ABSTRACT
BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group. INTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. FUNDING: Merck Sharp & Dohme.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Cetuximab/therapeutic use , Head and Neck Neoplasms/drug therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , Aged , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Fluorouracil/therapeutic use , Head and Neck Neoplasms/mortality , Humans , Male , Middle Aged , Progression-Free Survival , Squamous Cell Carcinoma of Head and Neck/mortalityABSTRACT
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.
Subject(s)
Adenocarcinoma, Follicular/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Thyroid Cancer, Papillary/drug therapy , Thyroid Neoplasms/drug therapy , Adenocarcinoma, Follicular/metabolism , Adult , Aged , B7-H1 Antigen/metabolism , Colitis/chemically induced , Diarrhea/chemically induced , Fatigue/chemically induced , Female , Humans , Male , Middle Aged , Progression-Free Survival , Proof of Concept Study , Response Evaluation Criteria in Solid Tumors , Thyroid Cancer, Papillary/metabolism , Thyroid Neoplasms/metabolism , Treatment Outcome , Young AdultABSTRACT
KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (RECIST version 1.1), and ECOG performance status (PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co-primary end-points were safety and overall response rate (RECIST version 1.1, central review). Secondary end-points included overall survival and response duration. Patients enrolled at any of the five centers throughout the Asia-Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. The median age was 62 years, 65% of patients had ECOG PS 1, and 62% had received two or more prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment-related adverse event of any grade, including two (8%) patients who experienced one or more events of grade 3 severity. No treatment-related deaths occurred. The overall response rate was 19% (95% confidence interval, 7%-39%). After a median follow-up of 12 months (range, 2-21 months), a median response duration was not reached (range, 6 to 17+ months); four of five responses lasted ≥6 months. Median overall survival was 11.6 months (95% confidence interval, 4.7-17.7 months). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region. (Trial registration no. NCT01848834.).
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Asia , Cohort Studies , Drug Administration Schedule , Female , Humans , Male , Squamous Cell Carcinoma of Head and Neck , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Merck & Co.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/secondary , Female , Follow-Up Studies , Head and Neck Neoplasms/pathology , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Safety , Survival Rate , Young AdultABSTRACT
Fibroblast activation protein (FAP) is a serine protease selectively expressed on tumor stromal fibroblasts in epithelial carcinomas and is important in cancer growth, adhesion, and metastases. As FAP enzymatic activity is a potent therapeutic target, we aimed to identify inhibitory antibodies. Using a competitive inhibition strategy, we used phage display techniques to identify 53 single-chain variable fragments (scFvs) after three rounds of panning against FAP. These scFvs were expressed and characterized for binding to FAP by surface plasmon resonance and flow cytometry. Functional assessment of these antibodies yielded an inhibitory scFv antibody, named E3, which could attenuate 35% of FAP cleavage of the fluorescent substrate Ala-Pro-7-amido-4-trifluoromethylcoumarin compared with nonfunctional scFv control. Furthermore, a mutant E3 scFv was identified by yeast affinity maturation. It had higher affinity (4-fold) and enhanced inhibitory effect on FAP enzyme activity (3-fold) than E3. The application of both inhibitory anti-FAP scFvs significantly affected the formation of 3-dimensional FAP-positive cell matrix, as demonstrated by reducing the fibronectin fiber orientation from 41.18% (negative antibody control) to 34.06% (E3) and 36.15% (mutant E3), respectively. Thus, we have identified and affinity-maturated the first scFv antibody capable of inhibiting FAP function. This scFv antibody has the potential to disrupt the role of FAP in tumor invasion and metastasis.
