A Proof-of-Concept Study of Sequential Treatment with the HDAC Inhibitor Vorinostat following BRAF and MEK Inhibitors in BRAFV600-Mutated Melanoma.

Purpose: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi.

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer.

Lessons Learned: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.

Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib +/- binimetinib or alpelisib.

Background: Treatment strategies inhibiting BRAF in combination with EGFR have been developed in patients with BRAF mutant metastatic colorectal cancer, but intrinsic and secondary resistance remains a challenge. We aimed to investigate which genetic alterations cause intrinsic non-response and/or acquired resistance in these patients receiving therapies consisting of a backbone of BRAF and EGFR inhibition.

Methods: This was a cohort study on genetic alterations in patients with BRAF mutant advanced colorectal cancer treated with inhibitors of the MAPK pathway.

Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer.

Purpose: KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R).

Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer.

Background: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g.

Vorinostat in patients with resistant mutated advanced melanoma: a proof of concept study.

The clinical benefit of treatment with BRAF- and MEK-inhibitors in melanoma is limited due to resistance associated with emerging secondary mutations. Preclinical and clinical studies have shown that short-term treatment with the HDAC inhibitor vorinostat can eliminate cells harboring these secondary mutations causing resistance. This proof of concept study is to determine the efficacy of sequential treatment with vorinostat and BRAFi/MEKi in resistant mutant melanoma.

Encorafenib, binimetinib and cetuximab combined therapy for patients with mutant metastatic colorectal cancer.

Approximately 10-15% of colorectal cancers (CRCs) harbor an activating mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR.

Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study.

Purpose: To determine the safety and preliminary efficacy of selective combination targeted therapy for V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35).

Patients And Methods: Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with V600E-mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab.

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.

BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS).

End-of-life care during and after an acute hospitalization in older patients with cancer, end-stage organ failure, or frailty: A sub-analysis of a prospective cohort study.

Background: Many patients show deterioration in functioning and increased care needs in the last year of life. End-of-life care needs and health care utilization might differ between groups of acutely hospitalized older patients.

Aim: To investigate differences in geriatric conditions, advance care planning, and health care utilization in patients with cancer, organ failure, or frailty, who died within 1 year after acute hospitalization.