ABSTRACT
BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.
ABSTRACT
BACKGROUND: Optimizing immune checkpoint inhibitor (ICI) therapy may require identification of co-targetable checkpoint pathways via immune profiling. Herein, we analyzed the transcriptomic expression and clinical correlates of V-domain immunoglobulin suppressor of T-cell activation (VISTA), a promising targetable checkpoint. PATIENTS AND METHODS: RNA sequencing was carried out on 514 tissues reflecting diverse advanced/metastatic cancers. Expression of eight immune checkpoint markers [lymphocyte-activation gene 3 (LAG-3), tumor necrosis factor receptor superfamily 14 (TNFRSF14), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), programmed death-ligand 2 (PD-L2), B- and T-lymphocyte attenuator (BTLA), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), cytotoxic T-lymphocyte antigen 4 (CTLA-4)], in addition to VISTA, was analyzed, along with clinical outcomes. RESULTS: High VISTA RNA expression was observed in 32% of tumors (66/514) and was the most common highly expressed checkpoint among the nine assessed. High VISTA expression was independently correlated with high BTLA, TIM-3, and TNFRSF14, and with a diagnosis of pancreatic, small intestine, and stomach cancer. VISTA transcript levels did not correlate with overall survival (OS) from metastatic/advanced disease in the pan-cancer cohort or with immunotherapy outcome (progression-free survival and OS from the start of ICI) in 217 ICI-treated patients. However, in ICI-treated pancreatic cancer patients (n = 16), median OS was significantly shorter (from immunotherapy initiation) for the high- versus not-high-VISTA groups (0.28 versus 1.21 years) (P = 0.047); in contrast, VISTA levels were not correlated with OS in 36 pancreatic cancer patients who did not receive ICI. CONCLUSION: High VISTA expression correlates with high BTLA, TIM-3, and TNFRSF14 checkpoint-related molecules and with poorer post-immunotherapy survival in pancreatic cancer, consistent with prior literature indicating that VISTA is prominently expressed on CD68+ macrophages in pancreatic cancers and requiring validation in larger prospective studies. Immunomic analysis may be important for individualized precision immunotherapy.
Subject(s)
B7 Antigens , Neoplasms , Humans , Neoplasms/immunology , B7 Antigens/metabolism , Male , Female , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Middle Aged , Biomarkers, Tumor/metabolism , Immune Checkpoint Proteins/metabolism , AgedABSTRACT
Inequities in preventive cancer screening, diagnosis, treatment, and inferior cancer outcomes continue to pose challenges across the cancer continuum. While the exact reasons for these inferior outcomes are unknown, multiple barriers to various domains of social determinants of health (SDOH) play a vital role, leading to inequities in cancer care. These include barriers to transportation, housing, and food insecurities, contributing to delays in preventive screening and treatment. Furthermore, aggressive biologies also exist across various racial profiles with accompanying germline mutations. For example, African Americans (AAs) have a higher incidence of triple-negative breast cancer subtype and a high prevalence of BRCA1/2 gene mutations, increasing the risk of multiple cancers, warranting high-risk screening for these populations. Unfortunately, other barriers, such as financial insecurities, low health literacy rates, and lack of awareness, lead to delays in cancer screening and genetic testing, even with available high-risk screening and risk reduction procedures. In addition, physicians receive minimal interdisciplinary training to address genetic assessment, interpretation of the results, and almost no additional training in addressing the unique needs of racial minorities, leading to suboptimal delivery of genetic assessment provision resources among AAs. In this review, we discuss the confluence of factors and barriers limiting genetic testing among AAs and highlight the prevalence of germline mutations associated with increased risk of breast cancer among AAs, reflecting the need for multi-panel germline testing as well as education regarding hereditary cancer risks in underserved minorities.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Humans , Female , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Breast Neoplasms/epidemiology , BRCA1 Protein/genetics , Germ-Line Mutation , Black or African American/genetics , BRCA2 Protein/genetics , Genetic Testing/methods , Triple Negative Breast Neoplasms/geneticsABSTRACT
Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance.
