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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 716-716
    Abstract: 716 Background: CRP, a biomarker of systemic inflammation, has been shown to have prognostic value in numerous tumour types, including mRCC. The combination of the immune check inhibitor (ICI), pembro, and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) axi is one of several internationally approved combination ICI/VEGFR-TKI treatment options. We evaluated the predictive value of biomarkers of systemic inflammation in a real-world cohort of patients with mRCC treated with pembro and axi. Methods: Retrospective data of patients treated with pembro and axi were collected from a regional electronic database from two large cancer centres. Inflammatory biomarkers from routine blood tests (including haemoglobin, neutrophil count, platelets, albumin and CRP) prior to starting treatment were recorded. The IMDC score and modified Glasgow Prognostic Score (combining albumin and CRP) were calculated. The primary end point, progression free survival (PFS), was defined as the time between initiation of treatment and clinical or radiographical progression or death, or censorship. Overall survival, defined as the time between initiation of treatment and death, or censorship was also calculated. Univariate and multivariate analyses were undertaken using Cox Regression model and the relationship between different markers and PFS was assessed using Kaplan-Meier curves. Results: Data were available for 93 patients. 74 pts (80%) had clear cell histology, 19 pts (20%) had non-clear cell and 11 pts (12%) had sarcomatoid component. 46 patients had previous nephrectomy. 15 (16%), 46 (50%) and 32 (34%) pts respectively were classified as favourable, intermediate, and poor risk group as per IMDC score. Median PFS was 10.7 (IQR 4.6-not reached) months after a minimum 12.5 months follow-up. Baseline CRP was recorded in 77 (83%) patients, reflecting current routine clinical guidelines. On univariate analysis, neutrophils (≤7.5x10 9 /L/ 〉 7.5x10 9 /L) (p=0.044), platelets (≤400 x10 9 /L/ 〉 400x10 9 /L) (p=0.043), CRP (≤10mg/L/ 〉 10mg/L) (p=0.001), mGPS (0/1/2) (p=0.004) and IMDC risk group (low/intermediate/poor) (p=0.038) were predictive of PFS. On multivariate analyses only CRP was associated with PFS (HR2.78 (95% CI, 1.42-5.44) (p=0.003). At a 1-year landmark PFS was 62% (CRP ≤10mg/L) v 29% (CRP 〉 10mg/L) (p=0.002). CRP also predicted OS ((HR4.50 (95% CI, 1.58-12.8) (p=0.005)) with 1-year OS 85% (CRP ≤10mg/L) v 59% (CRP 〉 10mg/L) (p=0.002). Conclusions: CRP, a biomarker of systemic inflammation, predicts survival in mRCC patients undergoing combined ICI/VEGF-TKI therapy. Our findings support comparable studies in the mRCC population and routine recording of CRP in patients with mRCC. We advocate further work to validate utilisation of CRP as a prognostic biomarker for mRCC in clinical practice.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 3094-3094
    Abstract: 3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The C max and AUC 0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the C min (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 3
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 7 ( 2021-07), p. e002447-
    Abstract: Probody ® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing ‘off-tumor’ toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). Methods In the dose-escalation phase of this multicenter, open-label study ( NCT03013491 ), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC] ; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS] ; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET] ); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). Results An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, 〉 50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). Conclusions Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression. Trial registration number NCT03013491 .
    Type of Medium: Online Resource
    ISSN: 2051-1426
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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  • 4
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e16524-e16524
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e16524-e16524
    Abstract: e16524 Background: Clinicians in 17 UK oncology centres comprise the National Radium-223 Dichloride Audit (NRDA) group which is evaluating treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride (Xofigo). Methods: Patients commencing treatment from 1 st September 2017 were included. Clinical and laboratory parameters were collected throughout treatment. Analyses used frequency tables and univariate analysis. Results: As of February 2019, data from 400 patients has been collected. We report the outcomes on the first 150 patients who are evaluable. At first treatment, median age was 72 years (25 th to 75 th centile: 67-78), 54% of patients had an ECOG performance status (PS) of 1, 32.6% of patients had a WHO pain score of 1, 60% of patients had an ALP level of 〈 220U/L and 26% of patients received docetaxel for mCRPC. The mean number of cycles completed was 5. Sixty patients (40%) did