Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma.

Chénard-Poirier, Maxime; Kaiser, Martin; Boyd, Kevin; Sriskandarajah, Priya; Constantinidou, Anastasia; Harris, S.J.; Fandos, Sonia Serrano; Ryan, Alison A.; Witt, Karolina D; Dawes, Joanna; Parmar, Mona; Turner, Alison; Tovey, Holly; Hall, Emma; López, Raquel Pérez; Tunariu, Nina; Lopez, Juanita; Bono, Johann S. de; Banerji, Udai

doi:10.1200/jco.2017.35.15_suppl.2506

Cited by 28 publications

(26 citation statements)

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“…However, feedback induction of MEK phosphorylation is still observed with trametinib, and multiple upstream mechanisms of acquired resistance (i.e., RAS mutations) are observed clinically in patients treated with trametinib (38). The MEK inhibitor CH5126766 inhibits both MEK and RAF because its binding to MEK results in a conformational change that interferes with the MEK phosphorylation by RAF and thus its release from RAF-MEK complexes (54), and early clinical data suggest this MEK inhibitor may have increased activity against RAS-mutant tumors, particularly non-small cell lung cancers (55).…”

Section: Mek Inhibitorsmentioning

confidence: 99%

Targeting Alterations in the RAF–MEK Pathway

2019

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The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. Although RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAF V600 mutations, for which several approved therapeutic regimens exist, other alterations in the RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specifi c RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets.Signifi cance: Alterations in the RAF and MEK genes represent promising therapeutic targets in multiple cancer types. However, given the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations observed in cancer can possess distinct functional characteristics. As outlined in this review, understanding the key functional properties of different RAF and MEK alterations is fundamental to selecting the optimal therapeutic approach.Research. on July 5, 2020.

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Section: Mek Inhibitorsmentioning

confidence: 99%

Targeting Alterations in the RAF–MEK Pathway

2019

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“…Recently, promising results have been communicated with a novel MEK inhibitor with functional pan-RAF inhibition (RO5126766). In a biomarker-driven basket trial, patients with KRAS-mutant lung adenocarcinomas (n = 10) derived significant treatment benefits, with 60% of patients showing tumour reductions, of which 30% were partial responses [57]. The drug was well tolerated, with a low frequency of grade 3/4 adverse events.…”

Section: Targeting Downstream Effectors Of Kras Pathwaymentioning

confidence: 99%

KRAS-Mutant non-small cell lung cancer: From biology to therapy

Zugazagoitia²,

et al. 2018

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In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation. 1. Introduction Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in approximately 20-25% of lung adenocarcinomas in Western countries [1-3] and in approximately 10-15% of cases in Asia [4,5]. Considered globally, KRAS-mutant tumours constitute the most frequent potentially targetable molecular subtype of non-small-cell lung cancer (NSCLC) [6]. As is the case with the vast majority of potentially

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“…One major design challenge is to capitalize on the correlated responses in baskets where the drug truly works, while simultaneously screening and dropping baskets where the drug is truly futile. Empirical results from published trials suggest that we can expect heterogeneity in efficacy across baskets [1,2,3,4].…”

Section: Introductionmentioning

confidence: 99%

Variance prior specification for a basket trial design using Bayesian hierarchical modeling

et al. 2018

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Background: In the era of targeted therapies, clinical trials in oncology are rapidly evolving, wherein patients from multiple diseases are now enrolled and treated according to their genomic mutation(s). In such trials, known as basket trials, the different disease cohorts form the different baskets for inference. Several approaches have been proposed in the literature to efficiently use information from all baskets while simultaneously screening to find individual baskets where the drug works. Most proposed methods are developed in a Bayesian paradigm that requires specifying a prior distribution for a variance parameter, which controls the degree to which information is shared across baskets. Methods: A common approach used to capture the correlated binary endpoints across baskets is Bayesian hierarchical modeling. We evaluate a Bayesian adaptive design in the context of a non-randomized basket trial and investigate three popular prior specifications: an inverse-gamma prior on the basket-level variance, a uniform prior and half-t prior on the basket-level standard deviation. Results: From our simulation study, we can see that the inverse-gamma prior is highly sensitive to the input hyperparameters. When the prior mean value of the variance parameter is set to be near zero [Formula: see text], this can lead to unacceptably high false-positive rates [Formula: see text] in some scenarios. Thus, use of this prior requires a fully comprehensive sensitivity analysis before implementation. Alternatively, we see that a prior that places sufficient mass in the tail, such as the uniform or half-t prior, displays desirable and robust operating characteristics over a wide range of prior specifications, with the caveat that the upper bound of the uniform prior and the scale parameter of the half-t prior must be larger than 1. Conclusion: Based on the simulation results, we recommend that those involved in designing basket trials that implement hierarchical modeling avoid using a prior distribution that places a majority of the density mass near zero for the variance parameter. Priors with this property force the model to share information regardless of the true efficacy configuration of the baskets. Many commonly used inverse-gamma prior specifications have this undesirable property. We recommend to instead consider the more robust uniform prior or half-t prior on the standard deviation.

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Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma.

Cited by 28 publications

References 0 publications

Targeting Alterations in the RAF–MEK Pathway

Targeting Alterations in the RAF–MEK Pathway

KRAS-Mutant non-small cell lung cancer: From biology to therapy

Variance prior specification for a basket trial design using Bayesian hierarchical modeling

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