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Hydra , Neoplasms , Animals , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Medical OncologyABSTRACT
BACKGROUND: We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers. MATERIALS AND METHODS: We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N = 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N = 16)]. RESULTS: Patients whose cancers harbored FGF/FGFR alterations (N = 1074) versus those without them (N = 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P = 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P = 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR) = 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well. CONCLUSIONS: FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.
Subject(s)
Neoplasms , Quinolines , Humans , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Receptors, Fibroblast Growth Factor/genetics , Phenylurea Compounds , Neoplasms/drug therapy , Neoplasms/geneticsABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) and genomic biomarker-driven targeted therapies have revolutionized the modern oncologic treatment arsenal. The next step has been to combine targeted agents and ICIs. In doing so, some combination regimens may be more logical than others. PATIENTS AND METHODS: Whole-exome and whole-transcriptome sequencing were performed on 2739 unselected later-stage clinical cases from 24 solid tumor subtypes in the NantHealth database, and data were also curated from 5746 similarly sequenced patients across 28 solid tumor subtypes in The Cancer Genome Atlas (TCGA). Significant differential expression of 10 immunoregulatory molecules [IRMs (genes)] was analyzed for association with mutant versus wild-type genes. RESULTS: Twenty-three significant associations between currently actionable variants and RNA-expressed checkpoint genes were identified in the TCGA cases; 10 were validated in the external cohort of 2739 clinical cases from NantHealth (P values were adjusted using Benjamini-Hochberg multiple hypothesis correction to reduce false-discovery rate). Within the same 5746 TCGA profiles, 2740 TCGA patients were identified as having one or more potentially oncogenic single-nucleotide variant (SNV) mutation within an established 50-gene hotspot panel. Of the 50 genes, SNVs within 15 were found to be significantly associated with differential expression of at least one IRM after adjusting for tissue enrichment; six were confirmed significant associations in an independent set of 2739 clinical cases from NantHealth. CONCLUSIONS: Logically combining ICIs with targeted therapies may offer unique treatment strategies for patients with cancer. The presence of specific mutations impacts the expression of IRMs, an observation of potential importance for selecting combinations of gene- and immune-targeted therapeutics.
Subject(s)
Biomarkers, Tumor , Neoplasms , Biomarkers, Tumor/genetics , Clinical Trials as Topic , Cohort Studies , Humans , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Research DesignSubject(s)
Neoplasms , Physicians , Adult , Antibodies, Monoclonal, Humanized , Child , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Power, PsychologicalABSTRACT
BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.
Subject(s)
Breast Neoplasms , Carcinoma , Salivary Gland Neoplasms , Antineoplastic Combined Chemotherapy Protocols , Humans , Molecular Targeted Therapy , Receptor, ErbB-2/genetics , Salivary Gland Neoplasms/drug therapy , Salivary Gland Neoplasms/genetics , Salivary Glands , TrastuzumabABSTRACT
BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Approval , Evidence-Based Medicine , Neoplasms/drug therapy , Off-Label Use/standards , Patient Care Management/standards , Practice Guidelines as Topic/standards , Humans , Neoplasms/pathology , Off-Label Use/legislation & jurisprudence , Off-Label Use/statistics & numerical data , Prognosis , Randomized Controlled Trials as Topic , United States , United States Food and Drug AdministrationABSTRACT
Novel patterns of response and progression to immunotherapy have been reported that are not observed with conventional cytotoxic or targeted anticancer treatments. A major breakthrough with immunotherapy is its potential to achieve durable responses in a subset of patients with advanced cancer that can be maintained several years even after stopping the treatment. No standardized definition of durable response exists in the literature, and the optimal duration of treatment in case of durable response is not clearly established. However, the majority of patients do not respond to immunotherapy. Initially reported in advanced melanoma patients, pseudoprogression occurs when tumor index lesions regress after initial progression, supporting the concept of treating some patients beyond progression. Overall, reported rates of pseudoprogression never exceeded 10%, meaning that the large majority of patients who have a disease progression will not eventually respond to treatment. The decision to pursue treatment beyond progression must therefore only be taken in carefully selected patients with clinical benefit, who did not experience severe toxicities with immunotherapy. Conversely, rapid progressions, called hyperprogressions, were reported by several teams with rates ranging from 4% to 29%. These observations need to be confirmed from randomized trials. It is essential to interrupt the treatment in patients with hyperprogression, in order to switch to another potentially active treatment. Finally, some patients experience dissociated responses, with some lesions shrinking and others growing. Local treatment with surgery or radiotherapy for growing lesions may be considered. Several immune-specific-related response criteria were developed to better capture benefits of immunotherapy. These criteria only address the pseudoprogression pattern of response, and do not capture the other patterns of response such as hyperprogression and dissociated response. The classic RECIST remains a reasonable and meaningful method to assess response to immunotherapy in the clinic.
