A collection of research papers published by the staff of The Christie NHS Foundation Trust between 1999 to present day. The collection is intended to back date all publications published since 1999. Older papers may be submitted by request to the Kostoris Library.

 

Recent Submissions

  • Advanced small intestine well-differentiated neuroendocrine tumors (WD-SiNET): A survey of practice on 3rd line treatment

    Lamarca, Angela; Cives, M.; de Mestier, L.; Crona, J.; Spada, F.; Oberg, K.; Pavel, M.; Alonso-Gordoa, T.; The Christie NHS Foundation Trust, Manchester, (2021)
    Introduction: Selection of third-line treatment after somatostatin analogues (SSA) and Peptide Receptor Radionuclide Therapy (PRRT) for WD-SiNETs remains challenging. Aim(s): Understand current practice and rationale for decision-making in the 3rd-line setting after SSA and PRRT. Materials and methods: An online survey (replies collected between 5/8/2020 and 21/9/2020) was built. Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. Results: A total of 28 replies; medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from ENETS CoE (57.1%), who followed ENETS guidelines (82.1%). Overall, 3rd-line treatment for WD-SiNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%) or personal experience (22.2%). EVE was likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); irrespective of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was chosen if rapid progression (within 6 months) (WA 3.35/4), Ki-67 10-20% (WA 2.77/4), negative SSTR2 imaging (WA 2.65/4) or high tumor burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-FU (57.7%), FOLFOX (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). Conclusion: Selection of 3rd line therapy is based on multiple factors mainly Ki-67, rate of progression, CS and tumor burden; decisions should be made within a multidisciplinary setting
  • Systemic and intracranial efficacy of brigatinib vs.crizotinib: updated results from the ALTA-1L Trial

    Popat, S.; Kim, H. R.; Ahn, M. J.; Yang, J. C. H.; Han, J. Y.; Hochmair, M.; Lee, K. H.; Delmonte, A.; Campelo, M. R. G.; Kim, D. W.; et al. (2021)
    Background: At ALTA-1L (NCT02737501) first interim analysis (IA1), brigatinib demonstrated superior BIRC-assessed PFS and iPFS vs crizotinib. We report IA2 results, planned at w75% of 198 expected PFS events. Methods: Patients with TKI-naive advanced ALK+ NSCLC were randomized 1:1 to brigatinib 180 mg qd (7-day lead-in at 90 mg) or crizotinib 250 mg bid. Endpoints: Primary, BIRC-assessed PFS (RECIST v1.1); secondary included confirmed ORR and iORR, and iPFS (BIRC). Results: 275 patients were randomized (brigatinib/crizotinib, n¼137/ 138); median age, 58/60 years; prior chemotherapy, 26%/27%; baseline brain metastases (BIRC), 34%/36%; brain radiotherapy, 13%/ 14% (WBRT/SRS balanced across arms). At data cutoff (28 June 2019, median follow-up [brigatinib/crizotinib], 24.9/15.2 months, 150 PFS events): BIRC-assessed PFS HR, 0.49 (95% CI, 0.35e0.68, log-rank P<0.0001); brigatinib mPFS, 24.0 months (95% CI, 18.5eNE) vs crizotinib 11.0 months (9.2e12.9). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31e0.61, median 29.4 vs 9.2 months). OS was immature (total events: 33/37, brigatinib/crizotinib). In patients with baseline brain metastases, PFS HR was 0.25; data were less mature in brigatinib patients without brain metastases. Additional results in Table. Radiological overall disease progression occurred in (brigatinib vs crizotinib) 54 (39%) vs 74 (54%) patients (BIRC) and 50 (36%) vs 84 (61%) (investigator); of these, brain was first site of progression more frequently with crizotinib vs brigatinib: 31 (42%) vs 17 (31%) patients (BIRC); 22 (26%) vs 7 (14%) (investigator). Most common TEAEs grade 3: brigatinib: increased CPK (24.3%) and lipase (14.0%), hypertension (11.8%); crizotinib: increased ALT (10.2%), AST (6.6%), lipase (6.6%). Brigatinib significantly delayed median time to deterioration vs crizotinib for global health score/QoL (log-rank P¼0.0485), emotional and social functioning, fatigue, nausea and vomiting, appetite loss, constipation. Conclusions: Brigatinib demonstrated superior systemic and intracranial efficacy vs crizotinib in all patients with TKInaive ALK+ NSCLC and in patients with baseline brain metastases.
  • Molecular profiling of well-differentiated neuroendocrine tumors: Role of ctDNA