Subject(s)
Gelatinases/antagonists & inhibitors , Gelatinases/immunology , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/immunology , Serine Endopeptidases/immunology , Single-Chain Antibodies/immunology , Animals , Antibody Affinity , Endopeptidases , Flow Cytometry , Gelatinases/genetics , Gelatinases/metabolism , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Molecular Targeted Therapy , Mutagenesis, Site-Directed , Mutant Proteins/genetics , Mutant Proteins/immunology , Neoplasms/drug therapy , Neoplasms/enzymology , Peptide Library , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Chain Antibodies/genetics , Single-Chain Antibodies/metabolism , Surface Plasmon ResonanceABSTRACT
Fibroblast activation protein-alpha (FAPα) is a cell surface glycoprotein which is selectively expressed by tumor-associated fibroblasts in malignant tumors but rarely on normal tissues. FAPα has also been reported to promote tumor growth and invasion and therefore has been of increasing interest as a promising target for designing tumor-targeted drugs and imaging agents. Although medicinal study on FAPα inhibitors has led to the discovery of many FAPα-targeting inhibitors including a drug candidate in a phase II clinical trial, the development of imaging probes to monitor the expression and activity of FAPα in vivo has largely lagged behind. Herein, we report an activatable near-infrared (NIR) fluorescent probe (ANP(FAP)) for in vivo optical imaging of FAPα. The ANP(FAP) consists of a NIR dye (Cy5.5) and a quencher dye (QSY21) which are linked together by a short peptide sequence (KGPGPNQC) specific for FAPα cleavage. Because of the efficient fluorescence resonance energy transfer (FRET) between Cy5.5 and QSY21 in ANP(FAP), high contrast on the NIR fluorescence signal can be achieved after the cleavage of the peptide sequence by FAPα both in vitro and in vivo. In vitro assay on ANP(FAP) indicated the specificity of the probe to FAPα. The in vivo optical imaging using ANP(FAP) showed fast tumor uptake as well as high tumor to background contrast on U87MG tumor models with FAPα expression, while much lower signal and tumor contrast were observed in the C6 tumor without FAPα expression, demonstrating the in vivo targeting specificity of the ANP(FAP). Ex vivo imaging also demonstrated ANP(FAP) had high tumor uptake at 4 h post injection. Collectively, these results indicated that ANP(FAP) could serve as a useful NIR optical probe for early detection of FAPα expressing tumors.
Subject(s)
Fluorescent Dyes/chemistry , Gelatinases/metabolism , Infrared Rays , Membrane Proteins/metabolism , Molecular Imaging/methods , Serine Endopeptidases/metabolism , Amino Acid Sequence , Animals , Carbocyanines/chemistry , Cell Line, Tumor , Drug Design , Endopeptidases , Female , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/metabolism , Gelatinases/chemistry , Gene Expression Regulation, Neoplastic , Humans , Membrane Proteins/chemistry , Optical Imaging , Serine Endopeptidases/chemistry , Substrate SpecificityABSTRACT
A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.
Subject(s)
Gelatinases/antagonists & inhibitors , Membrane Proteins/antagonists & inhibitors , Pyrrolidines/pharmacology , Serine Endopeptidases/metabolism , Acylation , Endopeptidases , Prolyl Oligopeptidases , Pyrrolidines/chemistry , Structure-Activity RelationshipABSTRACT
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 ß1-integrin/FAK mediated. CONCLUSION: Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and ß1-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking ß1-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.
Subject(s)
Adenocarcinoma/pathology , Extracellular Matrix Proteins/metabolism , Extracellular Matrix/physiology , Fibroblasts/enzymology , Gelatinases/physiology , Membrane Proteins/physiology , Neoplasm Invasiveness/pathology , Neoplasm Proteins/physiology , Pancreatic Neoplasms/pathology , Serine Endopeptidases/physiology , Tumor Microenvironment/physiology , Adenocarcinoma/enzymology , Animals , Blotting, Western , Breast Neoplasms/pathology , Cell Culture Techniques , Cell Line, Tumor/enzymology , Cell Line, Tumor/pathology , Cell Movement , Collagen Type I/metabolism , Endopeptidases , Extracellular Matrix/ultrastructure , Fibronectins/metabolism , Fibronectins/ultrastructure , Focal Adhesion Kinase 1/physiology , Gelatinases/genetics , Humans , Integrin beta1/physiology , Membrane Proteins/genetics , Mice , Mice, Inbred ICR , Mice, SCID , NIH 3T3 Cells/enzymology , Pancreatic Neoplasms/enzymology , Recombinant Fusion Proteins/physiology , Serine Endopeptidases/genetics , Time-Lapse Imaging , Transplantation, HeterologousABSTRACT
