Now showing items 1-20 of 7476

    • Construction of the immune landscape of durable response to checkpoint blockade therapy by integrating publicly available datasets

      Rudqvist, NP; Zappasodi, R; Wells, D; Thorsson, V; Cogdill, A; Monette, A; Najjar, Y; Sweis, R; Wennerberg, E; Bommareddy, P; et al. (2020)
      Background Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, long-term benefits are only achieved in a small fraction of patients. Understanding the mechanisms underlying ICB activity is key to improving the efficacy of immunotherapy. A major limitation to uncovering these mechanisms is the limited number of responders within each ICB trial. Integrating data from multiple studies of ICB would help overcome this issue and more reliably define the immune landscape of durable responses. Towards this goal, we formed the TimIOs consortium, comprising researchers from the Society for Immunotherapy of Cancer Sparkathon TimIOs Initiative, the Parker Institute of Cancer Immunotherapy, the University of North Carolina-Chapel Hill, and the Institute for Systems Biology. Together, we aim to improve the understanding of the molecular mechanisms associated with defined outcomes to ICB, by building on our joint and multifaceted expertise in the field of immuno-oncology. To determine the feasibility and relevance of our approach, we have assembled a compendium of publicly available gene expression datasets from clinical trials of ICB. We plan to analyze this data using a previously reported pipeline that successfully determined main cancer immune-subtypes associated with survival across multiple cancer types in TCGA.1 Methods RNA sequencing data from 1092 patients were uniformly reprocessed harmonized, and annotated with predefined clinical parameters. We defined a comprehensive set of immunogenomics features, including immune gene expression signatures associated with treatment outcome,1,2 estimates of immune cell proportions, metabolic profiles, and T and B cell receptor repertoire, and scored all compendium samples for these features. Elastic net regression models with parameter optimization done via Monte Carlo cross-validation and leave-one-out cross-validation were used to analyze the capacity of an integrated immunogenomics model to predict durable clinical benefit following ICB treatment. Results Our preliminary analyses confirmed an association between the expression of an IFN-gamma signature in tumor (1) and better outcomes of ICB, highlighting the feasibility of our approach. Conclusions In line with analysis of pan-cancer TCGA datasets using this strategy (1), we expect to identify analogous immune subtypes characterizing baseline tumors from patients responding to ICB. Furthermore, we expect to find that these immune subtypes will have different importance in the model predicting response and survival. Results of this study will be incorporated into the Cancer Research Institute iAtlas Portal, to facilitate interactive exploration and hypothesis testing.
    • An evaluation of continuous subcutaneous infusions across seven NHS acute hospitals: is there potential for 48-hour infusions?

      Baker J; Dickman, A; Mason, S; Bickerstaff, M; Jackson, R; McArdle, A; Lawrence, I; Stephenson, F; Paton, Nina; Kirk, J; et al. (2020)
      Background: Continuous subcutaneous infusions (CSCIs) are commonly used in the United Kingdom as a way of administering medication to patients requiring symptom control when the oral route is compromised. These infusions are typically administered over 24 h due to currently available safety data. The ability to deliver prescribed medication by CSCI over 48 h may have numerous benefits in both patient care and health service resource utilisation. This service evaluation aims to identify the frequency at which CSCI prescriptions are altered at NHS Acute Hospitals. Methods: Pharmacists or members of palliative care teams at seven acute NHS hospitals recorded anonymised prescription data relating to the drug combination(s), doses, diluent and compatibility of CSCIs containing two or more drugs on a daily basis for a minimum of 2 days, to a maximum of 7 days. Results: A total of 1301 prescriptions from 288 patients were recorded across the seven sites, yielding 584 discrete drug combinations. Of the 584 combinations, 91% (n = 533) included an opioid. The 10 most-common CSCI drug combinations represented 37% of the combinations recorded. Median duration of an unchanged CSCI prescription across all sites was 2 days. Conclusion: Data suggests medication delivered by CSCI over 48 h may be a viable option. Before a clinical feasibility study can be undertaken, a pharmacoeconomic assessment and robust chemical and microbiological stability data will be required, as will the assessment of the perceptions from clinical staff, patients and their families on the acceptability of such a change in practice. Keywords: CSCI; Palliative therapy; Subcutaneous infusions.
    • Variables associated with survival in patients with invasive bladder cancer with and without surgery.

      Longdon E; Mistry H; Pratt, O; Donnelly, A; O'Neill, S; Nachlappan, M; Darwin, L; Clarke, Noel W; Hartley, R; Nachiappan, M; et al. (2020)
      We recorded the survival of 141 patients assessed for radical cystectomy, which included cardiopulmonary exercise testing. The median Kaplan-Meier survival estimates were: 1540 days for the whole cohort; 2200 days after cystectomy scheduled (n = 108); and 843 days without surgery. The mortality hazard remained double that expected for a matched general population, but survival was better in patients scheduled for surgery than those who were not: the mortality hazard ratio (95%CI) after cystectomy was 0.43 (0.26-0.73) the mortality hazard without surgery, p = 0.001. The mortality hazard ratios for the three-variable Bayesian Model Averaging survival model for all 141 patients were: referral for surgery (0.5); haemoglobin concentration (0.98); and efficiency of carbon dioxide output (1.05). Efficiency of carbon dioxide output was the single variable in the postoperative model (n = 108), mortality hazard 1.08 (per unit increase). The ratio of observed to expected peak oxygen consumption associated best with mortality in 33 patients not referred for surgery, hazard ratio 0.001. Our results can inform consultations with patients with invasive bladder cancer and suggest that interventions to increase fitness and haemoglobin may improve survival in patients who do and who do not undergo radical cystectomy. Keywords: bladder cancer; cardiopulmonary exercise testing; radical cystectomy; survival; transitional cell carcinoma.
    • Oncologic sepsis on the ICU: two decades of improving outcomes