    Lamarca, Angela; Frizziero, Melissa; Barriuso, Jorge; Kapacee, Zainul Abedin; Mansoor, Was; McNamara, Mairead G; Hubner, Richard A; Valle, Juan W; The Christie NHS Foundation Trust, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2021)
    Introduction: Tumor molecular profiling has proven relevant for the clinical management of cancer. Circulating tumor DNA (ctDNA) may be a useful surrogate of tumor tissue when this is insufficient for analysis. Aim(s): Aims: Rate of test failure, detection rate of pathological alterations (PAs) and impact on management. Materials and methods: Patients (pts) with well-differentiated neuroendocrine tumors (WdNETs) underwent ctDNA-based molecular profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly differentiated neuroendocrine carcinoma) were used for comparison. Results: Fifteen pts with WdNET (18 ctDNA samples) included: 8 female (53.33%), median age 63.2 years (range 23.5-86.8). Primary: small bowel (8;53.3%); pancreas (5;33.3%); gastric (1;6.7%) and unknown primary (1;6.7%); grade (G)1 (n=5;33.3%); G2 (9;60.0%) and G3 (1;6.7%); median Ki-67: 5% (range 1-30). Thirty pts with non-WdNETs pts (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs 17.65% in non-WdNETs; p 0.395). Of 13 WdNET samples with successful ctDNA, PAs were detected in 6 (46.15%) (vs 82.14% in non-WdNETs; p 0.018). In WdNETs, PA rate was independent of anti-cancer systemic therapy (2/7;28.57% vs 4/6;66.67%; p 0.286) at time of ctDNA: 4, 1 and 1 samples had 1, 2 and 3 PAs, respectively; these were: CDKN2A mutation (m) (1 sample), CHEK2m (1), TP53m (2), FGFR2amplif (1), IDH2m (1), CTNNB1m (1), NF1m (1), PALB2m (1); nontargetable (0%) or impacted management (0%). There was a trend towards lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs non-WdNETs (mean 26.99); p 0.0584. Conclusion: Although feasible, ctDNA molecular profiling was of limited clinical utility for advanced WdNETs. Identification of PAs and mMAF seem higher in non-WdNETs.
  • Incidence of brain metastases (BMs) and outcomes in patients (pts) with extrapulmonary neuroendocrine neoplasms (EP-NENs)

