ABSTRACT
BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.
Subject(s)
Antineoplastic Agents , Biomarkers, Tumor , Docetaxel , Growth Differentiation Factor 15 , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Growth Differentiation Factor 15/blood , Docetaxel/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/mortality , Biomarkers, Tumor/blood , Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Middle Aged , Interleukin-4/blood , Interleukin-6/blood , Drug Resistance, Neoplasm , Monocytes/pathology , Monocytes/drug effectsABSTRACT
OBJECTIVES: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. STUDY DESIGN: Retrospective observational study; review of patient records in fifteen Australian institutions. SETTING, PARTICIPANTS: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. MAIN OUTCOME MEASURES: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. RESULTS: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths. CONCLUSION: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Male , Adult , Humans , Aged , Female , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Retrospective Studies , Immune Checkpoint Inhibitors/therapeutic use , Cohort Studies , Australia/epidemiologyABSTRACT
BACKGROUND: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. METHODS: In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. RESULTS: Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0-47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. CONCLUSIONS: Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT02660034.
Subject(s)
BRCA1 Protein , Triple Negative Breast Neoplasms , Humans , BRCA2 Protein , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.
Subject(s)
Brain Neoplasms , Melanoma , Skin Neoplasms , Humans , Melanoma/pathology , Nivolumab/therapeutic use , Ipilimumab , Skin Neoplasms/pathology , Brain Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. METHODS: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. CONCLUSIONS: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Biomarkers, Tumor/genetics , Docetaxel/therapeutic use , Female , Humans , Lipidomics , Lipids , Male , Phosphatidylinositol 3-Kinases/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , Sphingolipids/therapeutic useABSTRACT
Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.
ABSTRACT
BACKGROUND: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. METHODS: Lipidomic analysis (â¼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). FINDINGS: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity. INTERPRETATION: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors. FUNDING: None.
Subject(s)
Benzamides/therapeutic use , Ceramides/metabolism , Lysophospholipids/metabolism , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapy , Sphingosine/analogs & derivatives , Aged , Aged, 80 and over , Androstenes/therapeutic use , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Circulating Tumor DNA/metabolism , Drug Resistance, Neoplasm/drug effects , Humans , Male , Progression-Free Survival , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , Signal Transduction/drug effects , Sphingosine/metabolismABSTRACT
BACKGROUND: Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a "lighter" treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. METHODS/DESIGN: MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. DISCUSSION: MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12618000233224 , prospectively registered 14 February 2018.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Mutation , Proto-Oncogene Proteins B-raf/genetics , ras Proteins/genetics , Aged , Clinical Trials, Phase II as Topic , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Male , Multicenter Studies as Topic , Neoplasm Metastasis , Panitumumab/administration & dosage , Prognosis , Prospective Studies , Randomized Controlled Trials as TopicABSTRACT
Immunotherapy is increasingly defining a role in a wide variety of tumours such that as use becomes more ubiquitous, so too will the complications. A relatively rare complication of immunotherapy use is immune-related gastritis. In this case series, we present two cases of immunotherapy-related gastritis from our institution and undertake a comprehensive review and analysis of the literature around this less common adverse event.
ABSTRACT
BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Cisplatin/administration & dosage , Lung Neoplasms/drug therapy , Mesothelioma/drug therapy , Pemetrexed/administration & dosage , Pleural Neoplasms/drug therapy , Adolescent , Adult , Aged , Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Anti-Idiotypic/adverse effects , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Australia/epidemiology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , Cisplatin/adverse effects , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Mesothelioma/genetics , Mesothelioma/immunology , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Pemetrexed/adverse effects , Pleural Neoplasms/genetics , Pleural Neoplasms/immunology , Pleural Neoplasms/pathology , Progression-Free SurvivalABSTRACT
INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. METHODS AND ANALYSIS: The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. ETHICS AND DISSEMINATION: The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. DRUG SUPPLY: Tilray. PROTOCOL VERSION: 2.0, 9 June 2017. TRIAL REGISTRATION NUMBER: ANZCTR12616001036404; Pre-results.
Subject(s)
Antineoplastic Agents/adverse effects , Cannabidiol/therapeutic use , Cannabinoid Receptor Agonists/therapeutic use , Dronabinol/therapeutic use , Nausea/prevention & control , Phytotherapy , Secondary Prevention , Vomiting/prevention & control , Administration, Oral , Cannabidiol/economics , Cannabinoid Receptor Agonists/economics , Cost-Benefit Analysis , Double-Blind Method , Dronabinol/economics , Drug Combinations , Humans , Multicenter Studies as Topic , Nausea/chemically induced , Patient Reported Outcome Measures , Phytotherapy/economics , Pilot Projects , Randomized Controlled Trials as Topic , Vomiting/chemically inducedABSTRACT
Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Bone Neoplasms/blood , Lipids/blood , Prostatic Neoplasms, Castration-Resistant/blood , Soft Tissue Neoplasms/blood , Adult , Aged , Aged, 80 and over , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Grading , Prognosis , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Soft Tissue Neoplasms/drug therapy , Soft Tissue Neoplasms/secondary , Survival RateABSTRACT
IMPORTANCE: Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression. OBJECTIVE: To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression. DESIGN, SETTING, AND PARTICIPANTS: Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017. INTERVENTIONS: Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion. MAIN OUTCOMES AND MEASURES: Tumor response and safety in TBP and non-TBP patients. RESULTS: Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively). CONCLUSIONS AND RELEVANCE: A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067).
