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Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. We enrolled 206 patients (median age 58·5 years, range 19–92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. GlaxoSmithKline.

MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma. We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622. 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0–7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%). Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future. GlaxoSmithKline.

The addition of a MEK inhibitor to a BRAF inhibitor improved response rates by nearly 16 percentage points (from 51% to 67%) and improved progression-free survival by 0.5 months (from 8.8 to 9.3 months). Targeted inhibition of the RAF–MEK–ERK (MAPK) pathway with BRAF inhibitors dabrafenib or vemurafenib, as compared with chemotherapy, improves the progression-free and overall survival of patients who have metastatic melanoma with BRAF V600 mutations. 1 , 2 However, resistance develops in a majority of patients, resulting in a median progression-free survival of 6 to 7 months. 3 , 4 Most reported resistance mechanisms reactivate the MAPK pathway. 5 – 7 In addition, BRAF-inhibitor–induced paradoxical activation of the MAPK pathway 8 – 10 can result in secondary cancers, including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant tumors. 11 – 13 Independently, single-agent trametinib, a MEK inhibitor, improves the overall survival of patients . . .

BackgroundPancreatic cancer (PaC) is immune-quiescent and resistant to single-agent checkpoint inhibitor (CPI). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME) and may enhance tumor responsiveness to CPI therapy. We hypothesize that the combination of NT-I7 and pembrolizumab may result in enhanced efficacy in CPI-naïve advanced PaC.MethodsThis is an open-label, phase 2a, study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R PaC. Subjects received NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Antitumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Biomarker analyses of peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 26 subjects were enrolled in the CPI naïve R/R PaC cohort. Median age 69 years [31–81], ECOG PS 0 (35%), 1 (65%). Twenty-one (81%) subjects had ≥ 2 prior therapies All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 3.3 months. Among 10 subjects with at least 1 post-treatment tumor assessment, the RECIST1.1-based ORR and disease-control rate (DCR) were 10% and 50%, respectively. One subject with MSS and TMB of 1, achieved a confirmed partial response (cPR) with 65% tumor reduction and drastically improving CA19-9. Treatment-related adverse events (AEs) occurred in 14 (53.8%) subjects, 9 (34.6%) G1–2, 3 (11.5%) G3; 2 (7.7%) G4; no G5 AEs were reported. No subjects discontinued from treatment due to AE. NT-I7 + pembro elicited a significant increase in the peripheral absolute lymphocyte count that peaked at week 3 (>3X from baseline, p<0.0001) and was sustained at least until week 18. CD4+/CD8+ T-cells subsets followed the same response pattern. Importantly, Stem-Cell Memory CD8+ T-cells (TSCM), the potential target for CPI, were markedly increased (>15X, p<0.05) post-study treatment. The CD8+ Effector-to-Treg ratio and plasmatic chemokines (CXCL9, CXCL10, CXCL11 and CCL9) were also significantly increased. The cPR subject had enhanced T-cell infiltration in the TME at week 5. Subject’s follow-up continues and updated data will be presented.ConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed promising anti-tumor activity in subjects with CPI-naïve R/R PaC. Increased TSCM and CD8+ T-cell infiltration within TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in subjects with CPI-naïve R/R PaC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.

