Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR. See related commentary by Janku, p. 389. See related article by Hazar-Rethinam et al., p. 417. This article is highlighted in the In This Issue feature, p. 371

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110.

Ifosfamide is an alkylating agent used in the treatment of a variety of solid tumours. Ten to 15% of patients treated with ifosfamide develop an encephalopathy. Methylene blue (MB) may be used in the treatment of this encephalopathy. The purpose of this study was to evaluate the neuroprotective effect of MB in these patients and to review the literature. Between 1993 and 1997, 52 patients (age 16–77 years) with solid tumours were treated with ifosfamide in dosages ranging from 3 to 5 g m^–2 q3w when given in combination schedules and up to 12 g m^–2 q4w when given as a single agent. Twelve patients developed central nervous system (CNS) depression, defined as National Cancer Institute Common Toxicity Criteria (NCI-CTC) neurocortical toxicity grade 2 or higher. Eight were treated with MB at a dose of 6 × 50 mg day^–1 intravenously (i.v.). Four recovered fully within 24 h, two recovered partially after 24 h and completely after 48 h while two recovered only after 72 h. Four patients did not receive MB and all recovered only after 48 h. Three patients received prophylaxis with MB at a dose of 4 × 50 mg day^–1 i.v. for the subsequent chemotherapy cycles. Two developed milder encephalopathy; one had no CNS depression at all. We conclude that MB is an effective treatment for ifosfamide-induced encephalopathy. Our findings suggest that it may also be used as a prophylactic agent. © 2000 Cancer Research Campaign

Background Glioma patients suffer from a wide range of symptoms which influence quality of life negatively. The aim of this review is to give an overview of symptoms most prevalent in glioma patients throughout the total disease trajectory, to be used as a basis for the development of a specific glioma Patient Reported Outcome Measure (PROM) for early assessment and monitoring of symptoms in glioma patients. Methods A systematic review focused on symptom prevalence in glioma patients in different phases of disease and treatment was performed in MEDLINE, CINAHL and EMBASE according to PRISMA recommendations. We calculated weighted means for prevalence rates per symptom. Results The search identified 2.074 unique papers, of which 32 were included in this review. In total 25 symptoms were identified. The ten most prevalent symptoms were: seizures (37%), cognitive deficits (36%), drowsiness (35%), dysphagia (30%), headache (27%), confusion (27%), aphasia (24%), motor deficits (21%), fatigue (20%) and dyspnea (20%). Conclusions Eight out of ten of the most prevalent symptoms in glioma patients are related to the central nervous system and therefore specific for glioma. Our findings emphasize the importance of tailored symptom care for glioma patients and may aid in the development of specific PROMs for glioma patients in different phases of the disease.

Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody–drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma. Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150–200 mg/m² day 1–5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival. Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3–4 adverse events in 25–30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93). This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406)