    Kapacee, Zainul Abedin; Dawod, Mohammed; Allison, Jennifer; Frizziero, Melissa; Chakrabarty, Bipasha; Manoharan, Prakash; McBain, Catherine A; Mansoor, Was; Lamarca, Angela; Hubner, Richard A; et al. (2021)
    Introduction: The incidence, management and outcomes of pts with EP-NENs and BMs are unclear. Aim(s): To investigate outcomes in pts with EP-NENs ± BMs. Materials and methods: A retrospective study of consecutive pts with EP-NENs and BMs treated at a single ENETS CoE was performed. Median (med) overall survival (OS)/survival from BM diagnosis were estimated (Kaplan Meier). Results: Between Aug 04-Feb 20, 730 pts with an EP-NEN diagnosis were identified: med age 64 yrs (15-90); 56% male, 67% had advanced disease (ADVD). In pts with ADVD, the primary NEN site were: small bowel 42%, pancreas 22%, unknown 14%, large bowel 10%, other 5%, stomach 4% and appendix <1%; 37%, 30% and 30% pts had grade (G)1, 2 and 3 EP-NENs respectively (no grading 3%). Med OS for pts with ADVD G1, 2 and 3 EP-NENs without BMs were 95.8 (95% C.I 77.0-177.1), 61.7 (95% C.I 50.1-124.4) and 11.3 (95% C.I 9.3-14.4) months (mo) respectively. 17 pts (2.3%) developed BMs; 2 at initial diagnosis, 15 metachronously; 5 pts (29%) had a solitary BM, 12 (71%) had multiple BMs. The primary sites of origin were: unknown 41%, oesophagus 18%, pancreas 17%, small bowel 12%, cervix 6% and bladder 6%; 6%, 24% and 70% had G1, G2 and G3 EP-NENs respectively. Most common presenting symptoms of pts with BMs were limb weakness and cognitive impairment. Pts with BMs received high dose steroids and best supportive care (35%), whole brain radiotherapy with steroids (29%), surgery (18%) and localised radiotherapy (6%). Med OS for pts with G1+2 EP-NENs and BMs was not reached. Med OS in pts with G3 EP-NENs and BMs was 9.0 mo (95% CI 6.0-12.1); med survival from BM diagnosis was 2.0 mo (95% CI 0.0-4.4). Conclusion: BMs in pts with EP-NENs are rare, predominant in G3 NENs, and have a poor prognosis. Improved therapeutic options are needed.
  • Assessing the management of bone metastases in patients diagnosed with neuroendocrine neoplasms: Re-audit of clinical practice

    Garcia-Torralba, E; Lim, Kok Haw Jonathan; Barriuso, Jorge; McNamara, Mairead G; Hubner, Richard A; Mansoor, Was; Valle, Juan W; Lamarca, Angela; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, (2021)
    Introduction: There remains no global consensus on the optimal management of bone metastases in patients with neuroendocrine neoplasms (BM-NEN). Aim(s): To re-audit the clinical management of BM-NEN following the incorporation of institutional guidelines (TC-BM Guid) established in 2018 (PMID: 31639796). Materials and methods: Retrospective study of all patients with BM-NEN diagnosed from Jan-Dec 2019 following TC-BM Guid. Characteristics of BM-NEN and treatment received were evaluated against TC-BM Guid. Statistical analysis was performed using STATA v14. Results: Of 354 patients, 40 (11%) had BM (gastrointestinal: 53%, N=21; lung: 15%, N=6; unknown primary: 12%, N=5; other: 20%, N=8). BM were “widespread” in 80% (N=32). Compared to the cohort prior to TC-BM Guid implementation (2002-2018, N=85), incidence of symptoms (any), pain/hypercalcemia, and skeletal-related events were lower (45%, N=18 vs 78%, N=66; 40%, N=16 vs 64%, N=54; 13%, N=5 vs 20%, N=17, respectively). Use of analgesia for symptomatic BMs (80%, N=32 vs 44%, N=37) and use of bisphosphonates (33%, N=13 vs 22%, N=19) were higher. Use of radiotherapy and surgery were similar (23%, N=9 and 3%, N=1 respectively). The re-audit showed that management adhered to TC-BM Guid in the majority of patients (95%, N=38), including 4 patients who received best supportive care due to poor performance status (PS) and short prognosis (<3 months), which was not previously detailed in the guidelines. Conclusion: TC-BM Guid are deliverable, and current management of BM-NEN mostly adhered to these. Following this, TC-BM Guid were updated to reflect recommendations for symptomatic management only (best supportive care) for patients with poor PS/short life-expectancy.
  • Empowerment survey for patients with neuroendocrine tumors - A pilot study in Spanish population