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Clinical Trials, Phase III as Topic , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Male , Melanoma/pathology , Middle Aged , Nivolumab , Retrospective Studies , Risk Factors , Skin Neoplasms/pathology , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Biomarkers of therapeutic response and prognosis are needed to assist in the sequencing of treatments for metastatic castration-resistant prostate cancer (CRPC). Previously in a Phase 1 discovery study, we identified 14 circulating microRNAs that were associated with response to docetaxel chemotherapy or overall survival. We performed a Phase 2 validation study to verify these findings. METHODS: Using real-time PCR, the levels of the 14 microRNAs were measured in plasma collected before and after the first cycle of docetaxel from a Phase 2 cohort of 89 patients. RESULTS: The microRNAs were not associated with docetaxel response in the Phase 2 cohort. Higher baseline levels of six microRNAs, predominantly of the miR-200 family, were confirmed to be associated with shorter overall survival. A microRNA signature comprising these six microRNAs predicted high-risk patients in the Phase 2 cohort with a hazard ratio of 4.12 (95% CI 2.20-7.70, P=0.000001). The signature was an independent predictor in multivariable analysis with clinicopathological factors. CONCLUSIONS: The association of circulating microRNAs with overall survival suggests their involvement in CRPC progression.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , MicroRNAs/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Taxoids/therapeutic use , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Clinical Trials, Phase I as Topic , Cohort Studies , Disease Progression , Docetaxel , Follow-Up Studies , Humans , Male , MicroRNAs/blood , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Proportional Hazards Models , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy , Real-Time Polymerase Chain Reaction , Survival RateABSTRACT
Nivolumab is a fully humanized monoclonal antibody to PD-1, which has shown improved overall and progression-free survival. Across studies of nivolumab, grade 3 or 4 rash has been noted in <1% of patients. We present a case report of patient with metastatic melanoma treated with nivolumab through expanded access program, who developed toxic epidermal necrolysis. Ours is the first case report, reporting grade 4 skin toxicity associated with nivolumab. A 64-year-old female presented with widespread maculopapular skin rash with bullae and areas of skin detachment after receiving 2 doses of nivolumab for ipilimumab refractory metastatic melanoma (BRAF wild-type). She was initially treated with prednisone, which was soon changed to methyprednisone followed by immunoglobulin with minimal response to the rash. After discussion with Dermatology, she was given cyclosporine and high-dose prednisone with gradual but significant improvement in her rash. Her skin biopsy showed interface dermatitis with a lymphocytic infiltrate in the dermoepidermal junction and apoptotic keratinocytes with focal areas of complete necrosis of the epidermis with minimal infiltrate.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Melanoma/complications , Stevens-Johnson Syndrome/diagnosis , Stevens-Johnson Syndrome/etiology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Biopsy , Disease Progression , Drug Resistance, Neoplasm , Fatal Outcome , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Ipilimumab , Melanoma/drug therapy , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Nivolumab , Skin/pathology , Steroids/therapeutic use , Stevens-Johnson Syndrome/drug therapyABSTRACT
BACKGROUND: We sought to determine the minimum survival benefits that patients judged sufficient to make adjuvant chemotherapy for early colon cancer worthwhile, factors associated with these judgments; and, to compare a self-administered questionnaire with a validated, scripted interview. PATIENTS AND METHODS: One twenty three subjects who completed adjuvant chemotherapy for early colon cancer 3-60 months earlier completed a questionnaire; 97 were randomised to complete an interview before or after the questionnaire. Preferences were elicited by the time trade-off method in 4 hypothetical scenarios. Concordance between the interview and questionnaire was assessed with the intraclass correlation coefficient (ICC). RESULTS: Median age was 65 years (range 19-86), 52% were female and 74% had involved lymph nodes. Over 60% of patients judged an additional 1 month beyond life expectancies of 5 years or 15 years, and an additional 1-2% beyond 5-year survival rates of 85% or 65%, sufficient to make chemotherapy worthwhile. Subjects with tertiary education (p=0.003) or aged 75 years or less (p=0.02) judged larger benefits necessary to make chemotherapy worthwhile. Concordance between the interview and questionnaire was high (ICCs 0.71-0.82). CONCLUSIONS: Most subjects judged small survival benefits sufficient to make adjuvant chemotherapy worthwhile. A self-administered questionnaire was a valid and acceptable way of eliciting preferences.