Molecular markers in gliomas: impact for the clinician

Over the last decade, understanding of glioma on a molecular level has greatly expanded. However, optimal incorporation of molecular markers into clinical care is controversial. We briefly review the potential utility of molecular stratification in refining histologic diagnosis, prognosis, and treatment decisions, focussing on 1p/19q co-deletion, MGMT promoter methylation, EGFR mutations, and IDH mutation. The most recently discovered IDH mutation is a striking example of a rapid implementation of a molecular marker for prognostication into common clinical us

ACTION:a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma

BACKGROUND: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma.METHODS: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.</p

Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P &lt; .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P &lt; .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P &lt; .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR&gt;25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P &lt; .01) and adequate power (&gt;80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR &gt;25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.</p

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematological tumors. We assessed intra-tumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status≥60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) pre-operatively (Arm A; N=8 patients). Patients not undergoing surgery received 50mg/m(2) (Arm B, N=24), or 60mg (Arm C, N=14) twice weekly, or 80mg once weekly (Arm D; N=30). Primary endpoint was six-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving pre-surgical selinexor was 105.4nM (range 39.7-291nM). In Arms B, C, and D, respectively, the PFS6 was 10% (95%CI, 2.79-35.9), 7.7% (95%CI, 1.17-50.6), and 17% (95%CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% (Arm B, 8.3% (95%CI, 1.0-27.0); C:7.7% (95%CI, 0.2-36.0); D:10% (95%CI, 2.1-26.5)), with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; one (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%) and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC=0.88). CONCLUSION: At 80mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198634

Melanoma central nervous system metastases: current approaches, challenges, and opportunities

Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area

Discordant attitudes and beliefs about cancer clinical trial participation between physicians, research staff, and cancer patients

Background/aims: Essential to bringing innovative cancer treatments to patients is voluntary participation in clinical trials but approximately 8% of American cancer patients are enrolled onto a trial. We used a domain-oriented framework to assess barriers to cancer clinical trial enrollment. Methods: Physicians (MD, DO, fellows, residents) and research staff (physician assistants, nurse practitioners, staff and research nurses, clinical assistants, and program coordinators) involved in clinical research at a comprehensive cancer center completed an online survey in 2017; adult cancer patients not currently enrolled in a trial were interviewed in 2018. To inform the construct of our physician/staff and patient surveys and to assess barriers to clinical trial enrollment, we first conducted in-depth interviews among 14 key informants representing medical, hematologic, gynecologic, neurologic, radiation oncology, as well as members of the clinical research team (one clinical research coordinator, one research nurse practitioner). Perceived structural, provider- and patient-level barriers to clinical trial enrollment were assessed. Differences in perceptions, attitudes, and beliefs toward clinical trial enrollment between (1) physicians and staff, (2) patients by ethnicity, and (3) physicians/staff and patients were examined. Results: In total, 120 physicians/staff involved in clinical research (39.2% physicians, 60.8% staff; 48.0% overall response rate) and 150 cancer patients completed surveys. Nearly three-quarters of physician/staff respondents reported difficulty in keeping track of the eligibility criteria for open studies but was more often cited by physicians than staff (84.4% vs 64.3%, p = 0.02). Physicians more often reported lack of time to present clinical trial information than did staff(p < 0.001); 44.0% of staff versus 18.2% of physicians reported patient family interaction as a clinical trial enrollment barrier (p = 0.007). Hispanic patients more often stated they would join a trial, even if standard therapy was an option compared to non-Hispanic patients (47.7% vs 20.8%, p = 0.002). Comparing the beliefs and perceptions of physicians/staff to those of patients, patients more often reported negative beliefs about clinical trial enrollment (e.g. being in a trial does not help patients personally, 32.9% vs 1.8%, p < 0.001) but less often felt they had no other options when agreeing to join (38.1% vs 85.6%, p < 0.001), and less often refused clinical trial enrollment due to lack of understanding (9.1% vs 63.3%, p = 0.001) than reported by physicians/staff. Conclusion: Our findings indicate a wide gap between physician/staff and patient attitudes and beliefs about clinical trial enrollment and highlight the importance of focusing future initiatives to raise awareness of this incongruency. Reconciling these differences will require tailored education to reduce implicit biases and dispel misperceptions. Strategies to improve the quality of patient-provider communication and address infrastructure and resource issues are also needed to improve patient enrollment onto cancer clinical trials

Anticipated and experienced discrimination amongst people with schizophrenia, bipolar disorder and major depressive disorder: a cross-sectional study.

BACKGROUND: The unfair treatment of individuals with severe mental illness has been linked to poorer physical and mental health outcomes. Additionally, anticipation of discrimination may lead some individuals to avoid participation in particular life areas, leading to greater isolation and social marginalisation. This study aimed to establish the levels and clinical and socio-demographic associations of anticipated and experienced discrimination amongst those diagnosed with a schizophrenia and comparator severe mental illnesses (bipolar and major depressive disorders). METHODS: This study was a cross-sectional analysis of anticipated and experienced discrimination from 202 individuals in South London (47% with schizophrenia, 32% with depression and 20% with bipolar disorder). RESULTS: 93% of the sample anticipated discrimination and 87% of participants had experienced discrimination in at least one area of life in the previous year. There was a significant association between the anticipation and the experience of discrimination. Higher levels of experienced discrimination were reported by those of a mixed ethnicity, and those with higher levels of education. Women anticipated more discrimination than men. Neither diagnosis nor levels of functioning were associated with the extent of discrimination. Clinical symptoms of anxiety, depression and suspiciousness were associated with more experienced and anticipated discrimination respectively. CONCLUSIONS: The unfair treatment of individuals with severe mental illnesses remains unacceptably common. Population level interventions are needed to reduce levels of discrimination and to safeguard individuals. Interventions are also required to assist those with severe mental illness to reduce internalised stigma and social avoidance

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma

Purpose: To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss. Methods: This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded. Results: 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug–drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%). Conclusion: The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes. Trial registration: NCT01870726