      Cooksley, Timothy J; Haji-Michael, Philip; Department of Acute Medicine and Critical Care, The Christie, Manchester (2020)
    • Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial

      Ledermann, JA; Oza, AM; Lorusso, D; Aghajanian, C; Oaknin, A; Dean, A; Colombo, N; Weberpals, JI; Clamp, Andrew R; Scambia, G; et al. (2020)
      Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. Methods: In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Findings: Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. Interpretation: In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports.
    • Risk stratification for prostate cancer management: value of the Cambridge Prognostic Group classification for assessing treatment allocation

      Parry, MG; Cowling, TE; Sujenthiran, A; Nossiter, J; Berry, B; Cathcart, P; Aggarwal, A; Payne, H; van der Meulen, J; Clarke, Noel W; et al. (2020)
      Background: The five-tiered Cambridge Prognostic Group (CPG) classification is a better predictor of prostate cancer-specific mortality than the traditional three-tiered classification (low, intermediate, and high risk). We investigated radical treatment rates according to CPG in men diagnosed with non-metastatic prostate cancer in England between 2014 and 2017. Methods: Patients diagnosed with non-metastatic prostate cancer were identified from the National Prostate Cancer Audit database. Men were risk stratified according to the CPG classification. Risk ratios (RR) were estimated for undergoing radical treatment according to CPG and for receiving radiotherapy for those treated radically. Funnel plots were used to display variation in radical treatment rates across hospitals. Results: A total of 61,999 men were included with 10,963 (17.7%) in CPG1 (lowest risk group), 13,588 (21.9%) in CPG2, 9452 (15.2%) in CPG3, 12,831 (20.7%) in CPG4, and 15,165 (24.5%) in CPG5 (highest risk group). The proportion of men receiving radical treatment increased from 11.3% in CPG1 to 78.8% in CGP4, and 73.3% in CPG5. Men in CPG3 were more likely to receive radical treatment than men in CPG2 (66.3% versus 48.4%; adjusted RR 1.44; 95% CI 1.36-1.53; P < 0.001). Radically treated men in CPG3 were also more likely to receive radiotherapy than men in CPG2 (59.2% versus 43.9%; adjusted RR, 1.18; 95% CI 1.10-1.26). Although radical treatment rates were similar in CPG4 and CPG5 (78.8% versus 73.3%; adjusted RR 1.01; 95% CI 0.98-1.04), more men in CPG5 had radiotherapy than men in CPG4 (79.9% versus 59.1%, adjusted RR 1.26; 95% CI 1.12-1.40). Conclusions: The CPG classification distributes men in five risk groups that are about equal in size. It reveals differences in treatment practices in men with intermediate-risk disease (CPG2 and CPG3) and in men with high-risk disease (CPG4 and CPGP5) that are not visible when using the traditional three-tiered risk classification. Keywords: CPG; Cambridge Prognostic Groups; Non-metastatic disease; Prostate cancer; Risk stratification; Treatment selection.
    • Independence of HIF1a and androgen signaling pathways in prostate cancer

      Tran, MGB; Bibby, Becky A; Yang, LJ; Lo, F; Warren, AY; Shukla, D; Osborne, M; Hadfield, J; Carroll, T; Stark, R; et al. (2020)
      Background: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. Methods: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. Results: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. Conclusions: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted. Keywords: Androgen signaling; HIF1a signaling; Hypoxia; Prostate cancer.
    • Technical Note: GATE-RTion: a GATE/Geant4 release for clinical applications in scanned ion beam therapy

      Grevillot, L; Boersma, DJ; Fuchs, H; Aitkenhead, Adam H; Elia, A; Bolsa, M; Winterhalter, Carla; Vidal, M; Jan, S; Pietrzyk, U; et al. (2020)
      Purpose: GATE-RTion is a validated version of GATE for clinical use in the field of light ion beam therapy. This paper describes the GATE-RTion project and illustrates its potential through clinical applications developed in three European centers delivering scanned proton and carbon ion treatments. Methods: GATE-RTion is a collaborative framework provided by the OpenGATE collaboration. It contains a validated GATE release based on a specific Geant4 version, a set of tools to integrate GATE into a clinical environment and a network for clinical users. Results: Three applications are presented: Proton radiography at the Centre Antoine Lacassagne (Nice, France); Independent dose calculation for proton therapy at the Christie NHS Foundation Trust (Manchester, UK); Independent dose calculation for protons and carbon ions at the MedAustron Ion Therapy center (Wiener Neustadt, Austria). Conclusions: GATE-RTion builds the bridge between researchers and clinical users from the OpenGATE collaboration in the field of Light Ion Beam Therapy. The applications presented in three European facilities using three completely different machines (three different vendors, cyclotron- and synchrotron-based systems, protons, and carbon ions) demonstrate the relevance and versatility of this project. Keywords: GATE; Geant4; Independent dose calculation; Monte Carlo simulation; clinical; ion beam therapy.
    • Image quality determination of a novel digital detector for X-ray imaging and cone -beam computed tomography applications