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen. METHODS: Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires. RESULTS: The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = -3.00 to 3.78) but worsened for SOC (LSM = -5.86, 95% CI = -9.68 to -2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = -4.57 to 16.99) or pembrolizumab vs cetuximab (-1.44, 95% CI = -11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC. CONCLUSIONS: GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/administration & dosage , Cetuximab/adverse effects , Disease-Free Survival , Docetaxel/administration & dosage , Docetaxel/adverse effects , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , Patient Reported Outcome Measures , Quality of Life , Squamous Cell Carcinoma of Head and Neck/pathologyABSTRACT
PURPOSE: Molecular profiling of large databases of human tumor gene expression profiles offers novel opportunities for informing decisions in clinical development programs. EXPERIMENTAL DESIGN: Gene expression profile of programmed death ligand 1 (PD-L1) was explored in a dataset of 16,000 samples, including approximately 4,000 metastatic tumors, across >25 tumor types prevalent in the United States, looking for new indications for the programmed death 1 (PD-1) inhibitor pembrolizumab. PD-L1 expression was highly concordant with several genomic signatures indicative of immune-inflamed tumor microenvironment. Prevalence of activated immune-inflamed tumors across all tumor types was explored and used to rank tumor types for potential response to pembrolizumab monotherapy. RESULTS: The analysis yielded 3 tiers of indications in which high levels of PD-L1 and immune-inflamed signatures were found in up to 40% to 60%, 20% to 40%, and 0% to 20% of tumors. Tier 1 contained novel indications known at the time of analysis to be responsive to PD-1 checkpoint blockade in the clinic (such as melanoma and non-small cell lung cancer), as well as indications not studied in the clinic previously, including microsatellite instability-high colorectal, head and neck, bladder, and triple-negative breast cancers. Complementary analysis of an Asian/Pacific cancer dataset (gastric cancer) revealed high prevalence of immune-inflamed tumors in gastric cancer. These data contributed to prioritization of these indications for clinical development of pembrolizumab as monotherapy. CONCLUSIONS: Data highlight the value of molecular profiling in identifying populations with high unmet needs with potentially favorable response characteristics and accelerating development of novel therapies for these patients.See related commentary by Mansfield and Jen, p. 1443.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers, Tumor , Gene Expression Profiling , Neoplasms/drug therapy , Neoplasms/genetics , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Clinical Decision-Making , Databases, Genetic , Disease Management , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mutation , Neoplasms/pathology , Research Design , Transcriptome , Treatment Outcome , United StatesABSTRACT
PURPOSE: The feasibility of combining concomitant boost-accelerated radiation regimen (AFX-C) with cisplatin was previously demonstrated in this Phase II trial. This article reports the long-term toxicity, relapse patterns, and survival in patients with advanced head and neck carcinoma. METHODS AND MATERIALS: Between April and November 2000, 84 patients with Stage III-IV HNC were enrolled, and 76 patients were analyzable. Radiation consisted of 72 Gy over 6 weeks. Cisplatin dose was 100 mg/m(2) on Days 1 and 22. Tumor and clinical status were assessed, and acute-late toxicities were graded. RESULTS: The median follow-up for surviving patients is 4.3 years. The 2- and 4-year locoregional failure rates were 33% and 36%, respectively, and the 2- and 4-year survival rates were 70% and 54%, respectively. The worst overall late Grade 3 or 4 toxicity rate was 42%. The prevalence rates of a gastrostomy at any time during follow-up, at 12 months, and at 48 months were 83%, 41%, and 17%, respectively. Five of 36 patients (14%) alive and without disease at last follow-up were gastrostomy-tube dependent. CONCLUSION: These data of long-term follow-up of patients treated with AFX-C with cisplatin show encouraging results with regard to locoregional disease control and survival, with few recurrences after 2 years. The late toxicity rates are relatively high. However, although prolonged dysphagia was noted in our preliminary report, its prevalence does decreased over time. A Phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin has completed accrual.