not complete 6 cycles and 42/60 (70%) discontinued due to disease progression. Changes in variables between treatment 1 and 6 are shown in Table. Adverse events reported were fatigue (76%), diarrhoea (38%), nausea/vomiting (35%), constipation (32%), anaemia (28%), thrombocytopaenia (12%) and neutropaenia (5%). There was no overall change in ECOG PS. In those who completed quality of life (QOL) questionnaires at treatment 1 and 6 (58%), there was no difference. Conclusions: The ongoing NRDA Group records data from mCRPC patients treated across the UK in routine care. To our knowledge, it is the first prospective analysis of such patients and the largest in assessing treatment patterns and outcomes including QOL data as well as standard laboratory parameters. Disclosures: The NRDA Group has been funded by a research grant from Bayer.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 6_suppl ( 2020-02-20), p. 59-59
    Abstract: 59 Background: Clinicians in 20 UK oncology centres comprise the National Radium-223 Dichloride Audit group which is evaluating treatment patterns and outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with Radium-223 dichloride (Xofigo). Methods: Pts first treated with Xofigo from September 2017 were included and demographics, treatment, clinical, biochemical and outcome data collected prospectively. Analysis was carried out using frequency tables, univariate and survival analysis. Results: We report the outcomes on the first 100 pts in 4 centres with good quality data. Median values of each characteristic including 25 th and 75 th percentiles are as follows: Age at diagnosis = 67 years (62-72), weight = 83.5kgs (73.6-92.8), Hb = 139g/L (118 – 136), WCC = 7.3X10 9 /L (5.7 – 8.7), plt count = 252x10 9 /L (208 – 290), ALP = 128U/L (96-263) and PSA = 42.1ug/L (21.5 – 125.7). A majority of pts had an ECOG PS of 0-1. The number of pts having Xofigo as 1 st , 2 nd , 3 rd and 4 th line treatment was 15, 64, 20 and 1 respectively. There was a statistically significant decline in median weight, Hb, WCC, plt count and ALP and a rise in PSA between cycle 1 and cycle 6. Thirty eight pts did not complete 6 cycles with 31 of these (82%) discontinuing due to disease progression. The prevalence of adverse events was 5% (20/100). Twenty nine pts had a skeletal event by 12 months. There was no change in the WHO analgesic score, QOL scores or ECOG PS between treatment 1 and 6. Thirty nine pts had subsequent lines of treatment with 31 of these having only 1 line of treatment. Median overall survival was 363 days (95% CI 312-426 days). Conclusions: The ongoing National Radium-223 Dichloride Audit records data from approximately 600 mCRPC pts treated across the UK in routine clinical NHS care. To our knowledge, it is the first prospective analysis of such pts and the largest in assessing treatment patterns, outcomes and quality of life data in addition to standard biochemical and clinical parameters. Further multivariate analysis will be presented and the implications of the licensing change of Xofigo will be illustrated in the final analysis.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 6
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    Online Resource
    Informa UK Limited ; 2020
    In:  Expert Review of Precision Medicine and Drug Development Vol. 5, No. 2 ( 2020-03-03), p. 55-57
    In: Expert Review of Precision Medicine and Drug Development, Informa UK Limited, Vol. 5, No. 2 ( 2020-03-03), p. 55-57
    Type of Medium: Online Resource
    ISSN: 2380-8993
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2020
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3005-3005
    Abstract: 3005 Background: Monotherapy with immune checkpoint inhibitors (ICIs) has demonstrated efficacy in many cancers. Combining ICIs PD-L1 + CTLA-4 enhanced efficacy but worsened toxicity vs monotherapy; therefore, CTLA-4 dose modifications are often needed, despite a dose-response effect having been shown for efficacy. CX-072 is an investigational PD-L1 PROBODY therapeutic that is preferentially activated in the tumor microenvironment (TME); localized activation may reduce immune-related AEs (irAEs). PROCLAIM-CX-072-001 identified 10 mg/kg Q2W (Mono10) as the recommended monotherapy dose. Here we provide data for Mono10 and for dose escalation of CX-072 in combination with IPI (Combo), with a focus on long-term (≥6 mo) therapy. Methods: Mono10 was evaluated in multiple tumor types. Combo doses evaluated were CX-072 0.3–10 mg/kg and IPI 3–10 mg/kg Q3W. Patients (pts) with ≥6 mo treatment duration (≥6M-TD) were compared to those with 〈 6 mo of treatment ( 〈 6M-TD) as of November 30, 2019. Results: Disease control rates (DCR = CR+PR+SD) were 41% for Mono10 (n = 47 of 114; 10 PRs) and 37% for Combo (n = 10 of 27; 1CR + 4 PRs (1CR and 3PRs at 3 mg/kg IPI [IPI3]). Additional results are shown in the table. No treatment-related adverse events (TRAEs) led to death. The most common reason for discontinuation (dc) in all groups was disease progression. Conclusions: CX-072 monotherapy demonstrated durable responses consistent with activation of the PROBODY therapeutic in the TME. The safety profile supports the tolerability of CX-072 as monotherapy and when combined with IPI3. CX-072 + IPI3 demonstrated activity in heavily pretreated pts with various tumors. The safety profile of the combination of CX-072 with IPI3 compares favorably to historical data (grade ≥3 TRAEs 55% and leading to dc in 36%; Larkin J, et al. N Engl J Med. 2015;373:23-34). CX-072 + IPI3 is being explored in a phase 2 study in 2L melanoma Clinical trial information: NCT03993379 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 645-645
