Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer.

Cutsem, Éric Van; Hidalgo, Manuel; Bazin, I.; Canon, Jean-Luc; Poddubskaya, Elena; Manojlovic, Nebojsa; Milella, Michèle; Radenković, Dejan; Verslype, Chris; Guo, Wei; Damstrup, Lars; Hammel, Pascal

doi:10.1200/jco.2015.33.3_suppl.344

Cited by 17 publications

(9 citation statements)

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“…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: 67%

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: 67%

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

Vijayvergia

Cohen

2016

J. Gastrointest. Oncol.

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“…Pancreatic cancer is driven by dysregulated KRAS signaling and our CRISPR screen confirmed that KRAS is indispensable in the subset of pancreatic cancers that are Wnt driven. Almost all efforts targeting KRAS downstream signaling including the MAPK cascade and PI3K/mTOR cascade in pancreatic cancer have failed in clinical trials [39,40,[46][47][48]. In our study, although the genetic screen identified PI3K/mTOR signaling to be essential in Wntdriven pancreatic cancer, treatment with the pan-PI3K inhibitor GDC-0941 alone at a dose that substantially blocked the PI3K pathway only moderately delayed the tumor progression in the HPAF-II xenograft model.…”

Section: Discussionmentioning

confidence: 60%

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

et al. 2019

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Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly improve its outcome. PORCN inhibitors show efficacy in preclinical models of Wnt-addicted cancers, including RNF43mutant pancreatic cancers and have advanced to clinical trials. In this study, we aimed to develop drug combination strategies to further enhance the therapeutic efficacy of the PORCN inhibitor ETC-159. To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers, we performed an in vivo CRISPR loss-of-function screen. CTNNB1, KRAS, and MYC were reidentified as key oncogenic drivers. Notably, glucose metabolism pathway genes were important in vivo but less so in vitro. Knockout of multiple genes regulating PI3K/mTOR signaling impacted the growth of Wnt-driven pancreatic cancer cells in vivo. Importantly, multiple PI3K/mTOR pathway inhibitors in combination with ETC-159 synergistically suppressed the growth of multiple Wnt-addicted cancer cell lines in soft agar. Furthermore, the combination of the PORCN inhibitor ETC-159 and the pan-PI3K inhibitor GDC-0941 potently suppressed the in vivo growth of RNF43mutant pancreatic cancer xenografts. This was largely due to enhanced suppressive effects on both cell proliferation and glucose metabolism. These findings demonstrate that dual PORCN and PI3K/mTOR inhibition is a potential strategy for treating Wnt-driven pancreatic cancers.

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“…It has been proposed that non-V600 BRAF mutant melanoma are sensitive to single-agent MEKi, prompting an ongoing trial recruiting non-V600 mutant melanoma patients for treatment with trametinib (39,40). Since these initial observations, several clinical trials investigating single-agent MEKi have failed to yield sustained clinical benefit in a variety of indications (41)(42)(43). In BRAF V600 mutant melanoma, trametinib has a much lower overall response rate (22%) than single-agent BRAFi (48%-51%; ref.…”

Section: Discussionmentioning

confidence: 99%

Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas

Dankner

Lajoie

Moldoveanu

et al. 2018

Clinical Cancer Research

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Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi. BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi. Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma.

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Phase II randomized trial of MEK inhibitor pimasertib or placebo combined with gemcitabine in the first-line treatment of metastatic pancreatic cancer.

Cited by 17 publications

References 0 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?

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class II BRAF Mutant Melanomas

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