Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical ...efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST.
In this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response PR). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity.
Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%).
The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.
Background
Immune checkpoint blockade (ICI) of programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1) can induce durable responses in patients who have colorectal cancer (CRC) with a high ...tumor mutational burden (TMB). Two recurring clinical dilemmas show how to manage oligoprogressive disease and stable disease after ICI.
Methods
A cohort study was conducted to analyze patients with metastatic CRC who underwent PD-1 or PD-L1 blockade. Tumors were mismatch repair (MMR) deficient or had more than 25 mutations per megabase. Patients were identified who had local therapy (surgery, ablation, or radiotherapy) for one to three sites of progressive disease (PD) or surgery to consolidate SD. The study evaluated clinical and biologic factors associated with patient selection, outcomes, and pathologic response rates.
Results
From 2014 to 2020, treatment was administered to 111 patients with ICI. Of these 111 patients, 19 (17%) survived fewer than 6 months, whereas to date, 50 have not had progression of disease. The remaining 42 patients experienced PD, and 16 (38%) were treated with local therapy for oligoprogression. Selection for local therapy was associated with response to ICI. The 2-year progression-free survival (PFS) after local therapy was 62%. Finally, 6 of the 50 patients without PD had consolidation of SD, and 5 had complete or near complete pathologic responses.
Conclusions
Oligoprogression, a frequent pattern of failure after ICI, can be managed effectively with local therapy. In contrast, it may not be necessary to consolidate SD for selected patients. Further research is essential to define management algorithms better and to explore heterogeneity in response patterns.
We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC).
A query of our institutional clinical ...sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations.
Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% 95% confidence interval (CI), 12.7%-17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%-11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the
gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16-6.16; Fisher's
= 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46-5.40;
= 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors.
RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.
•TP53 mutations are frequent events in certain subtypes of PTCL.•A subset of patients with TP53-mutated PTCL experience high relapse rates when treated with curative-intent CHOP-based chemotherapy.
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Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (trade name Oncovin), and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering integrated mutational profiling of actionable cancer targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with increased risk of progression (by multivariate analysis) included advanced-stage disease (hazard ratio HR, 5.1; 95% confidence interval CI, 1.1-22.5; P = .03) and bone marrow involvement (HR, 3.0; 95% CI, 1.1-8.4; P = .04). The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations (HR, 3.1; 95% CI, 1.4-6.8; P = .005) and TP53/17p deletions (HR, 4.1; 95% CI, 1.1-15.0; P = .03). PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months (95% CI, 3.8-13.9) for PTCL with a TP53 mutation (n = 21) vs 10.5 months (95% CI, 7.8-18.1; P < .001) for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months (95% CI, 12.8-not reached) vs 56.7 months (95% CI, 44.6-101.0; P = .004) for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.
ZusammenfassungIn den letzten Jahren haben viele Studien untersucht, welche Faktoren das Vertrauen in Medien beeinflussen können. Zu einigen dieser Faktoren gibt es vorläufige wissenschaftliche ...Erkenntnisse, die eine klare Richtung andeuten, zu anderen ist die Forschungslage eher heterogen. Wir überprüfen daher anhand einer Trendstudie mit Befragungsdaten aus den Jahren 2017, 2018 und 2019 mit je 1200 Befragten, welche Personenmerkmale sich in Deutschland über einen längeren Zeitraum als stabile Einflussfaktoren erwiesen haben. Dazu führen wir blockweise Regressionsanalysen im Zeitverlauf durch. Neben soziodemografischen Faktoren und der Mediennutzung gehören dazu die Einstellungen zu Politik, Verschwörungsglaube und interpersonales Vertrauen. Die Ergebnisse zeigen, dass alle Gruppen von Variablen mit Medienvertrauen im Zusammenhang stehen, dass ihr Einfluss jedoch unterschiedlich groß ist. In komplexeren Regressionsmodellen wird der Einfluss mancher Variablen vom Effekt anderer Variablen überlagert – dies könnte eine Erklärung für die bislang äußerst heterogene Forschungslage zu beispielsweise dem Einfluss der Soziodemografika auf Medienvertrauen sein. Die Ergebnisse verdeutlichen auch, welche Rezipientinnen und Rezipienten den Medien weniger oder gar nicht vertrauen.
Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, ...sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on ...clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
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