Subject(s)
Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Cisplatin/therapeutic use , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Radiation-Sensitizing Agents/therapeutic use , Carcinoma, Squamous Cell/pathology , Cisplatin/adverse effects , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Feasibility Studies , Gastrostomy , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Neoplasm Recurrence, Local , Radiation-Sensitizing Agents/adverse effects , Radiotherapy Dosage , Treatment OutcomeABSTRACT
PURPOSE: Human fibroblast activation protein (FAP)/seprase is a 97-kDa surface glycoprotein expressed on tumor associated fibroblasts in the majority of epithelial cancers including colon adenocarcinomas. FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated. The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty. EXPERIMENTAL DESIGN: Sections of paraffin-embedded resected primary human colon cancer specimens from 1996 through 2001 within the Fox Chase Cancer Center tumor bank were stained with D8 antibody directed against FAP/seprase. Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes. Overall percentage of stromal FAP staining of the primary tumor was assessed semiquantitatively (0, 1+, 2+, 3+) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models. RESULTS: One hundred thirty-eight patients with resected specimens were available for study (mean follow-up, 1,050 days) with 6 (4%) stage I, 52 (38%) stage II, 43 (31%) stage III, and 37 (27%) stage IV patients. FAP was detected in >93% of specimens. Semiquantitative staining was scored as 1+ in 28 (20%), 2+ in 52 (38%), and 3+ in 49 (35%). FAP staining intensity was graded as weak in 45 (33%), intermediate in 48 (35%), and dark in 36 (26%). Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, -0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors. Furthermore, greater stromal FAP for patients with known metastatic disease was associated with a decreased survival. CONCLUSION: Our data indicate that patients whose colon tumors have high levels of stromal FAP are more likely to have aggressive disease progression and potential development of metastases or recurrence. This study affirms the rationale for ongoing clinical investigations using FAP as a therapeutic target to disrupt FAP-driven tumor progression in patients with metastatic disease. It also suggests that the effects of FAP inhibition should be investigated in earlier-stage tumors, given its high levels and potential effect earlier in the course of the disease.
Subject(s)
Adenocarcinoma/genetics , Antigens, Neoplasm/genetics , Biomarkers, Tumor/genetics , Colonic Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Serine Endopeptidases/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Animals , Antigens, Neoplasm/metabolism , Biomarkers, Tumor/metabolism , Colonic Neoplasms/metabolism , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Endopeptidases , Female , Gelatinases , HT29 Cells , Humans , Immunohistochemistry , Male , Membrane Proteins , Mice , Mice, Inbred C57BL , Mice, SCID , Middle Aged , Serine Endopeptidases/metabolism , Xenograft Model Antitumor AssaysABSTRACT
The proline-specific dipeptidyl peptidases (DPPs) are emerging as a protease family with important roles in the regulation of signaling by peptide hormones. Inhibitors of DPPs have an intriguing, therapeutic potential, with clinical efficacy seen in patients with diabetes. Until now, only recombinant forms of DPP8 and DPP9 have been characterized. Their enzymatic activities have not been demonstrated in or purified from any natural source. Using several selective DPP inhibitors, we show that DPP activity, attributable to DPP8/9 is present in human PBMC. All leukocyte types tested (lymphocytes, monocytes, Jurkat, and U937 cells) were shown to contain similar DPP8/9-specific activities, and DPPII- and DPPIV-specific activities varied considerably. The results were confirmed by DPPIV/CD26 immunocapture experiments. Subcellular fractionation localized the preponderance of DPP8/9 activity to the cytosol and DPPIV in the membrane fractions. Using Jurkat cell cytosol as a source, a 30-fold, enriched DPP preparation was obtained, which had enzymatic characteristics closely related to the ones of DPP8 and/or -9, including inhibition by allo-Ile-isoindoline and affinity for immobilized Lys-isoindoline.
Subject(s)
Dipeptidases/metabolism , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Leukocytes/immunology , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Antibodies, Monoclonal/metabolism , Dipeptidases/antagonists & inhibitors , Dipeptidyl Peptidase 4/immunology , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Enzyme Activation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacology , Isoleucine/analogs & derivatives , Isoleucine/chemistry , Isoleucine/pharmacology , Molecular Conformation , Nitriles/chemistry , Nitriles/pharmacology , Organophosphonates/chemistry , Organophosphonates/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Stereoisomerism , Structure-Activity Relationship , VildagliptinABSTRACT
OBJECTIVES: A wide range of objective response rates (ORRs: 0-53%) among available treatments in patients with R/M HNSCC with progression on or after platinum-based chemotherapy (PBT) renders treatment selection a challenge. This systematic literature review (SLR) was intended to aid clinical decision-making by classifying historical studies to accurately characterize the response in second-line (progression on/after platinum-based therapy), and third-line (progression on/after platinum and cetuximab/other drug) settings. METHODS: SLR was performed to characterize the ORR, duration of response (DOR), progression-free survival (PFS) and overall survival (OS) with therapies recommended by the National Comprehensive Cancer Network (NCCN) guidelines. Clinical trials published in English between January 1, 1985, and September 30, 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: The SLR identified 34 key studies in second-line R/M HNSCC patients, and one of these included a third-line patient cohort. However, several studies did not enrol a strictly second-line population. Response in a true second-line setting was elucidated by categorizing the studies using a novel framework defined according to the extent to which enrolled patients were second-line. Only seven studies were strictly second-line, with an estimated pooled ORR of 4% (95% CIâ¯=â¯2-8%; Nâ¯=â¯414) for methotrexate and 11% (95% CIâ¯=â¯7-15%; Nâ¯=â¯235) for cetuximab, and a reported ORR of 14% (Nâ¯=â¯78) from a single study of paclitaxel. The median DOR was limited with cetuximab (â¼4 months) and paclitaxel (â¼7 months), and not reported for methotrexate. Median PFS or time to progression (TTP) ranged from 1.7 to 3.5â¯months, and median OS from 4.3 to 6.7â¯months. The ORR in the only third-line study was 0% (95% CIâ¯=â¯0-7; Nâ¯=â¯53) for the platinumâ¯+â¯cetuximab combination. CONCLUSION: These findings emphasize the historically bleak prognoses in patients with R/M HNSCC following PBT progression. Anti-PD-1 therapies, namely pembrolizumab and nivolumab, represent novel treatment options that may improve clinical outcomes.