      Alzahrani, H; Richards, S; Sedgwick, I; Seller, P; Konstantinidis, Anastasios; Royle, G; Ricketts, K; Research Department of Tissue and Energy, Division of Surgery and Interventional Science, University College London, London (2020)
      The demand for adequate image quality with low radiation doses for patients has greatly increased. This is especially true in the case of position verification in radiotherapy which requires a high number of images per patient. This study presents a physical characterisation of a new clinical detector named “Lassena (CsI)” based on a thick layer of structured thallium activated caesium iodide and complementary metal-oxide semiconductor technology with active pixel sensor architecture for general X-ray imaging and cone-beam computed tomography (CBCT) applications. We made a critical appraisal of its performance for the first time and determined its signal transfer property (STP) and its detective quantum efficiency (DQE) by acquiring the pre-sampling modulation transfer function (pMTF) and normalised noise power spectrum (NNPS) in addition to the dark current calculation. The investigation was conducted with the application of three X-ray beam qualities: (50 kV (RQA3), 70 kV (RQA5) and 90 kV (RQA7)) in compliance with the International Electrotechnical Commission (IEC 62220-1(2003)) standard. The STP was found to be linear with the coefficient of determination (R²) more than 0.9995 in all cases. The spatial resolution and NNPS results led to acceptable DQE values at all energies; in particular the DQE values at 0.5 line pairs per mm (DQE(0.5)) which were 0.46 for RQA3, 0.52-0.56 for RQA5 and 0.55-0.59 for RQA7. Lastly, the dark current was 2.51 pA/cm² for a 50?m pixel pitch. For CBCT applications, Lassena (CsI) showed very promising results.
    • Health-related quality of life (HRQoL) in monarcHER: Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in HR+, HER2+advanced breast cancer

      Tolaney, SM; Wardley, Andrew M; Zambelli, S; Hilton, JF; Troso-Sandoval, TA; Ricci, F; Im, SA; Kim, SB; Johnston, SRD; Chan, A; et al. (2020)
      Background: Abemaciclib is an oral selective inhibitor of cyclin-dependent kinases 4 and 6 approved for hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer. In the randomized, 3-arm, phase 2 study monarcHER (NCT02675231) for HR+, HER2+ advanced breast cancer (ABC), abemaciclib in combination with trastuzumab (T) and fulvestrant (F) significantly improved investigator-assessed progression-free survival (whereas abemaciclib + T did not) versus (vs) T + physician's choice of chemotherapy and demonstrated a tolerable safety profile. Here, patient-reported HRQoL, functioning, and symptoms are reported. Methods: In monarcHER, 237 postmenopausal (surgical, natural, or chemical ovarian suppression) women with ABC and ?2 prior HER2+ directed therapies in the advanced setting were randomized 1:1:1 to abemaciclib (150 mg PO Q12H every 21 days) + T (IV infusion on D1 every 21 days) with F (500 mg IM on Cycle 1 D1 and D15 and Cycle 2 D8, then Q4W; Arm A) or without F (Arm B) vs T + physician's choice of chemotherapy (per label every 21 days; Arm C). Supportive measures to manage diarrhea were permitted. Patient-reported outcomes were measured at baseline and at each cycle using the modified Brief Pain Inventory-short form (mBPI-sf) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The EuroQol 5-Dimension 5 Level (EQ-5D 5L) questionnaire was also collected. Higher scores on EORTC QLQ-C30 functional and health status/QoL scales indicate improvement whereas higher scores on EORTC QLQ-C30 symptom scales and mBPI-sf indicate worsening of symptoms/pain. The EQ-5D 5L index score was calculated from a set of item weights to derive a score of 0-1, with 1 representing the best health status. Treatment arm comparisons of change from baseline (all post-baseline visits) were conducted using a mixed model repeated measure, with .05 considered statistically significant. Clinical meaningfulness was defined as a ?10-point score change from baseline (on a 0-100 scale) for EORTC QLQ-C30 and a 2-point score change from baseline for mBPI-sf. Results: Patient-reported outcome compliance rates were ?90% through Cycle 15; the range for median duration of each treatment component of each arm was 7.5-10.0 cycles. Overall, no statistically significant or clinically meaningful changes from baseline differences were observed between treatment arms for mBPI-sf pain scores or EORTC QLQ-C30 global health score, function scales, or for symptoms of fatigue, dyspnea, appetite loss, or financial difficulties. Least square (LS) mean change from baseline differences showed statistically significant improvements in Arm A vs C for EORTC QLQ-C30 symptoms of pain (-6.81; p=.026) and insomnia (-6.39; p=.041). Worsening for the symptom of nausea/vomiting was statistically significant but not clinically meaningful in Arm A vs C (4.08; p=.043). Diarrhea showed a statistically significant and clinically meaningful worsening in Arm A vs C (19.27; p<.001). A by-cycle analysis showed mean nausea/vomiting and diarrhea symptom scores were generally higher during earlier visits and returned to near-baseline levels after treatment discontinuation. The EQ-5D 5L index score improved in Arm A vs C, with an LS mean change from baseline difference of .05 (p=.033). Conclusions: Quality of life was maintained for patient-reported pain, global health, functioning, and most symptoms when abemaciclib was added to T + F compared with physician's choice of chemotherapy in patients with HR+, HER2+ ABC. Gastrointestinal-related symptoms were transient and consistent with the manageable, reversible adverse event profile.
    • National utilisation of neoadjuvant systemic therapy and impact on surgical treatment - A prospective multi-centre cohort study