    Hernando, J.; Sampedro-Nunez, M.; de Nova, J. L. M.; Trivino, E. M.; Vazquez, G.; Hernandez, X.; Fernandez, E.; Cusido, E.; Guaras, B.; Olmo-Garcia, M.; et al. (2021)
    Introduction: Quality of life is very important in patients with neuroendocrine tumors (NET), but other aspects such as satisfaction and empowerment of patients have been less studied. In Spain, there is a lack of validated cancer empowerment questionnaires. Aim(s): The aim of the present study is to conduct a pilot test with an online survey of patient’s empowerment in NET in the Spanish population. Materials and methods: The Spanish survey was designed with previous general health empowerment questionnaires (Health Education Impact Questionnaire, Maunsell 2014), internal hospital satisfaction scores, and direct feedback from NET-España Patient Advocacy group. The final survey was approved by GETNE Academy taskforce. Anonymous online survey was conducted between August and November 2020 in NET patients from NET-España association in Spain. Results: 67 NET patients answered (95.5% completed all questions). Scale internal consistency was good. Most patients had medium or high levels of general empowerment-related to NET. We identified two main areas where most patients had a low level of empowerment, including psychological support and patient's self-management groups. Specific questions related to NET characteristics and NET-specific treatments reflect the situation of NET management in Spain and reveals a high knowledge about the biology of the disease and current available therapies. Conclusion: This NET empowerment survey is understandable, easy to answer, and useful to measure the empowerment of the Spanish population with NET. After this initial pilot experience, a larger study in an unselected population is necessary for the validation of this questionnaire.
  • To determine the true incidence of brain metastases in atypical lung neuroendocrine tumors and explore factors that increase the risk of intracranial disease

    Jones, J; Spurgeon, Laura; Shaheen, Fadhel; Lewis, Alexandra R; Mansoor, Was; Khan, Adeel; The Christie NHS Foundation Trust, Manchester (2021)
    Introduction: Lung neuroendocrine tumors (NETs) make up 25% of all NETs. Typical carcinoid (TC) and atypical carcinoid (AC) account for 2% and 0.2% of all lung NETs respectively, and AC tend to be more aggressive. Although both can metastasise, AC are more likely; common sites include bone and liver. Currently, brain imaging is not included in the work-up of TC/AC, as <5% of cases are thought to develop brain metastases (BM). However, evidence suggests this may be an underestimate. Identifying BM would inform management and could improve prognosis. Thus, evaluating the incidence in TC/AC is needed to ascertain whether there is justification for baseline brain imaging. Furthermore, Ki-67 could be useful as a predictive tool. Aim(s): To review the incidence of BM in TC/AC to determine whether there is justification for routine brain imaging and to explore factors which could increase the risk of BM. Materials and methods: Single site, retrospective analysis of 287 patients with TC/AC over a 13-year period. Incidence of BM (as detected on CT/MRI), at diagnosis or during the course of the disease, was reviewed. Results: None of the 215 TC patients developed BM, whereas 8 out of 72 (11.1%) with AC did; 50% of these were present at diagnosis. 13.04% of AC with BM had evidence of both bone and liver involvement. 75% of AC with BM had Ki-67 expression >15%. Conclusion: Over 10% of the AC developed BM, half of which were present at diagnosis. This provides convincing evidence of the need for baseline brain imaging in AC, particularly for patients with Ki-67 expression >15% or with bone and liver involvement, as these factors were associated with increased risk. Early detection and treatment of BM can improve outcomes
  • Predominantly solid hemangioblastoma presenting as an extra-axial cerebellopontine angle lesion

    Ahmed, Gasim; Sheikh, U.; Masri, S.; Joseph, J.; Sonwalker, H.; Radiology, Lancashire Teaching Hospital Foundation Trust, Presto (2021)
    Hemangioblastomas (HBs) are typically intra-axial, highly vascular tumors of the central nervous system and account for up to 2.5% of all intracranial tumors and up to 12% of posterior fossa neoplasms. Extra-axial HBs are rarely described in the literature. The radiological appearances of cerebellopontine angle (CPA) extra-axial HB can lead to a diagnostic conundrum as they may mimic the appearance of dural metastasis, vestibular schwannoma, or meningioma. Here, we describe a patient who presented with an extra-axial CPA HB and explore the literature of the condition.
  • Outcome of Stage IV completely necrotic wilms tumour and local stage III treated according to the SIOP 2001 protocol

