A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non–Small Cell Lung Cancer with a <i>KRAS</i> Mutation

Dingemans, Anne‐Marie C.; Mellema, Wouter W.; Groen, Harry J.M.; Wijk, A. van; Burgers, Sjaak A.; Kunst, Peter W.A.; Thunnissen, Erik; Heideman, Daniëlle A.M.; Smit, Egbert F.

doi:10.1158/1078-0432.ccr-12-1779

Cited by 70 publications

(58 citation statements)

References 42 publications

(44 reference statements)

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“…Sorafenib is an oral multitarget TKI which inhibits RAF and related transmembrane receptors. Phase II trials showed promising results with a disease control rate of ∼50% [25,26,28]. Yet subgroup analyses performed in the KRAS-mutated group of the phase III MISSION trial did not reveal any specific efficacy of sorafenib in the third or fourth chemotherapy line [27].…”

Section: If Direct Blocking Of Rasmentioning

confidence: 99%

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

et al. 2016

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KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclindependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. @ERSpublications MEK inhibition and immunotherapy are very promising therapeutic advances in KRAS-mutated nonsmall cell lung cancer http://ow.ly/U2ohp KRAS mutations in lung cancer: epidemiology and clinical outcomesSince the beginning of the 21st century, the paradigm of precision medicine has shaken up the landscape of lung cancer classification and treatment. The discovery of cancer-related driver molecular abnormalities led to the development of efficient targeted therapies. RAS proteins are GTP kinases, discovered in the 1960s, whose GTP-RAS active isoform stimulates several pathways involved in cellular growth. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are found in ∼25-35% of newly diagnosed nonsmall cell lung cancer (NSCLC), with a higher proportion in the adenocarcinoma subtype [1,2]. Figure 1 summarises the main amino acid substitutions and genomic features that are associated with KRAS mutations in NSCLC [3,4]. Other molecular abnormalities related to RAS pathway activation are diagnosed in 25% of NSCLC cases, such as epidermal growth factor receptor (EGFR) (10-23%), BRAF mutations (2%), MET amplifications (2%), human epidermal growth factor (HER)2 (1%) and NRAS (0.2%) mutations. Loss of the negative regulator neurofibromin is found in ∼11% of other cases.

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Section: If Direct Blocking Of Rasmentioning

confidence: 99%

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

et al. 2016

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“…Clinical trials of sorafenib in patients with advanced non-smallcell lung cancer have demonstrated modest activity, with no survival advantage (7,20). Though it is attractive to consider ARAF/ RAF1 mutations as possible biomarkers of sorafenib response in lung adenocarcinoma, additional profiling and functional characterization studies will be required to establish this link.…”

Section: Figurementioning

confidence: 99%

Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

et al. 2014

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Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

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“…Analysis of TA performance by Kuiper et al [32] in serum from 50 chemotherapy-naïve patients treated with erlotinib plus sorafenib [33] again confirmed superior outcomes for patients classified as good outcome versus poor outcome (OS: 13.7 vs. 5.6 months; HR: 0.30; p 5 .009; PFS: 5.5 vs. 2.7 months; HR: 0.40; p 5 .035), whereas the objective RR was not significantly different [32]. For sorafenib monotherapy, as reported by Dingemans et al in 55 pretreated patients, PFS was significantly longer in TA-discerned good-outcome patients versus poor-outcome patients (2.6 vs. 1.5 months; HR: 1.4; p 5 .029), whereas OS was not significantly different (6.0 vs. 2.5 months; HR: 1.3; p 5 .166), probably due to a relatively large variation in OS duration [34]. Stinchcombe et al applied the TA to sera of 98 elderly patients treated in a randomized phase II trial of first-line therapy with gemcitabine, erlotinib, or combination [64].…”

Section: Studies Reporting Profiling Prior To Systemic Therapymentioning

confidence: 87%

Mass Spectrometry-Based Serum and Plasma Peptidome Profiling for Prediction of Treatment Outcome in Patients With Solid Malignancies

et al. 2014

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Introduction. Treatment selection tools are needed to enhance the efficacy of targeted treatment in patients with solid malignancies. Providing a readout of aberrant signaling pathways and proteolytic events, mass spectrometry-based (MS-based) peptidomics enables identification of predictive biomarkers, whereas the serum or plasma peptidome may provide easily accessible signatures associated with response to treatment. In this systematic review, we evaluate MS-based peptide profiling in blood for prompt clinical implementation. Methods. PubMed and Embase were searched for studies using a syntax based on the following hierarchy: (a) bloodbased matrix-assisted or surface-enhanced laser desorption/ ionization time-of-flight MS peptide profiling (b) in patients with solid malignancies (c) prior to initiation of any treatment modality, (d) with availability of outcome data. Results. Thirty-eight studies were eligible for review; the majority were performed in patients with non-small cell lung

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A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non–Small Cell Lung Cancer with a KRAS Mutation

Cited by 70 publications

References 42 publications

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

Mass Spectrometry-Based Serum and Plasma Peptidome Profiling for Prediction of Treatment Outcome in Patients With Solid Malignancies

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