A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

Infante, Jeffrey R.; Somer, Bradley G.; Park, Joon Oh; Li, Chung–Pin; Scheulen, M. E.; Kasubhai, Saifuddin M.; Oh, Do‐Youn; Liu, Yuan; Redhu, Suman; Steplewski, Klaudia; Le, Ngocdiep T.

doi:10.1016/j.ejca.2014.04.024

Cited by 294 publications

(198 citation statements)

References 18 publications

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“…Efforts to target the KRAS pathway by focusing on these downstream effectors of KRAS activation are being undertaken (81), although results have been discouraging thus far. A randomized, double-blind trial of gemcitabine with or without trametinib (MEK inhibitor) did not show any improvement in overall or progression free survival for the combination in the first line setting of metastatic pancreatic cancer (82). Similar results were seen with another MEK inhibitor, pimasertib, when given in combination with gemcitabine (83).…”

Section: Kras and Associated Targetssupporting

confidence: 66%

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Vijayvergia

Cohen

2016

J. Gastrointest. Oncol.

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In 2015, pancreatic cancer was the 10th most commonly diagnosed cancer and the fourth leading cause of cancer death in the United States. The incidence of pancreatic cancer has been slowly rising over the past 10 years. It is estimated that about 53,000 new cases were diagnosed and 42,000 people died from pancreatic cancer in 2015 (1). The small difference between the incidence and death rate of pancreatic cancer reflect the early distant spread and inadequacy of current therapies. The 5-year survival rates for localized and advanced pancreatic cancer are 27% and less than 5%, respectively, lower than all other common cancers (2). The majority of patients are diag nosed at an advanced stage and are not eligible for surgical resection (2). These patients are often symptomatic and quickly deteriorate in the absence of effective therapy and many are unable to receive second and third line therapies for the same reason. Hence, finding the optimal first line regimen may be the key to improving outcomes. Increases in our knowledge of hu man and cancer genomics provide opportunities to un derstand the impact of genetic alterations on pancreatic cancer outcomes and develop predictive biomarkers for newer targeted therapies (3,4). Unfortunately, the amount of tissue obtained by fine needle aspiration of the primary pancreatic tumor is usually insufficient to perform adequate molecular analysis. As we move into the era of personalized medicine, obtaining core biopsy samples from metastatic sites, like liver, may help eliminate this problem. What do we know about pancreatic cancer genetically?Pancreatic cancer is a disease of significant genetic variability. Recent whole exome and genome sequencing have identified a wide range of genetic alterations including mutations and copy number variations that characterize pancreatic cancer (4,5). Some of these are recurrent and are clearly needed to identify subsets of patients likely to benefit from these therapies. Advances in our understanding of the molecular drivers of pancreatic cancer offer the hope of personalized therapy that may benefit our patients. In this review, we summarize the current knowledge about the biology of pancreatic cancer and its implication for treatment. We discuss recent advances in targeted therapies and the role of potential biomarkers in predicting response to established therapies. We also review novel therapeutic approaches that may be able to fulfill the promise of personalized therapy for pancreatic cancer.

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Section: Kras and Associated Targetssupporting

confidence: 66%

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Vijayvergia

Cohen

2016

J. Gastrointest. Oncol.

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“…However, two phase II studies of MEK inhibitors have failed to demonstrate any significant survival advantage for patients with pancreatic cancer (38,39). Furthermore, although MEK inhibition conferred a significant survival advantage in the present orthotopic pancreatic cancer xenograft model, the effect was somewhat limited (median survival of 82 days vs. 101 days for vehicle vs. PD325901, respectively).…”

Section: Discussionmentioning

confidence: 47%

“…On the basis of our present data and previous clinical trials (38,39), it would appear difficult to achieve molecular targeted therapy using MEK inhibitors alone. However, in addition to the mechanisms involved in early invasion, an understanding of the mechanisms responsible for malignant transformation or resistance to molecular targeting drugs would facilitate the development of combination therapy that includes the use of MEK inhibitors.…”

Section: Discussionmentioning

confidence: 73%

“…One plausible explanation for these limitations may be that oncogenic pathway(s) other than RAS-MEK-ERK may also contribute to progression of early invasive cancers to aggressive malignant cancers, such as locally disseminated or distant metastatic cancers. Indeed, the two previous phase II studies of MEK inhibitors enrolled patients with metastatic or refractory pancreatic cancers (38,39). Furthermore, PANC-1 cells, from which we developed our orthotopic models, were derived from locally disseminated pancreatic cancers (40).…”

Section: Discussionmentioning

confidence: 99%

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Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

et al. 2016

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The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. Ó2016 AACR.

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“…These include trametinib, a MEK1/MEK2 inhibitor that does not appear to affect the VEGF pathway [93,94]. Interestingly, this effect was shown in patients with NSCLC, similar to TKIs that affect the VEGF pathway, and is not described in melanoma and pancreatic cancer [95][96][97]. Another non-VSP inhibitor TKI shown to induce hypertension is ibrutinib, a Bruton's tyrosine kinase inhibitor, used for treatment of various hematologic malignancies [98].…”

Section: Other Notable Vsp Inhibitorsmentioning

confidence: 99%

Hypertension in cancer patients treated with anti-angiogenic based regimens

et al. 2015

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New anti-cancer drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway are highly effective in the treatment of solid tumors, however concerns remain regarding their cardiovascular safety. The most common side effect of VEGF signaling pathway (VSP) inhibition is the development of systemic hypertension. We review the incidence, possible mechanisms, significance and management of hypertension in patients treated with VSP inhibitors.

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A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

Cited by 294 publications

References 18 publications

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma

Hypertension in cancer patients treated with anti-angiogenic based regimens

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