    Abstract: 645 Background: The Keynote 426 trial demonstrated 3-weekly pembrolizumab 200mg (pem3w) plus axi twice daily is effective in aRCC. We previously reported real-world experience of pem6w + axi demonstrating a comparable safety profile to pem3w + axi reported in Keynote 426, with the added benefit of less frequent hospital visits. Here we present updated results on progression free survival (PFS) and landmark analyses of overall survival (OS) at 6, 9 and 12-months. Methods: Electronic medical records of pts on pem6w + axi between 1st May 2020 & 1st June 2021 in two large cancer centres in Scotland were analysed retrospectively for pts’ characteristics, efficacy and treatment related adverse events (TRAE). A data cut-off of 1 st June 2022 was applied. Results: A total of 93 pts were identified (baseline demographics previously reported). 74 pts (80%) had clear cell histology, 19 pts (20%) had non-clear cell and 11 pts (12%) had sarcomatoid component. Approximately half had previous nephrectomy (46 pts). 15 (16%), 46 (50%) and 32 (34%) pts respectively were classified as favourable, intermediate, and poor risk group as per international metastatic renal cell carcinoma database consortium (IMDC) criteria. The median follow-up was 13 months (inter-quartile range [IQR] 8-17). At data cut off, 59 (63%) had progressed or died, with median PFS of 10.7 (IQR: 4.6-not reached) months. At landmark time-points of 6, 9 and 12 months 63 (68%), 50 (54%) and 42 (45%) of pts were progression free (Table). The median OS was not reached and follow up continues. At landmark time-points of 6, 9 and 12 months 88 (95%), 69 (74%) and 65 (70%) of pts were alive (Table). Clinician assessed radiological response was evaluable in 87 pts. Overall response rate (ORR), including partial response and complete response, was noted in 51 pts (59%). Clinical benefit rate including pts with ORR and stable disease was seen in 74 pts (85%). 82 pts (88%) had any grade and 28 pts (30%) had grade 3/4 TRAE. Any grade immune related AE (irAE) occurred in 62 pts (67%) and grade 3/4 in 19 pts (20%); g3/4 transaminitis (10%), colitis (8%), nephritis (2%) and skin (2%). Any grade AE due to axi occurred in 69 (74%) and grade 3/4 AE in 14 pts (15%). 25pts (27%) on Pem and 19pts (20%) on axi discontinued treatment due to TRAE. Conclusions: Our real-world experience demonstrates that pem6w + axi appears to have comparable efficacy and safety profile to pem3w + axi reported in Keynote 426 study. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 9
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    Online Resource
    Wiley ; 2019
    In:  Asia-Pacific Journal of Clinical Oncology Vol. 15, No. 4 ( 2019-08), p. 262-265
    In: Asia-Pacific Journal of Clinical Oncology, Wiley, Vol. 15, No. 4 ( 2019-08), p. 262-265
    Abstract: Checkpoint inhibition is the mainstay of treatment in metastatic melanoma. More recently combined cytotoxic T‐lymphocyte antigen‐4 and programmed‐death‐1 blockade has resulted in improved response rates and overall survival in treatment naïve patients compared to monotherapy albeit with increased rates of adverse events. Dermatologic toxicities are an emerging consequence of the use of checkpoint inhibitors and have reportedly been more prevalent with the use of combined therapy. However, grade 3 and 4 adverse event rates are still less than 5%. Here, we report a case of a 63‐year‐old Caucasian male with metastatic melanoma treated with first line combined ipilimumab and nivolumab who then developed a steroid refractory, biopsy confirmed pityriasis lichenoides‐like, drug related rash that resolved with cyclosporine. Time of onset was 24 days and presenting symptoms demonstrated a maculopapular rash presenting over the back and chest with pruritus. Unfortunately, the patient subsequently had multi‐organ failure with acute kidney injury requiring dialysis, hypotension requiring vasopressor support, hepatic dysfunction, and bilateral lung infiltrates resulting in a fatal outcome. This case report highlights the effective use of cyclosporine as an immunomodulatory agent in the management of severe dermatological toxicity due to combination immunotherapy.
    Type of Medium: Online Resource
    ISSN: 1743-7555 , 1743-7563
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2187409-8
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  • 10
    In: Pigment Cell & Melanoma Research, Wiley, Vol. 33, No. 2 ( 2020-03), p. 358-365
    Abstract: The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.
    Type of Medium: Online Resource
    ISSN: 1755-1471 , 1755-148X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2425880-5
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