Subject(s)
Immunotherapy , Neoplasms/epidemiology , Neoplasms/therapy , Response Evaluation Criteria in Solid Tumors , Disease Progression , Female , Humans , Male , Neoplasms/pathology , Progression-Free Survival , Treatment OutcomeABSTRACT
Metastatic basal cell carcinoma is an ultra-rare manifestation of a common disease, appearing in 0.0028%-0.5% of basal cell carcinomas. Initial therapeutic efforts focused on cytotoxic chemotherapy administration. However, it is now known that the Hedgehog signaling pathway is crucial for basal cell proliferation and Hedgehog pathway mutations may lead to tumorigenesis; thus, small-molecule inhibitors of alterations in the components of this pathway, including smoothened (SMO) and GLI, have been the focus of recent therapeutic developments. Indeed, the European Medicines Agency and the Food and Drug Administration have approved the SMO inhibitors, vismodegib and sonidegib, with additional GLI inhibitors currently in clinical trials. Molecular profiling of these tumors has revealed other potential targets for therapy, including high tumor mutational burden and PD-L1 amplification, which predict response to immune checkpoint blockade (PD-1 and PD-L1 inhibitors). An illustrative patient with a giant, advanced, unresectable basal cell carcinoma who obtained an ongoing complete remission after treatment with a combination of an immune checkpoint inhibitor (due to the tumor's high mutational burden) and the Hedgehog inhibitor vismodegib is described. A fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Cell Cycle Checkpoints/drug effects , Hedgehog Proteins/antagonists & inhibitors , Molecular Targeted Therapy , Neoplasms, Basal Cell/drug therapy , Skin Neoplasms/drug therapy , Animals , Humans , Neoplasms, Basal Cell/immunology , Skin Neoplasms/immunologyABSTRACT
PURPOSE: This systematic review aims to better define the limitations and patterns with which patients with MBC and CNS metastasis are enrolled into early phase developmental therapeutics trials. METHODS: In June 2016, PubMed search was conducted using the following keywords: "Breast cancer". Drug-development phase 1, phase 2 or phase 1/2 trials for patients with MBC were included. Multiple-histology trials and trials without an efficacy endpoint were excluded. RESULTS: In total, 1474 studies were included; Inclusion criteria for 423 (29%) allowed for CNS metastasis, 770 (52%) either excluded or did not document eligibility of patients with CNS disease. Trials accruing patients with HER2-positive MBC and including targeted therapies had higher odds of allowing for patients with CNS disease (adjusted OR 1.56, 95% CI 1.08-2.2.6; p=0.019 and 1.49, 95% 1.08-2.06; p=0.014, respectively). There were also higher odds of accrual of patients with CNS involvement into clinical trials over time (odds ratio=1.10, 95% CI 1.07-1.12; p<0.0001). CONCLUSION: Most published early phase clinical trials either did not clearly document or did not allow for accrual of patients with CNS disease. Early phase trials with targeted agents or enrolling HER2+ MBC had higher odds of permitting CNS metastases.