      McIntosh, SA; Irwin, GW; Bannon, F; Coles, C; Copson, E; Cutress, R; Dave, R; Grayson, M; Holcombe, C; Irshad, S; et al. (2020)
      Introduction: Potential advantages of neoadjuvant systemic therapy (NST) include downstaging disease to minimise surgery, and in vivo assessment of tumour sensitivity to therapeutic drugs. Considerable variation in NST use remains, however, and it is unclear whether pathological response rates reflect those reported in trials, or whether downstaging achieved impacts on surgical decision-making. The NeST prospective multicentre study will address these questions through investigating patterns of care in the UK. Methods: Women undergoing NST as their primary breast cancer treatment (chemotherapy (CT), endocrine (ET) and targeted therapies) in UK centres between December 2017 and November 2018 were included. Anonymised data was collected at 37 participating centres, and uploaded to REDCap. Results: 1179 patients received neoadjuvant treatment during the study period. 41% had HER2+ disease, 28% TNBC and 31% ER+ HER2- disease. 48% were node positive and 52% node negative. Cited indications for neoadjuvant treatment were (more than one option applicable to each patient): Downstaging (mastectomy to breast conservation) 37% Facilitate dual antiHER2 therapy 33% Inoperable disease 19% Improved cosmesis (reduced volume of excision) 17% Facilitate BRCA testing 9% Inflammatory breast cancer 6% In patients recommended to receive NST, the MDT decision was for neoadjuvant CT in 87% of cases and neoadjuvant ET in 13%. For ER+ disease, the commonest reasons for prescribing CT were high grade disease and pre-menopausal status. The majority were treated with anthracycline-taxane combinations. 21% of TNBC patients were treated with platinum-containing regimens. In HER2+ disease, 54% were treated with dual antiHER2 therapies/chemotherapy, with 10% receiving chemotherapy/single antiHER2 agent (trastuzumab). Centres were asked to indicate primary breast surgical treatment recommended prior to/without NST. At abstract submission, this data was available for 887 patients. 31 had inoperable disease. A total of 477 were considered to require mastectomy, with disease not amenable to breast conservation surgery (BCS). A further 379 patients were considered candidates for BCS. Data on final surgical procedure was available for 765 patients. Of those patients determined suitable only for mastectomy at diagnosis, 123 underwent BCS as their primary operation - a downstaging rate of 26%. The overall mastectomy rate in this cohort was 48%, with 33% having mastectomy and 15% mastectomy with immediate reconstruction. Pathological response data was available in 672 patients, with an overall pathological complete response (pCR) rate of 29% (defined as no residual invasive or in situ disease). pCR rate according to molecular subtype was 37% for HER2+ disease, 35% for TNBC and 7% for ER+, HER2-ve disease. The pCR rate in patients downstaged from mastectomy to BCS was 27%. Conclusions: This UK national prospective study suggests that surgical downstaging remains a key indication for the use of NST. This is reflected in the fact that 26% of patients in this series were downstaged from an original surgical plan for mastectomy, with NST enabling BCS in these patients. However, based on this data it appears that surgical downstaging is no more likely in those with pCR compared to those without a pCR. Additional indications for NST are emerging, according to disease biology. There is widespread use of dual antiHER2 targeted therapies in this setting, with increasing use of platinum-containing regimens for TNBC. Neoadjuvant CT continues to be frequently used in the treatment of ER+ disease, despite known low pCR rates in this context, which are again confirmed. Low rates of neoadjuvant ET use are reported.
    • Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

      Alba, KP; McMurtry, E; Vallier, AL; Grybowicz, L; Copson, E; Armstrong, Anne C; Roylance, R; Qian, WD; Demiris, N; Thomas, S; et al. (2020)
      Background: Triple negative breast cancers (TNBCs) are an aggressive and diverse subgroup with no specific targeted therapies currently available. Basal TNBCs show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors (olaparib) to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for gBRCA and/or basal TNBC is safe and improves efficacy (pathological complete response (pCR)). This is the first time a clinical trial provides safety data of the combination of olaparib with platinum and taxane chemotherapy in an early breast cancer setting. Methods: PARTNER is a 3-stage open label randomised Phase II/III trial of neoadjuvant Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 (CP) +/- olaparib (O) 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and/or gBRCA patients are eligible for inclusion. Primary endpoints are defined by stage: Stage 1 - Safety, Stage2 - Schedule selection, and Stage 3 - Efficacy (pCR rate). The trial is now powered for efficacy analysis in the BRCA and non-BRCA population independently. Stage 1 and 2 randomization was(1:1:1) to CP: CP + O from day (D) -2: or CP + O from D 3. G-CSF was mandatory during the first 4 cycles of treatment. We present a pooled-safety analysis from Stage 1 and 2 of the two research arms only. Recruitment continues into Stage 3. Results: Between June 2016 and April 2018, 159 patients were recruited among the three arms. Overall, median age was 48.2 [range 22.3- 70.9]; 12% had Tumours >5cm, 34% had Axillary involvement; 17% were gBRCA. Adverse events (AE) that were reported as common (in at least 10% of patients) were Anaemia 23%, Neutropenia 18% and Infection 10%. Fatigue and Diarrhoea were next most prevalent with 9% and 6% respectively. The most common AE Grade >=3 were haematological events. These include Neutropenia 19%, Anaemia 15%, and Thrombocytopenia 5%. Febrile Neutropenia and Haemorrhage were reported in only 2% and 1% of cases. Grade 3 Non- haematological events were Fatigue 7%, Hypertension 3%, Headache 3% and Diarrhoea 2%. Grade 3 Sensory neuropathy was present in 2% of patients. No grade 4 sensory or motor neuropathy events were described. Serious adverse reactions related to investigational regimen were reported in 17% of patients and include fever and infection with 8 and 4 events respectively. No toxicity related deaths were reported. As per July 8th 2019, 373 patients have been recruited from which 58 were gBRCA. Conclusions: Combinations of olaparib with neoadjuvant CP chemotherapy showed an acceptable and manageable toxicity profile. Although haematological events were the most common, they did not exceed historical frequencies reported for standard chemotherapy regimens. Final safety analysis will be performed once recruitment is complete and will include detailed long-term neuropathy data.
    • OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer

      Robson, M; Im, SA; Senkus, E; Xu, BH; Domchek, S; Masuda, N; Delaloge, S; Li, W; Tung, N; Armstrong, Anne C; et al. (2020)
      Background: In the OlympiAD study, olaparib showed a clinically meaningful benefit in progression-free survival compared with chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and HER2-negative metastatic breast cancer (mBC; Robson N Engl J Med 2017). Final prespecified median overall survival (OS) at 64% data maturity was 19.3 months with olaparib versus 17.1 months with TPC (Robson Ann Oncol 2019). At this time, 26 patients continued to receive olaparib, with none continuing to receive TPC as assigned. After consenting to a protocol amendment, post hoc follow-up of patients for survival status and serious adverse events continued. Patients and methods: OlympiAD is a Phase III, randomized, controlled, open-label trial (NCT02000622). Patients with a germline BRCAm and HER2-negative mBC who had received ?2 prior lines of chemotherapy for mBC were randomized to olaparib tablets (300 mg twice daily) or predeclared TPC (capecitabine, vinorelbine or eribulin). Extended OS and safety follow-up were exploratory endpoints; the study was not powered to detect an OS benefit or treatment effect between subgroups. The overall hazard ratio (HR) was estimated using a stratified log-rank test, and a single Cox proportional hazards model was used for analyses in prespecified subgroups. Results: Of patients randomized to olaparib (n=205) or TPC (n=97), 160 (78.0%) and 80 patients (82.5%) respectively had withdrawn from the study (majority due to death), and seven and eight patients, respectively, did not participate in the extended follow-up. At data cut-off (March 3, 2019), 223 patients had died (73.8% data maturity), 24 (11.7%) patients from the olaparib arm and nine patients (9.3%) from the TPC arm were continuing the study off treatment, no patients were continuing to receive TPC as assigned. Fourteen patients (6.8%) were continuing olaparib at this time; in this small number of patients at baseline their median age was 42.5 years, 42.9% had not received prior chemotherapy for mBC, 57.1% were TNBC, 50.0% had a BRCA1 mutation, 42.9% had liver metastasis and 57.1% had ?2 metastatic sites. Median follow-up was 18.9 months in the olaparib arm and 15.5 months in the TPC arm (40.7 and 29.2 months in censored patients, respectively). OS and landmark analyses for the overall population and prespecified key subgroups are reported in the Table. Of patients who discontinued study treatment, 2.0% in the olaparib arm and 11.3% in the TPC arm received subsequent PARP inhibitors, and 42.4% and 48.5%, respectively, received subsequent platinum chemotherapy. Median total study treatment duration was 251 days in the olaparib arm versus 105 days in the TPC arm, with 8.8% of olaparib patients receiving treatment for >3 years versus no TPC patients. During the extended follow-up period, there were no new serious adverse events suspected to be related to olaparib treatment, including no reports of myelodysplastic syndrome/acute myeloid leukemia.
    • ILROG emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic

      Yahalom, J; Dabaja, BS; Ricardi, U; Ng, A; Mikhaeel, NG; Vogelius, IR; Illidge, Timothy M; Qi, SN; Wirth, A; Specht, L; et al. (2020)
      The International Lymphoma Radiation Oncology Group (ILROG) guidelines for using radiation therapy (RT) in hematological malignancies are widely used in many countries. The emergency situation created by the COVID-19 pandemic may result in limitations of treatment resources. Furthermore, in recognition of the need to also reduce the exposure of patients and staff to potential infection with COVID-19, the ILROG task force has made recommendations for alternative radiation treatment schemes. The emphasis is on maintaining clinical efficacy and safety by increasing the dose per fraction while reducing the number of daily treatments. The guidance is informed by adhering to acceptable radiobiological parameters and clinical tolerability. The options for delaying or omitting RT in some hematological categories are also discussed.
    • Adjuvant immunotherapy: the sting in the tail

