIT, has activity across a range of solid tumors. We evaluated the activity of single-agent pazopanib in recurrent or metastatic breast cancer (MBC).
Patients and Methods.
Patients with recurrent breast cancer or MBC, treated with up to two prior lines of chemotherapy, were eligible to receive pazopanib, 800 mg daily until progression. The primary endpoint was the objective response rate as measured by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included time to progression, the stable disease rate, and toxicity. Using a two-stage design, confirmed response in three of 18 patients was required to proceed to stage 2.
Results.
Twenty evaluable patients were treated, with a median age of 56 years; 70% were estrogen receptor positive, all were human epidermal growth factor receptor 2 negative. The majority had one or two prior lines of chemotherapy. One patient (5%) had a partial response, 11 (55%) had stable disease (SD) [four (20%) with SD ≥6 months], and seven (35%) had progressive disease as their best response. One (5%) was not evaluable. The median time to progression was 5.3 months. Pazopanib did not cause significant severe toxicity aside from grade 3–4 transaminitis, hypertension, and neutropenia in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient (5%).
Conclusion.
Pazopanib provides disease stability in advanced breast cancer. The activity seen is comparable with that of other antiangiogenic agents in this setting. Pazopanib may be of interest for future studies in breast cancer, including in combination with other systemic agents.
doi:10.1634/theoncologist.2010-0081
PMCID: PMC3228026  PMID: 20682606
Breast neoplasms; Pazopanib; Targeted therapy; Phase II
6.  Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib 
Head & neck  2009;31(8):1006-1012.
Aim
Gene amplification status of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) were analyzed and correlated with clinical outcome in patients with progressive malignant salivary glands tumors (MSGT) treated with the dual EGFR/Her2 tyrosine kinase inhibitor lapatinib
Methods
Fluorescence in situ hybridization (FISH) analysis for both EGFR and HER2 gene amplification was performed successfully in the archival tumor specimens of 20 patients with adenoid cystic carcinomas (ACC) and 17 patients with non-ACC, all treated with lapatinib.
Results
For ACC, no EGFR or HER2 amplifications were detected. For non-ACC, no EGFR gene amplifications were detected but 3 patients (18%) were HER2 amplified and all had stained 3+ for both EGFR and HER2 by immunohistochemistry (IHC) in their archival specimens. Two of these patients had time-to-progression (TTP) durations of 8.3 months and 18.4 months respectively. Interestingly, patients with low and high HER2/chromosome-specific centromeric enumeration probe (CEP) 17 ratio had a prolonged TTP than those with moderate ratios for both ACC and non-ACC subtypes.
Conclusions
HER2 to CEP17 FISH ratio may predict which patients with MSGT have an increased likelihood to benefit from lapatinib. The finding of HER2:CEP17 ratio as a predictive marker of efficacy to lapatinib warrants further investigation.
doi:10.1002/hed.21052
PMCID: PMC2711990  PMID: 19309723
MSGT; lapatinib; EGFR and HER2 gene amplification; FISH
7.  New Developments in Mammalian Target of Rapamycin Inhibitors for the Treatment of Sarcoma 
Cancer  2011;118(6):1486-1497.
Although sarcomas account for a small portion of solid malignancies, currently, there are few treatment options for sarcomas, particularly for advanced disease. The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase in the phosphatidylinositol 3-kinase/serine/threonine protein kinase Akt signaling pathway, has an important role in the regulation of protein synthesis, cell proliferation, angiogenesis, and metabolism. Alterations of the mTOR signaling pathway are common in malignancies, including several types of sarcoma. Therefore, mTOR is a potentially important therapeutic target in these diseases. Rapamycin and its analogs (rapalogs) are effective anticancer agents in a broad range of preclinical models. Clinical trials with these agents alone and in combination with other anticancer agents, including chemotherapy and targeted therapies, have demonstrated potential clinical benefit in several types of sarcoma. The evidence from both preclinical and clinical studies supports further study of mTOR-targeting rapalogs in the treatment of various subtypes of sarcoma. Cancer 2011;. © 2011 American Cancer Society.
doi:10.1002/cncr.26361
PMCID: PMC3412949  PMID: 21837674
sarcoma; mammalian target of rapamycin (mTOR) protein; sirolimus; temsirolimus; ridaforolimus; everolimus

Results 1-7 (7)