Subject(s)
Brain Neoplasms/secondary , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Patient Selection , Breast Neoplasms/chemistry , Female , Humans , Molecular Targeted Therapy , Receptor, ErbB-2/analysisABSTRACT
The potential role of oncogenic viruses mediating development of proliferative skin lesions in patients treated with RAF inhibitors is poorly understood. The objective of this study was to investigate human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in skin lesions among patients treated with RAF inhibitors with the help of a case series describing prevalence of HPV, MCPyV, and RAS mutations in skin biopsies obtained from patients receiving RAF inhibitors and developing cutaneous lesions. HPV-DNA was amplified by PCR utilizing multiple nested primer systems designed for detection of a broad range of HPV types. MCPyV copy number determination with real time PCR technology was performed by a "Quantification of MCPyV, small t region" kit. Thirty-six patients were tested (squamous cell carcinoma (SCC) = 14; verruca vulgaris = 15; other = 11). Nine of 12 SCCs (75 %) and eight of 13 verruca vulgaris lesions (62 %) tested positive for MCPyV whereas none of the normal skin biopsies obtained from nine of these patients tested positive for MCPyV (p = 0.0007). HPV incidence in cutaneous SCCs was not different compared to normal skin (50 vs. 56 %, p = 0.86). The association between MCPyV and proliferative skin lesions after RAF inhibitor therapy merits further investigation.
Subject(s)
Carcinoma, Squamous Cell/virology , Imidazoles/adverse effects , Melanoma/drug therapy , Merkel cell polyomavirus/isolation & purification , Oximes/adverse effects , Papillomaviridae/isolation & purification , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Skin Neoplasms/virology , Warts/virology , Adult , Aged , Aged, 80 and over , Biopsy , Carcinoma, Squamous Cell/chemically induced , Carcinoma, Squamous Cell/pathology , Female , Humans , Imidazoles/therapeutic use , Male , Melanoma/genetics , Middle Aged , Mutation , Oximes/therapeutic use , Prospective Studies , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Skin/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Warts/chemically induced , Warts/pathologyABSTRACT
BACKGROUND: This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval. METHODS: Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival. RESULTS: Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156). CONCLUSION: Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal/administration & dosage , Colorectal Neoplasms/drug therapy , ErbB Receptors/genetics , Adult , Aged , Cetuximab/administration & dosage , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Panitumumab , Proto-Oncogene Proteins p21(ras)/genetics , RetreatmentABSTRACT
PURPOSE: Preclinically, pazopanib/lapatinib combination acted synergistically to suppress the activity of multiple tyrosine kinases, including VEGFR-1, 2, 3, PDGFR and c-kit (pazopanib), HER1/EGFR and HER2 (lapatinib), and several other tyrosine kinases including c-Met through, plausibly, network inhibition effects. Clinically, continuous dosing of pazopanib/lapatinib combination was associated with a higher response rate than with lapatinib monotherapy, with poor tolerance. We explored multiple intermittent dose levels of pazopanib combined with continuous daily dosing of lapatinib in patients with solid tumors. METHODS: The present study used a phase 1, modified 3 + 3, dose-escalation design to evaluate the safety and tolerability of the combination of orally received pazopanib once every other day with continuous daily dosing of lapatinib for 28 days. In the expansion phase, tumor response was evaluated in patients with specific genetic alterations (HER2 amplification, HER2 mutation, c-Met amplification, c-Met mutation, and EGFR mutation). RESULTS: Twenty-four patients were treated. The most common drug-related adverse events were fatigue 7/24 (29%), skin rash 5/21 (21%), and diarrhea 3/24 (17%), with 4/24 (16%) patients experiencing grade ≥3 drug-related adverse events. Escalation to the FDA-approved dose (800 mg daily for pazopanib and 1500 mg every day for lapatinib) was not feasible due to toxicities. Pazopanib 200 mg every other day + lapatinib 500 mg daily was considered the maximum tolerated dose (MTD). No tumor response was observed, including in patients with the specific molecular genetic alterations tested. CONCLUSION: Every other day dosing of pazopanib combined with daily lapatinib was tolerated at the established MTD, but no complete or partial tumor responses were observed at these dose levels.