      Higham, Claire E; Chatzimavridou-Grigoriadou, Viktoria; Fitzgerald, CT; Trainer, Peter J; Eggermont, AMM; Lorigan, Paul C; Department of Endocrinology, Christie Hospital NHS Foundation Trust, Manchester (2020)
      Adjuvant therapy with PD-1 inhibitors for resected Stage III/IV melanoma reduces the risk of recurrence by 40-50% and is now a standard of care. Immune-related adverse events occurred in approximately 37% of patients in the pivotal trials, 10-15% were severe (grade III-IV). Endocrine toxicities were common and mostly irreversible. Thyroid toxicity occurred in 15-20% of patients, hypophysitis (2.2%), insulin-dependent diabetes mellitus (1%) and adrenalitis (1%). Revision of the American Joint Committee on Cancer staging system (version 8) has resulted in a significant improvement in prognosis for patients with Stage III disease. As a result, clinicians may now offer adjuvant immunotherapy to patients with a lower risk of recurrence than those in the pivotal trials. There is a need to balance the relatively small reduction of absolute risk of recurrence against the risk and impact of toxicity. Five-ten percent of biochemically euthyroid patients on levothyroxine report symptoms of depression. Hypogonadism can result from toxicity to the hypothalamic-pituitary axis, and can lead to sexual dysfunction and subfertility. Secondary hypogonadism can be treated by the administration of Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) which induce spermatogenesis/ovulation in a functioning gonad but is not always successful. Insulin-dependent diabetes mellitus often presents with rapid onset of hyperglycemia and potentially life-threatening diabetic ketoacidosis. Long-term adverse outcomes are likely to mimic Type 1 DM with a 6-fold increase in cardiovascular disease related mortality and 3-fold in all-cause mortality. These survivorship issues are relevant to all melanoma patients but are particularly pertinent where the absolute benefit is modest. Keywords: Adjuvant immunotherapy; Endocrine toxicity; Fertility; Late effects; Melanoma.
    • Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patients with HR+/HER2-advanced breast cancer

      Bulat, I; Maglakelidze, M; Murias, C; Krastev, B; Baird, RD; Wardley, Andrew M; Roylance, R; Crijanovschi, A; Gogiladze, M; Pritchett, Y; et al. (2020)
      Approved CDK4/6 inhibitors have demonstrated significant improvements in progression free survival when combined with fulvestrant in patients with HR+/HER2- advanced breast cancer, though limited by neutropenia and gastrointestinal side effects. Lerociclib is a potent selective CDK4/6 inhibitor with a differentiated PK/PD profile from currently approved CDK4/6 inhibitors that has demonstrated clinical proof-of-concept (Phase 1b data ASCO 2018). This Phase 1b/2a study assesses lerociclib dose escalation in combination with 500 mg fulvestrant using a 3+3 design followed by dose expansion in patients with metastatic or locally advanced HR+/HER2- breast cancer that had progressed following endocrine therapy. Up to two prior chemotherapies in Phase 1b and one prior in Phase 2a in the advanced setting are allowed. Prior fulvestrant was excluded for all patients; prior CDK4/6 inhibitors were excluded in Phase 2a only. Lerociclib is administered daily without a drug holiday. The objectives are to evaluate DLTs, safety, tolerability, PK, and tumor response and to determine the recommended dose and schedule (QD or BID) of lerociclib administered with fulvestrant for randomized trials. The BID dosing regimen demonstrated optimal safety, tolerability, and antitumor activity. To date, 35 patients (6 patients @ 100 mg BID, 9 patients @ 150 mg BID, 17 patients @ 200 mg BID, and 3 patients @ 250 mg BID) with mean age of 54 years, ECOG of 0 (86%) or 1 (14%), and a median of two prior anticancer therapies in the advanced setting have received lerociclib + fulvestrant for up to 804 days. A dose proportional increase in drug exposure has been observed. The most common lerociclib-related adverse events were neutropenia (63%), leukopenia (57%), nausea (37%), anemia (29%), diarrhea (20%), and thrombocytopenia (20%). The rates of lerociclib-related Grade 3 and Grade 4 neutropenia were 29% and 9%, respectively. Following an initial decline, ANC plateaued beginning at week 4. There were no reports of Grade 3 or greater nausea, vomiting, or diarrhea. One DLT of dose interruption due to Grade 2 fatigue and nausea was observed at 200 mg BID. There have been no reports of venous thromboembolism, QT prolongation or drug-induced liver injury. Twenty patients were evaluable for tumor response based on RECIST v1.1. Five patients (25%) had a confirmed PR; 8 patients (40 %) had stable disease; 6 patients (30 %) had PD. The CBR (CR + PR + SD ? 24 weeks) was 67% (12 of 18 patients either had SD at the week 24 tumor assessments or achieved an objective response). A population PK/PD/efficacy model was developed, and simulation data are concordant with existing clinical results. Additional patients are being enrolled at 150 mg BID and 200 mg BID, and updated data will be presented. Lerociclib, dosed BID with no drug holiday, has a favorable safety profile with low rates of gastrointestinal AEs and Grade 3/4 neutropenia, as well as encouraging antitumor activity in patients with HR+/HER2- advanced breast cancer. Phase 2b is ongoing to confirm the BID dose (150 mg or 200 mg) for randomized clinical trials. Clinical trial information: NCT02983071.
    • Results from plasmaMATCH trial treatment cohort D: A phase II trial of capivasertib in patients with an AKT activation basket mutation identified via ctDNA testing or tumour sequencing (CRUK/15/010)