    Dávila Fajardo, R.; Furtwängler, R.; van Grotel, M.; van Tinteren, H.; Pasqualini, C.; Pritchard-Jones, K.; Al-Saadi, R.; de Camargo, B.; Ramírez Villar, G. L.; Graf, N.; et al. (2021)
    Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP- Renal Tumour Study Group (SIOP-RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. Methods and materials: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. Results: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1-151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. Conclusions: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP-RTSG 2016 UMBRELLA protocol.
  • Developing tumor radiosensitivity signatures using LncRNAs

    Khan, Mairah T; Yang, Lingjian; More, Elisabet; Irlam-Jones, Joely J; Valentine, Helen R; Hoskin, Peter J; Choudhury, Ananya; West, Catharine M L; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester M20 4BX (2021)
    Long non-coding RNAs (lncRNAs) are involved in diverse biological processes, including DNA damage repair, and are of interest as potential biomarkers of radiosensitivity. We investigated whether lncRNA radiosensitivity signatures could be derived for use in cancer patients treated with radiotherapy. Signature development involved radiosensitivity measurements for cell lines and primary tumor samples, and patient outcome after radiotherapy. A 10-lncRNA signature trained on radiosensitivity measurements in bladder cell lines showed a trend towards independent validation. In multivariable analyses, patients with tumors classified as radioresistant by the lncRNA signature had poorer local relapse-free survival (P = 0.065) in 151 patients with muscle-invasive bladder cancer who underwent radiotherapy. An mRNA-based radiosensitivity index signature performed similarly to the lncRNA bladder signature for local relapse-free survival (P = 0.055). Pathway analysis showed the lncRNA signature associated with molecular processes involved in radiation responses. Knockdown of one of the lncRNAs in the signature showed a modest increase in radiosensitivity in one cell line. An alternative approach involved training on primary cervical tumor radiosensitivity or local control after radiotherapy. Both approaches failed to generate a cervix lncRNA radiosensitivity signature, which was attributed to the age of samples in our cohorts. Our work highlights challenges in validating lncRNA signatures as biomarkers in archival tissue from radiotherapy cohorts, but supports continued investigation of lncRNAs for a role in radiosensitivity.
  • Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer

    Garassino, M. C.; Paz-Ares, L.; Hui, R.; Faivre-Finn, Corinne; Spira, A.; Planchard, D.; Özgüroğlu, M.; Daniel, D.; Vicente, D.; Murakami, S.; et al. (2021)
    Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).
  • A position statement on the utility of interval imaging in standard of care brain tumour management: defining the evidence gap and opportunities for future research

    Booth, T. C.; Thompson, G.; Bulbeck, H.; Boele, F.; Buckley, C.; Cardoso, J.; Dos Santos Canas, L.; Jenkinson, D.; Ashkan, K.; Kreindler, J.; et al. (2021)
    Objectiv e: To summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics. Methods: Experts in 'interval imaging' (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed. Results: Meningioma and glioma were identified as priorities for interval imaging utility analysis. The "monitoring biomarkers" most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value. Conclusion: Evidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management.
  • Randomised controlled trial evidence questions the assumption that pulmonary metastasectomy benefits patients with colorectal cancer

    Batchelor, T.; Hasan, Jurjees; Macbeth, F.; Shackcloth, M.; Treasure, T.; Bristol Royal Infirmary, Bristol, UK. (2021)
    Pulmonary metastasectomy for sarcoma is surgery without proven benefit, and in the light of a randomized controlled trial examining pulmonary metastasectomy in colorectal cancer, it should be questioned.
  • Safety and activity of autologous T cells with enhanced NY-ESO-1-specific T-cell receptor (GSK3377794) in HLA-a*02(+) previously-treated and - untreated patients with advanced metastatic/unresectable synovial sarcoma: A master protocol study design (IGNYTE-ESO)