Subject(s)
Carcinoma, Squamous Cell/therapy , Head and Neck Neoplasms/therapy , Salvage Therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/secondary , Cetuximab/administration & dosage , Clinical Trials as Topic , Humans , Neoplasm Proteins/antagonists & inhibitors , Nivolumab/administration & dosage , Organoplatinum Compounds/administration & dosage , Paclitaxel/administration & dosage , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Progression-Free Survival , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: To determine whether 18-fluorodeoxyglucose positron emission tomography (PET) computed tomography scans predict the pathologic complete response and disease-free and overall survival in patients with esophageal carcinoma undergoing definitive or preoperative chemoradiotherapy. METHODS AND MATERIALS: The records of patients with esophageal carcinoma presenting for definitive or preoperative treatment and undergoing pre- and post-treatment 18-fluorodeoxyglucose PET-computed tomography scans were retrospectively reviewed. The histologic type, T stage, and nodal status were the variables investigated to determine a relationship with the baseline standardized uptake value (SUV) of the primary tumor at diagnosis. We also attempted to determine whether a relationship exists between the percent decrease in SUV and a pathologic complete response, overall and disease-free survival. RESULTS: A total of 81 patients, 14 women and 67 men, underwent 18-fluorodeoxyglucose PET-computed tomography scanning before treatment and 63 also had post-treatment scans. T stage and tumor location predicted in univariate, but not multivariate, analysis for the initial SUV. Of the patients with a postchemoradiotherapy SUV of <2.5, 66% had tumor in the surgical specimen and 64% of patients had positive lymph nodes at surgery that were not imaged on the postchemoradiotherapy PET scan. A trend existed for post-treatment SUV and the days from radiotherapy to surgery to predict for a pathologic complete response (p = 0.09 and p = 0.08, respectively). The post-treatment SUV predicted for disease-free survival in the definitive chemoradiotherapy group (p = 0.01). CONCLUSIONS: A correlation was found between the depth of tumor invasion and the baseline SUV. The post-treatment SUV predicted for disease-free survival in the definitive chemoradiotherapy group. Caution should be exercised in using post-treatment PET scans to determine the necessity for surgical resection.
Subject(s)
Esophageal Neoplasms/diagnostic imaging , Fluorodeoxyglucose F18 , Positron-Emission Tomography , Radiopharmaceuticals , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Analysis of Variance , Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/therapy , Combined Modality Therapy , Disease-Free Survival , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Esophagectomy , Female , Humans , Male , Neoplasm Staging , Radiotherapy Dosage , Retrospective Studies , Tomography, Emission-ComputedABSTRACT
OBJECTIVES: Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. METHODS: Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m/d over 96 h, weekly), paclitaxel (50 mg/m, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29). RESULTS: A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. CONCLUSIONS: Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/therapy , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Disease-Free Survival , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/mortality , Esophagectomy , Esophagogastric Junction/pathology , Esophagogastric Junction/surgery , Fluorouracil/administration & dosage , Humans , Middle Aged , Molecular Targeted Therapy , Paclitaxel/administration & dosage , Piperidines/administration & dosage , Quinazolines/administration & dosage , Treatment OutcomeABSTRACT
Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma/drug therapy , Nasopharyngeal Neoplasms/drug therapy , Adolescent , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/biosynthesis , B7-H1 Antigen/immunology , Carcinoma/immunology , Cohort Studies , Female , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/immunology , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/immunology , Young AdultABSTRACT
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.