Two-dimensional phase I study of neratinib (NER) combined with temsirolimus (TEM) in patients (Pts) with solid tumors.

Gandhi, Leena; Bahleda, R.; Cleary, J. M.; Hollebecque, Antoine; Kwak, Eunice L.; Pandya, Shivani; Tolaney, Sara M.; Abbas, Rachid; Ananthakrishnan, Revathi; Berkenblit, Anna; Clancy, James F.; Turnbull, Kathleen; VoVan, M.L.; Shapiro, G.; Soria, Jean‐Charles

doi:10.1200/jco.2011.29.15_suppl.3027

Cited by 11 publications

(8 citation statements)

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“…Amplification is higher in adenocarcinoma than in SCC, and it confers sensitivity to gefitinib (38)(39)(40)(41)(42). Mutations in the ERBB2 gene are rare (2% in adenocarcinoma and 1% in SCC) and are associated with resistance to EGFR inhibitors and sensitivity to Her2-targeted therapy (43)(44)(45)(46)(47)(48)(49).…”

Section: Translational Relevancementioning

confidence: 99%

See 1 more Smart Citation

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Pérez-Moreno

Brambilla

Thomas

et al. 2012

Clinical Cancer Research

284

210

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Lung cancer is the leading cause of cancer-related deaths worldwide. Next to adenocarcinoma, squamous cell carcinoma (SCC) of the lung is the most frequent histologic subtype in non-small cell lung cancer. Encouraging new treatments (i.e., bevacizumab, EGFR tyrosine kinase inhibitors, and ALK inhibitors) have afforded benefits to patients with adenocarcinoma, but unfortunately the same is not true for SCC. However, many genomic abnormalities are present in SCC, and there is growing evidence of their biologic significance. Thus, in the short term, the molecular characterization of patients with SCC in modern profiling platforms will probably be as important as deciphering the molecular genetics of adenocarcinoma. Patients with SCC of the lung harboring specific molecular defects that are actionable (e.g., fibroblast growth factor receptor 1 amplification, discoidin domain receptor 2 mutation, and phosphoinositide 3-kinase amplification) should be enrolled in prospective clinical trials targeting such molecular defects.

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Section: Translational Relevancementioning

confidence: 99%

“…MGAH22 is an antiHER2 antibody that is currently under phase I investigation in Her2-overexpressing tumors. Anecdotal activity has been reported with trastuzumab or pan-Her inhibitors (PF-00299804 and neratinib) in patients with NSCLC with Her2-mutated or amplified tumors (43)(44)(45).…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Pérez-Moreno

Brambilla

Thomas

et al. 2012

Clinical Cancer Research

284

210

View full text Add to dashboard Cite

show abstract

“…34 Although there are limited data regarding mTOR inhibitors in patients with HER2-mutant lung adenocarcinoma, a phase I trial of neratinib plus temsirolimus resulted in partial responses in two of six patients with HER2-mutant NSCLC. 37 An early report from a phase II trial of afatinib alone in molecularly selected lung adenocarcinoma (NCT00730925) describes partial responses in two of five patients with tumors harboring HER2 mutations 38 ; efficacy may have been limited by toxicity, which required several patients to come off study before progression. Interestingly, HER2-amplified NSCLC may also gain benefit from HER2 kinase inhibitors, based on a report of a marked response seen in one patient receiving dacomitinib.…”

Section: Her2 Insertionsmentioning

confidence: 99%

New Targetable Oncogenes in Non–Small-Cell Lung Cancer

Oxnard

Binder²,

Jänne

2013

JCO

267

205

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A B S T R A C TThe identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non-small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non-small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development.

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“…The preliminary results from an ongoing phase II trial of dacomitinib, another oral pan-HER irreversible TKI, described three responses out of 18 evaluable patients with HER2-mutant NSCLC (NCT00818441) (8). Promising results were also reported from a phase I trial of the irreversible pan-HER inhibitor, neratinib, and the mTOR inhibitor, temsirolimus, with partial responses in two of six patients with HER2-mutant NSCLC (6). A phase II trial of neratinib versus neratinib plus temsirolimus in patients with HER2-mutant NSCLC is planned (NCT01827267).…”

Section: Her2 Amplification and Insertionsmentioning

confidence: 95%

“…To highlight therapeutic implications, this perspective discusses oncogenic drivers grouped by the availability of targeted agents for the specific genetic alteration. Some of the results of the studies discussed in this review have been previously reported in the form of an abstract (6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

The Impact of Genomic Changes on Treatment of Lung Cancer

Cardarella

Johnson

2013

Am J Respir Crit Care Med

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The remarkable success of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in patients with EGFR mutations and ALK rearrangements, respectively, introduced the era of targeted therapy in advanced non-small cell lung cancer (NSCLC), shifting treatment from platinum-based combination chemotherapy to molecularly tailored therapy. Recent genomic studies in lung adenocarcinoma identified other potential therapeutic targets, including ROS1 rearrangements, RET fusions, MET amplification, and activating mutations in BRAF, HER2, and KRAS in frequencies exceeding 1%. Lung cancers that harbor these genomic changes can potentially be targeted with agents approved for other indications or under clinical development. The need to generate increasing amounts of genomic information should prompt health-care providers to be mindful of the amounts of tissue needed for these assays when planning diagnostic procedures. In this review, we summarize oncogenic drivers in NSCLC that can be currently detected, highlight their potential therapeutic implications, and discuss practical considerations for successful application of tumor genotyping in clinical decision making.Keywords: lung cancer; cancer genomics; molecular targeted therapy Lung cancer remains the leading cause of cancer-related mortality in the United States and worldwide. Approximately 85% of patients are diagnosed with non-small cell lung cancer (NSCLC), and most present with advanced disease that is not amenable to curative therapy. For these patients, cytotoxic chemotherapy offers modest prolongation in survival. Over the past 2 decades, modifications of chemotherapy combinations, the addition of monoclonal antibodies, including bevacizumab and cetuximab, and the incorporation of histologic subtype into treatment decisions have added incrementally to the survival of patients with advanced NSCLC. However, therapeutic outcomes appear to have reached a plateau, with response rates of 20 to 35% and median survival of 8 to 12 months (1-3). Recently, clinical and laboratory research have led to a better understanding of the molecular pathogenesis that causes lung cancer. The ongoing research of patients with NSCLC and their tumors has demonstrated that NSCLC can be further defined at the molecular level by the identification and characterization of oncogenic drivers that occur in genes critical to cellular proliferation and survival, leading to aberrant activation of signaling proteins that induce sustained growth of the lung cancer cells. These advances in the molecular pathogenesis of NSCLC have prompted investigators to systematically characterize lung cancers for these oncogenic drivers and treat with appropriate targeted therapies. A cohort of patients can now be prospectively identified who have significantly improved outcomes with such therapies, with median survival in excess of 2 years, necessitating the routine identification of these genomically defined patient subsets. In this perspective, we review oncogenic ...

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Two-dimensional phase I study of neratinib (NER) combined with temsirolimus (TEM) in patients (Pts) with solid tumors.

Cited by 11 publications

References 0 publications

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

New Targetable Oncogenes in Non–Small-Cell Lung Cancer

The Impact of Genomic Changes on Treatment of Lung Cancer

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