    D'Angelo, S. P.; Blay, J. Y.; Chow, W. A.; Demetri, G. D.; Thistlethwaite, Fiona C; Sen, S.; Razak, A. R. A.; Haanen, J.; Noujaim, J. C.; Johnson, M. L.; et al. (2020)
    Background: T cells modified to target NY-ESO-1 have shown encouraging activity in HLA-A*02+ patients with NY-ESO-1–positive synovial sarcoma. NY-ESO-1 is a cancer/testis antigen that is expressed across multiple tumor types and highly expressed in synovial sarcoma. NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR able to recognize NY-ESO-1 epitope in complex with HLA-A*02. Ongoing trials are evaluating GSK3377794 in multiple solid tumors and multiple myeloma. Methods: This study (NCT03967223) uses a Master Protocol design that allows investigation of GSK3377794 in multiple tumor types under the same protocol in separate substudies. The first two are single-arm substudies in patients with advanced metastatic or unresectable synovial sarcoma: treatment-naïve (1st line [1L], substudy 1; n = 10 planned) and progressing after anthracycline-based chemotherapy (2L+, substudy 2; n = 55 planned). Patients must be aged ≥10 years, have adequate organ function, ECOG performance status 0–1, measurable disease, and no central nervous system metastases. Excluded prior treatments include gene therapy with an integrating vector or NY-ESO-1–specific T cells, vaccine or targeting antibody, or allogeneic stem cell transplant. Patients will undergo leukapheresis and manufacture of GSK3377794; lymphodepletion then GSK3377794 infusion, followed by safety and disease assessments; and long-term follow-up for 15 years (under a separate protocol). The primary objective of substudy 2 is overall response rate per RECIST v1.1 by central independent review. Secondary objectives include time to response, duration of response, disease control rate, progression-free survival, overall survival, plus safety and tolerability. Exploratory objectives include assessment of the correlation of T-cell persistence with safety, clinical responses, and infused T-cell phenotype. Evaluation of quality of life and daily functioning of patients will also be assessed. Enrollment began in December 2019. These data are presented on behalf of the original authors with their permission. A similar presentation (P453) was presented at the SITC Annual Meeting, National Harbor, MD, USA, Nov 6–10, 2019. Funding: GlaxoSmithKline (208467) Clinical trial information: NCT03967223.
  • DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola plus ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014)

    Oza, A. M.; Pierce, A.; Lau, A.; Kurian, N.; Parr, G.; Lao-Sirieix, S. H.; Ah-See, M. L. W.; Dean, Emma J; Loembe, B.; Princess Margaret Cancer Centre, Toronto, ON, Canada (2020)
    Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of platinum-based chemotherapy (CR/PR or SD). The primary endpoint is to assess the efficacy of maintenance ola monotherapy and cer+ola combination therapy compared with placebo by PFS using blinded, independent central review. Secondary endpoints are overall survival, PFS2, ORR, DoR, safety and tolerability. Enrolment is planned to start in April 2020.
  • Phase I study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting DLL3, in patients with small cell lung cancer (SCLC)

    Owonikoko, T. K.; Borghaei, H.; Champiat, S.; Paz-Ares, L. G.; Govindan, R.; Boyer, M. J.; Johnson, M. L.; Udagawa, H.; Hummel, H. D.; Salgia, R.; et al. (2020)
    Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients.
  • NAPOLI-3: An open-label, randomized, phase III study of first-line liposomal irinotecan+5-fluorouracil/leucovorin plus oxaliplatin versus nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma

    Wainberg, Z. A.; Bekaii-Saab, T. S.; Hubner, Richard A; Macarulla, T.; Paulson, A. S.; Van Cutsem, E.; Maxwell, F.; Moore, Y.; Wang, H. T.; Zhang, B.; et al. (2020)
    Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up).
  • Genomic profiles of de novo high- and low-volume metastatic prostate cancer: results from a 2-stage feasibility and prevalence study in the STAMPEDE Trial

