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Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck.
This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT01848834 and is ongoing, but no longer enrolling patients.
Of the 104 patients screened between June 7, 2013, and Oct 3, 2013, 81 (78%) were PD-L1-positive. Of these, 60 patients with PD-L1-positive squamous cell carcinoma of the head and neck were enrolled and treated: 23 (38%) were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3–4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths. The proportion of patients with an overall response by central imaging review was 18% (eight of 45 patients; 95% CI 8–32) in all patients and was 25% (four of 16 patients; 7–52) in HPV-positive patients and 14% (four of 29 patients; 4–32) in HPV-negative patients.
Pembrolizumab was well tolerated and demonstrated clinically meaningful antitumour activity in recurrent or metastatic squamous cell carcinoma of the head and neck, supporting further study of pembrolizumab as anticancer therapy for advanced head and neck cancers.
Merck & Co.
Journal Article
IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.
Journal Article
Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced, PD-L1–positive papillary or follicular thyroid cancer
Background
Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid cancer expressing programmed death ligand 1 (PD-L1).
Methods
Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti–programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1.
Results
Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7–34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (
n
= 7) and fatigue (
n
= 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1–29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2–14 months); median overall survival was not reached (95% CI, 22 months to not reached).
Conclusions
Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings.
Trial registration
Clinicaltrials.gov
identifier:
NCT02054806
. Registered 4 February 2014.
Journal Article
Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies
Alzheimer’s (or Alzheimer) disease (AD) is the most prevalent subset of dementia, affecting elderly populations worldwide. The cumulative costs of the AD care are rapidly accelerating as the average lifespan increases. Onset and risk factors for AD and AD-like dementias have been largely unknown until recently. Studies show that chronic type II diabetes mellitus (DM) is closely associated with neurodegeneration, especially AD. Type II DM is characterized by the cells’ inability to take up insulin, as well as chronic hyperglycemia. In the central nervous system, insulin has crucial regulatory roles, while chronic hyperglycemia leads to formation and accumulation of advanced glycation end products (AGEs). AGEs are the major contributor to insulin resistance in diabetic cells, due to their regulatory role on sirtuin expression. Insulin activity in the central nervous system is known to interact with key proteins affected in neurodegenerative conditions, such as amyloid-β precursor protein (AβPP or APP), huntingtin-associated protein-1 (HAP1), Abelson helper integration site-1 (AHI1 or Jouberin), kinesin, and tau. Sirtuins have been theorized to be the mechanism for insulin resistance, and have been found to be affected in neurodegenerative conditions as well. There are hints that all these neuronal proteins may be closely related, although the mechanisms remain unclear. This review will gather existing research on these proteins and highlight the link between neurodegenerative conditions and diabetes mellitus.
Journal Article
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy
Clinical trial data can provide a wealth of information about how drugs work. Yet such information often belongs to pharmaceutical companies and is rarely accessible to the scientific community at large. Cristescu et al. provide exploratory analysis of a cancer genomics dataset, collected from four separate clinical trials of Merck's PD-1 immunotherapy drug, pembrolizumab. This informative public resource examines more than 300 patient samples representing 22 different tumor types. Two widely used signatures that currently predict immunotherapy response are tumor mutational burden and a “hot” T cell–inflamed microenvironment. The study analyzed these two proposed biomarkers in combination to see what predictive clinical utility they may hold. Science , this issue p. eaar3593 Genomic biomarkers will help to elucidate which cancer patients will benefit from PD-1 blockade immunotherapy. Programmed cell death protein–1 (PD-1) and programmed cell death ligand–1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell–inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti–PD-1 monotherapy and combination immunotherapy regimens.
Journal Article
Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer
Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein–Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein–Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(−) tumors (50.0% versus 0.0%,
P
value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.
Microsatellite instability and Epstein–Barr virus positivity represent novel biomarkers of clinical response to PD-1 blockade in patients with metastatic gastric cancer.
Journal Article
Experimental pub crawl from Rayleigh–Bénard to magnetostrophic convection
The interplay between convective, rotational and magnetic forces defines the dynamics within the electrically conducting regions of planets and stars. Yet their triadic effects are separated from one another in most studies, arguably due to the richness of each subset. In a single laboratory experiment, we apply a fixed heat flux, two different magnetic field strengths and one rotation rate, allowing us to chart a continuous path through Rayleigh–Bénard convection (RBC), two regimes of magnetoconvection, rotating convection and two regimes of rotating magnetoconvection, before finishing back at RBC. Dynamically rapid transitions are determined to exist between jump rope vortex states, thermoelectrically driven magnetoprecessional modes, mixed wall- and oscillatory-mode rotating convection and a novel magnetostrophic wall mode. Thus, our laboratory ‘pub crawl’ provides a coherent intercomparison of the broadly varying responses arising as a function of the magnetorotational forces imposed on a liquid-metal convection system.
Journal Article
FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells
Background
Alterations towards a permissive stromal microenvironment provide important cues for tumor growth, invasion, and metastasis. In this study, Fibroblast activation protein (FAP), a serine protease selectively produced by tumor-associated fibroblasts in over 90% of epithelial tumors, was used as a platform for studying tumor-stromal interactions.
We tested the hypothesis that FAP enzymatic activity locally modifies stromal ECM (extracellular matrix) components thus facilitating the formation of a permissive microenvironment promoting tumor invasion in human pancreatic cancer.
Methods
We generated a tetracycline-inducible FAP overexpressing fibroblastic cell line to synthesize an
in vivo
-like 3-dimensional (3D) matrix system which was utilized as a stromal landscape for studying matrix-induced cancer cell behaviors. A FAP-dependent topographical and compositional alteration of the ECM was characterized by measuring the relative orientation angles of fibronectin fibers and by Western blot analyses. The role of FAP in the matrix-induced permissive tumor behavior was assessed in Panc-1 cells in assorted matrices by time-lapse acquisition assays. Also, FAP
+
matrix-induced regulatory molecules in cancer cells were determined by Western blot analyses.
Results
We observed that FAP remodels the ECM through modulating protein levels, as well as through increasing levels of fibronectin and collagen fiber organization. FAP-dependent architectural/compositional alterations of the ECM promote tumor invasion along characteristic parallel fiber orientations, as demonstrated by enhanced directionality and velocity of pancreatic cancer cells on FAP
+
matrices. This phenotype can be reversed by inhibition of FAP enzymatic activity during matrix production resulting in the disorganization of the ECM and impeded tumor invasion. We also report that the FAP
+
matrix-induced tumor invasion phenotype is β
1
-integrin/FAK mediated.
Conclusion
Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and β
1
-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking β
1
-integrin dependent cell-matrix interactions. This provides a novel preclinical rationale for therapeutics aimed at interfering with the architectural organization of tumor-associated ECM. Better understanding of the stromal influences that fuel progressive tumorigenic behaviors may allow the effective future use of targeted therapeutics aimed at disrupting specific tumor-stromal interactions.
Journal Article