      Baird, RD; Kilburn, L; Kernaghan, S; Wardley, Andrew M; Macpherson, I; Roylance, R; Stephens, P; Oikonomidou, O; Braybrooke, JP; Tuthill, M; et al. (2020)
      Background: Activation of the AKT pathway can result from diverse rare genetic events, including mutation of AKT1, AKT2/3 E17K, and through inactivating mutation or homozygous deletion of PTEN. AKT1 mutations and genetic loss of PTEN are associated with activation of AKT signalling and selective sensitivity to AKT inhibition in pre-clinical models. Capivasertib is a potent catalytic inhibitor of AKT1, AKT2 and AKT3 with activity both in vivo and in the clinic. The plasmaMATCH trial assessed the efficacy of capivasertib in BC patients with rare AKT activating mutations. Methods: The plasmaMATCH trial is an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC. Patients with AKT1 mutations in ER negative BC; or AKT2/3 E17K mutations, PIK3R1 or PTEN inactivating mutations orhomozygous deletion of PTEN in both ER positive and ER negative BC were recruited. Mutations were identified in ctDNA testing in plasmaMATCH or in prior tumour sequencing. Patients were treated with capivasertib 480mg BID 4 days on - 3 days off. The primary endpoint for Cohort D is confirmed objective response rate as defined by RECIST v1.1. Using a single stage A'Hern design with a target response rate of 25%, unacceptable response rate of 5%, alpha=5% and power=80%, at least 3 responses out of 16 evaluable patients were required to infer efficacy for capivasertib. Results: In total 19 patients were recruited in Cohort D, 12 following ctDNA testing and 7 on tumour testing. Fifteen (79%) were ER positive, all were HER2 non-amplified, and 14 (74%) had visceral metastases. Mutations were AKT1 E17K (5 patients), AKT1 L52R (1), PTEN inactivating mutation (12), and PTEN homozygous deletion (1). All patients were evaluable with overall confirmed response rate of 10.5% (95%CI 1.3-33.1%, 2/19) (first 16 evaluable patients: 2/16, 12.5% (95%CI 1.6-38.3)). Two further patients had unconfirmed responses. Median progression free survival was 3.4 months (IQR 1.8-5.5 months) and median duration of response 3.9 months (IQR 3.7-4.2 months) with 1 patient continuing treatment. In patients with AKT1 mutations there was a 33% response rate (2/6) with 2 further unconfirmed responses. There were no responses in patients with PTEN mutations (0/13). The most common clinically significant grade 3 or 4 adverse events were rash (26%), hypertension (11%), transaminase increase (11%) and vomiting (11%). Conclusions: Capivasertib monotherapy did not meet pre-specified criteria for efficacy in this group of patients with a range of AKT pathway activating mutations. In exploratory analysis, capivasertib was active in patients with AKT1 mutations.
    • Results from plasmaMATCH trial treatment cohort C: A phase II trial of capivasertib plus fulvestrant in ER positive breast cancer patients with an AKT1 mutation identified via ctDNA screening (CRUK/15/010)

      Roylance, R; Kilburn, L; Kernaghan, S; Wardley, Andrew M; Macpherson, I; Baird, RD; Stephens, P; Oikonomidou, O; Braybrooke, JP; Tuthill, M; et al. (2020)
      Background: AKT1 mutation occurs in approximately 3% of breast cancer (BC), enriched in advanced BC. The AKT1 E17K mutation results in constitutive activation of AKT1, associated with sensitivity to AKT inhibitor capivasertib in pre-clinical models, and in a prior phase I trial with AKT1 mutations identified through tumour testing. The plasmaMATCH trial Cohort C assessed the efficacy of capivasertib and fulvestrant in ER positive BC patients with an AKT1 mutation in ctDNA testing. Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC. Patients with an AKT1 mutation identified via ctDNA testing were registered to Cohort C. Patients were treated with capivasertib 400mg BID 4 days on - 3 days off, plus fulvestrant 500mg intramuscularly on Cycle 1 Days 1 and 15, and Cycle 2 onwards every 28 days. The primary endpoint for Cohort C was confirmed objective response rate as defined by RECIST v1.1. Using a single stage A'Hern design with a target response rate of 25%, unacceptable response rate of 5%, alpha=5% and power=80%, at least 3 responses out of 16 evaluable patients were required to infer efficacy. Results: Following ctDNA testing, 18 patients enrolled in Cohort C (42% of patients with AKT1 mutations identified in ctDNA testing). All were ER positive, 1 (5.6%) was HER2 amplified, and 17 (94%) had visceral metastases. Mutation was AKT1 E17K in 17 patients and AKT1 L52R in 1 patient. All patients were evaluable with a confirmed response rate of 22.2% (95%CI 6.4-47.6%, 4/18) (first 16 evaluable patients: 3/16, 18.8% (95%CI 4.0-45.6)). A further 4 patients had an unconfirmed partial response. Median progression free survival was 10.2 months (IQR 3.2-18.2 months) and the median duration of response was 7.5 months (IQR 4.1-9.8 months) with 4 patients continuing on treatment. The most common clinically significant grade 3 or 4 adverse events were fatigue (22%), rash (17%), diarrhoea (11%) and hyperglycaemia (11%). Conclusions: Capivasertib plus fulvestrant was active in patients with ER positive breast cancer and AKT1 mutations identified in ctDNA testing, meeting the pre-specified threshold for efficacy
    • Results from plasmaMATCH trial treatment cohort A: A phase II trial of extended-dose fulvestrant in patients with an ESR1 mutation identified via ctDNA screening (CRUK/15/010)