    Gilson, C.; Ingleby, F.; Gilbert, D. C.; Parry, M. A.; Atako, N. B.; Ali, Adnan; Hoyle, Alex P; Clarke, Noel W; Gannon, M.; Wanstall, C.; et al. (2020)
    PURPOSE The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor (AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences (AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.
  • Quantification of the preclinical and clinical relationship between pRAD50 and efficacy after treatment with the ATR inhibitor ceralasertib (AZD6738)

    Yates, J. W. T.; Wilson, Z.; Jones, G. N.; Harrington, K.; Krebs, Matthew G; Dillon, M.; Pierce, A. J.; Dean, E.; Lau, A.; AstraZeneca R&D, Saffron Walden (2020)
    Ceralasertib is a potent and selective ATP competitive inhibitor of ataxia telangiectasia and Rad3 related (ATR) in clinical development as monotherapy and in combination with olaparib (Lynparza) and durvalumab (Imfinzi) in patients with advanced solid tumors. Paired pre- and on-treatment tumour samples from seven patients during ceralasertib monotherapy in Phase 1 studies (NCT02223923, NCT02264678), all ATM expressing, showed increases in pRAD50 on treatment. This study aimed to robustly understand the relationship between ceralasertib pharmacokinetics, pRAD50 (pSer635) induction by immunohistochemistry and anti-tumor efficacy, in mouse xenografted models; to enable interpretation of paired clinical tumour samples. First, in vivo data were generated in a range of xenografted models (HBCx9 [TNBC, Xentech], HCC1806 [BC], OCI-Ly19 [DLBCL] and OE21 [HNSCC]) and NSCLC and HNSCC PDX models at Champions). Mouse ceralasertib doses (6.25 - 25mg/kg BID and 50mg/kg QD) reflected the observed free drug exposure achieved at clinical doses. In pharmacodynamic studies, animals were dosed continuously for 5 days, with PKPD endpoints being assessed on the 5th day. In anti-tumor studies, animals were randomized and treated for at least 28 days continuously. Increases in pRAD50 on treatment, versus control, were both dose and time dependent. There was a wide range of baseline pRAD50 expression (H-Scores ranging from 2 to 48) but the fold increase was consistent; a 3-fold increase being seen at the highest dose. Similarly, the anti-tumor activity was dose dependent with a range of sensitivities being observed across the models; the OCI-Ly19 model was most sensitive with %TGI ranging 43% to 104%. Mathematical modelling confirmed a consistent PKPD relationship for the fold increase of pRAD50. The effect was not saturated at the tested drug exposures and the slope relating drug in plasma to fold pRAD50 increases was estimated to be 0.75 uM-1. Modelling also demonstrated a relationship between pRAD50 and the observed anti-tumor activity, across all models. Of note, the fold induction required for efficacy increased with the baseline pRAD50 The hypothesis for this observation is that the baseline pRAD50 H-score is a functional measure of DDR signaling and so low pRAD50 may be indicative of impaired signaling and thus sensitivity to inhibition of DDR signaling. The results demonstrate the utility of generating PKPD-Efficacy relationships across a range of patient relevant xenografts and PDXs. Here, a marker of ATR inhibitor pharmacology, pRAD50, has been related to anti-tumor activity increasing our understanding of predictive markers of drug sensitivity. Clinical translation of these findings is being tested in a Phase I study, where patients provide paired tumour biopsies pre-treatment and following ceralasertib monotherapy dosing
  • The natural history of fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA)

    Goyal, L.; Lamarca, Angela; Strickler, J. H.; Cecchini, M.; Ahn, D. H.; Baiev, I.; Boileve, A.; Tazdait, M.; Hannan, L. M.; Jia, J. Q.; et al. (2020)
    Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.

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