BackgroundLymphopenia is common after chemoradiation for treatment of high-grade gliomas (HGG) and is associated with reduced survival.1 Interleukin-7 (IL-7) promotes T-cell maturation and proliferation and is inappropriately low in lymphopenic patients with HGG.2 We previously demonstrated that first-in-class long-acting IL-7, NT-I7 (efineptakin alfa), reverses lymphopenia and improves survival in murine glioma models.3 This study reports the correlative immune changes after NT-I7 treatment in patients with newly diagnosed HGG in a Phase I/II clinical trial.MethodsEnrolled patients had newly diagnosed HGG treated with concurrent radiotherapy (RT) and temozolomide (TMZ) plus adjuvant TMZ every 4 weeks. NT-I7 was administered intramuscularly 1 week after completion of RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I utilized the 3+3 design to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 patients in each arm. Immune profiling of patients from the Phase I study was performed with multiparametric flow cytometry and multiplex cytokine analysis.ResultsPhase I was completed with 19 patients. The most common adverse events were grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 µg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting the selection of MTD as 720 µg/kg. Preliminary analysis of Phase I subjects demonstrated dose-dependent increases in absolute lymphocyte count (ALC; 1.3X-4.1X fold increase from pre-therapy measurements) that peaked at week 4, before adjuvant TMZ. Flow cytometry analysis of peripheral blood showed a significant increase in the frequency of CD8+ T-cells, CD4+ T-cells, and CD56bright natural killer (NK) cells after NT-I7 administration. There was no change in B cell counts. Expression of the IL-7 receptor (CD127) was downregulated on most immune subsets within 1 week after NT-I7 administration and recovered to baseline by week 4. Serum cytokine analysis showed a rapid and significant increase in tumor necrosis factor (TNF), chemokine ligand 9 (CXCL9), and a trend to higher interferon-gamma (IFNγ), 1 week after NT-I7 administration.ConclusionsNT-I7 is well tolerated when administered after RT/TMZ for HGG patients. NT-I7 administration prompted an increase in ALC, especially cytotoxic T-cells and NK cells. We also observed rapid increases in key cytokines and chemokines, suggesting immune activation. These findings provide insight into the mechanism of action for NT-I7. Phase II enrollment and additional immune profiling correlates are ongoing.Trial RegistrationNCT03687957ReferencesMendez JS, Govindan A, Leong J, Gao F, Huang J, Campian JL. Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma. J Neurooncol 2016;127:329.Campian JL, Ye X, Gladstone DE, Ambady P, Nirschl TR, Borrello I, Golightly M, king KE, Holdhoff M, Karp J, Drake CG, Grossman SA. Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas. J Neuro-Oncology 2015 1242. 2015;124:307–316.Ghosh S, Yan R, Thotala S, Jash A, Mahadevan A, Hu T, Lee B, Yang SH, Hallahan D, Chheda M, Thotala D, Campian J. 565 a novel long-acting interleukin-7 agonist, NT-I7, increases cytotoxic CD8+ T cells and enhances survival in mouse glioma models. J Immunother Cancer 2020;8(Suppl 3):A599–A599.Ethics ApprovalThis study was approved by Washington University’s ethics board (the Human Research Protection Office); approval number 201810185. Study participants provided written informed consent.

Receptor tyrosine kinases (RTKs) play an essential role in the development of multicellular organisms. A combination of studies using invertebrate genetics and mammalian biochemistry has proposed a unified model for signal transduction in RTK signaling. According to this model, following RTK stimulation the adaptor protein Grb2 binds directly to the tyrosine-phosphorylated RTK Grb2 also interacts with the guanine nucleotide exchange factor SOS. Binding of the Grb2-SOS complex to an activated RTK brings SOS into close proximity with RAS and allows SOS to catalyze RAS activation. However, it has become clear that Grb2 function involves interactions with other cytoplasmic signaling proteins besides SOS. In the present studies, biochemical approaches were employed to identity binding partners of DRK, the Drosophila homolog of Grb2. One of the identified candidates is Disabled (DAB). DAB has three notable characteristics: an N-terminally located phosphotyrosine-binding (PTB) domain, a centrally-located proline-rich region, and the presence of potential consensus binding sites for the SH2 domain. In vitro binding assays and immunoprecipitation experiments indicate that DAB and DRK form a complex which is dependent on the SH3 domains of DRK and the proline-rich region of DAB. Moreover, the DAB-DRK complex appears to be distinct from the SOS-DRK complex, suggesting that DRK is capable of forming multiple signaling complexes around the activated cell-surface receptor. Biochemical and genetic approaches were utilized to explore the role of DAB in the SEV RTK pathway. These studies find that DAB can bind SEV directly via its PTB domain. The expression of activated SEV leads to increased DAB tyrosine phosphorylation that may provide docking sites for SH2 domain-containing proteins. Moreover, in vivo functional analyses provide evidence that DAB is an important component of the SEV signaling pathway by showing that the removal of DAB function disrupts ommatidial development, and that either a reduction of DAB dosage or the expression of a PTB domain-mutated DAB suppresses the effects of excessive SEV signaling. Taken together, the results indicate that DAB is a novel component of the SEV signaling pathway, and that DAB probably functions as a phosphorylated adaptor protein.