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , ErbB Receptors/genetics , Female , Gene Amplification , Humans , Indazoles , Lapatinib , Male , Middle Aged , Mutation , Neoplasms/genetics , Proto-Oncogene Proteins c-met/genetics , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Quinazolines/administration & dosage , Quinazolines/adverse effects , Receptor, ErbB-2/genetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effectsABSTRACT
Fibroblast growth factor ligands and receptors (FGF and FGFR) play critical roles in tumorigenesis, and several drugs have been developed to target them. We report the biologic correlates of FGF/FGFR abnormalities in diverse malignancies. The medical records of patients with cancers that underwent targeted next generation sequencing (182 or 236 cancer-related genes) were reviewed. The following FGF/FGFR genes were tested: FGF3, 4, 6, 7, 10, 12, 14, 19, 23 and FGFR1, 2, 3, and 4. Of 391 patients, 56 (14.3%) had aberrant FGF (N = 38, all amplifications) and/or FGFR (N = 22 including 5 mutations and one FGFR3-TACC3 fusion). FGF/FGFR aberrations were most frequent in breast cancers (26/81, 32.1%, p = 0.0003). In multivariate analysis, FGF/FGFR abnormalities were independently associated with CCND1/2, RICTOR, ZNF703, RPTOR, AKT2, and CDK8 alterations (all P < 0.02), as well as with an increased median number of alterations (P < 0.0001). FGF3, FGF4, FGF19 and CCND1 were co-amplified in 22 of 391 patients (5.6%, P < 0.0001), most likely because they co-localize on the same chromosomal region (11q13). There was no significant difference in time to metastasis or overall survival when comparing patients harboring FGF/FGFR alterations versus those not. Overall, FGF/FGFR was one of the most frequently aberrant pathways in our population comprising patients with diverse malignancies. These aberrations frequently co-exist with anomalies in a variety of other genes, suggesting that tailored combination therapy may be necessary in these patients.
Subject(s)
Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/metabolism , Aged , Female , Humans , Male , Middle Aged , Signal Transduction/physiologyABSTRACT
BACKGROUND: Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity. PATIENTS AND METHODS: Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available). RESULTS: Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1. CONCLUSIONS: DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Mesoderm/pathology , Metaplasia/drug therapy , PTEN Phosphohydrolase/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Adult , Aged , Aged, 80 and over , Bevacizumab/administration & dosage , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Carboplatin/administration & dosage , Class I Phosphatidylinositol 3-Kinases , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Follow-Up Studies , Humans , Mesoderm/drug effects , Mesoderm/metabolism , Metaplasia/mortality , Metaplasia/pathology , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , PTEN Phosphohydrolase/genetics , Paclitaxel/administration & dosage , Phosphatidylinositol 3-Kinases/genetics , Polyethylene Glycols/administration & dosage , Polymerase Chain Reaction , Prognosis , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , Survival Rate , Young AdultABSTRACT
Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Clinical Trials as Topic/methods , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Precision Medicine/methods , Antineoplastic Agents/economics , Antineoplastic Agents/supply & distribution , Canada , Clinical Trials as Topic/economics , Clinical Trials as Topic/legislation & jurisprudence , France , Gene Expression Profiling , Genomics , Humans , Israel , Neoplasms/metabolism , Prospective Studies , Spain , United StatesABSTRACT
BACKGROUND: We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies. PATIENTS AND METHODS: Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available. RESULTS: Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively. CONCLUSION: The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01339871.