      Macpherson, I; Kilburn, L; Kernaghan, S; Wardley, Andrew M; Baird, RD; Roylance, R; Stephens, P; Oikonomidou, O; Braybrooke, JP; Tuthill, M; et al. (2020)
      Background: Ligand binding domain ESR1 mutations are acquired in ER positive cancers during prior aromatase inhibitor therapy for advanced ER positive breast cancer (BC). ESR1 mutant cancer models are sensitive to fulvestrant at high concentrations, however standard dose fulvestrant may not achieve the concentration required to fully inhibit mutant ESR1 in the clinic. The plasmaMATCH trial Cohort A assessed the efficacy of extended-dose fulvestrant (double the current standard dose achieved by doubling the frequency of administration) in patients with an ESR1 mutation identified via ctDNA testing. Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC. Patients with an ESR1 mutation identified in ctDNA testing were potentially eligible to enter Cohort A. Patients were treated with fulvestrant 500mg intramuscularly on Cycle 1 Days 1, 8 and 15 of a 28 day cycle, and from Cycle 2 onwards every 15 days. Pharmacokinetics samples were collected pre-dose on Day 1 of Cycles 2, 3 and 4. The primary endpoint for Cohort A was confirmed objective response rate as defined by RECIST v1.1. The original planned sample size was 40 patients, to detect a 25% response rate, assuming predominantly clonally dominant mutations. As the trial progressed it became apparent that ctDNA screening may also detect sub clonal ESR1 mutations, which were expected to have a lower response rate. Using a single-stage A'Hern design with a target response rate of 20%, unacceptable response rate of 10%, alpha=5%, power=80, the sample size was increased to 78 evaluable patients with 13 or more responses required to infer efficacy. Results: Following ctDNA testing, 84 patients enrolled in Cohort A (38% of patients with ESR1 mutations identified in ctDNA testing). All were ER positive, seven were HER2 amplified, 78 (93%) had visceral metastases. The most common ESR1 mutations detected in baseline plasma were D538G (52.4%), Y537S (35.7%), E380Q (33.3%). In the 74 evaluable patients, confirmed response rate was 8.1% (95%CI 3.0-16.8%, 6/74). One additional patient had an unconfirmed partial response. Median progression free survival was 2.2 months (IQR 1.7-5.3 months) and median duration of response was 7.0 months (IQR 3.7-8.3 months) with 4 patients continuing on treatment. In exploratory analysis, 39 patients had clonally dominant ESR1 mutations in baseline ctDNA analysis whilst 25 patients had subclonal mutations and 10 had unknown clonality. The response rate in those with clonally dominant ESR1 mutations was 10% (95%CI: 2.9-24.2%, 4/39) with no confirmed responses in those with subclonal mutations. The most common clinically significant grade 3 or 4 adverse event was hypertension (13%). Pharmacokinetic analysis was consistent with elevated fulvestrant exposure compared to approved 500mg PopPk model (pre-dose Cycle 3, 71% increase, and pre-dose Cycle 4 66% increase). Conclusion: In the pre-treated population studied, the response rate of extended-dose fulvestrant did not meet pre-specified criteria for efficacy in patients with ESR1 mutations identified in ctDNA testing. Extended-dose fulvestrant was well tolerated and enhanced exposure was observed. Assessment of clonal dominance of ESR1 mutations in ctDNA may identify patients who are more likely to benefit from extended-dose fulvestrant therapy.
    • Results from the plasmaMATCH trial: A multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010)

      Turner, N; Kingston, B; Kilburn, L; Kernaghan, S; Wardley, Andrew M; Macpherson, I; Baird, RD; Roylance, R; Stephens, P; Oikonomidou, O; et al. (2020)
      Background: Circulating tumour DNA (ctDNA) testing may provide a more current assessment of the genetic profile of advanced breast cancer (BC) compared with analysis of the primary tumour, with repeat advanced disease biopsy conducted infrequently in routine clinical practice. The plasmaMATCH trial was designed to assess the clinical utility of using ctDNA testing to select patients for targeted therapies. Methods: The plasmaMATCH trial was an open-label, multi-centre, multi-cohort platform trial, consisting of ctDNA testing in ~1000 patients with advanced BC, with patients recruited into four parallel treatment cohorts with therapies matched to mutations identified in ctDNA (A: ESR1 mutation - extended-dose fulvestrant 500mg every 2 weeks, B: HER2 mutation - neratinib +/- fulvestrant (standard dosing), C: AKT1 in ER positive BC -capivasertib + fulvestrant (standard dosing), D: AKT1 in ER negative BC or PTEN inactivating mutation - capivasertib). A fifth cohort (E) recruited patients with triple negative BC with no actionable mutation to receive olaparib + AZD6738, and will be reported separately. Each cohort had a specific phase II single arm design. ctDNA testing was conducted with two technologies: digital droplet PCR (ddPCR) at a central laboratory prospectively in all patients, and error corrected sequencing with Guardant360 prospectively from part-way through recruitment and retrospectively for the remaining patients. Tumour sequencing from an advanced disease biopsy was conducted retrospectively, not influencing cohort entry. The primary endpoint for Cohorts A-D is confirmed objective response rate by RECIST v1.1. Secondary endpoints include clinical benefit rate, progression-free survival, safety and frequency of mutations identified in ctDNA screening. Results: Entry into ctDNA testing for Cohorts A-D was closed on 26/Apr/2019 with 1044 patients registered. ctDNA screening results were received for 1033 patients (99%), with 142 patients entered into Cohorts A-D (A 84, B 21, C 18, D 19). Agreement between ctDNA digital PCR and sequencing results was high (individual gene level agreement 95.5%-99.4%, kappa 0.89-0.93). Predefined efficacy criteria were met in Cohorts B (neratinib for HER2 mutations) and C (capivasertib for AKT mutations), with exploratory analysis of Cohort D identifying activity of capivasertib in AKT1 mutations (Table 1). Efficacy criteria were not met in Cohort A (extended-dose fulvestrant for ESR1 mutations). Adverse events were consistent with prior reports, with extended-dose fulvestrant well tolerated.