Now showing items 21-40 of 12098

    • 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.
    • The Hodgkin lymphoma international study for individual care (HoLISTIC): Enhancing decision making in pediatric and adult Hodgkin lymphoma (HL)

      Parsons, S. K.; Rodday, A. M.; Scharman, C.; Andre, M.; Federico, M.; Friedberg, J. W.; Friedman, D. L.; Gallamini, A.; Hay, A. E.; Hoskin, P.; et al. (2020)
      Background: Decision making in HL is complicated by clinical trial results that differ, a growing range of treatment options, and the absence of ideal, objective information on long term outcomes from modern therapy. Methods: We formed an international consortium, HoLISTIC, consisting of 50+ pediatric & adult HL providers, decision scientists, statisticians, epidemiologists, and patient (pt) advocates and are creating a data repository of individual pt data (IPD) from 16 contemporary, pediatric & adult clinical trials for newly diagnosed pts with HL, and 6 large HL registries/survivorship cohorts, the latter enriched with LE data (Table). We will enhance our prior decision model (DM) from group-level data (Parsons S et al. B J Haem 2018) to establish a dynamic HL DM from IPD. Using statistical and simulation modeling of IPD, the enhanced DM will project outcomes of interest, including quality-adjusted life years (QALYs), reflecting both mortality and morbidity. Results will be validated and calibrated against prominent external cohorts (e.g., St. Jude LIFE Cohort, Dutch HL registry). The DM then will be converted to a web-based platform that we will test and evaluate among HL providers and pts at the point of care. Results: To date, we have harmonized IPD from 10 trials (~8,000 HL pts), ranging in size from 165-1925 pts. At diagnosis, median age was 26 y (IQR 18-38); 51.5% were male. 43% had B symptoms, 34% had mediastinal bulk, and 79% had nodular sclerosis histology. Median follow up was 5.0 y (IQR 3.5-7.4). IPD harmonization is ongoing, which will be followed by creation of the enhanced DM. Conclusions: HoLISTIC capitalizes on a multidisciplinary pediatric & adult oncology collaborative, harmonizing extensive IPD by linking data from clinical trials and real world registries/survivorship cohorts. This work will inform questions about the influence of Tx options on both acute and potential long term events and how those options align with pt values and preferences.
    • Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas

      Hapuarachi, Sonal B; Dawod, Mohammed; Weaver, Jamie M; Shaheen, Fadhel; Khan, Adeel; Hubner, Richard A; Waddell, Tom; Mansoor, Was; Christie NHS Foundation Trust, Manchester (2020)
      Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.
    • Viral vectored vaccines for prostate cancer

      Hill, A. V. S.; Tuthill, M.; Cappuccini, F.; Carter, L.; Pollock, E.; Poulton, I.; Verrill, C.; Evans, T.; Marshall, M.; Gillessen, Silke; et al. (2021)
      New therapeutic antigen-specific approaches are required to generate and sustain therapeutic immune responses against tumour specific antigens in cancer. Based on twenty years of experience with attempt to maximise the induction of potent T cell responses against infectious pathogens in humans we have begun to assess the utility of non-replicating viral vectors in cancer. Two trials in prostate cancer patients have completed enrolment and another in lung cancer is planned. We have reported efficacy data for a novel vaccine based on two replication-deficient viruses, chimpanzee adenovirus (ChAdOx1) and MVA, targeting an oncofetal self-antigen 5T4, administered as a single agent and in combination with anti-PD-1 in mouse tumour models. Based on recently reported encouraging safety and exceptional T cell immunogenicity in a phase I “VANCE” study (NCT02390063) of me with localised prostate cancer, the phase I/II trial, ADVANCE (NCT03815942) was undertaken to test vaccine safety and efficacy in combination with PD-1 blockade in metastatic prostate castrate-resistant cancer (mCPRC). We find a satisfactory safety profile for the use of these viral vectored vaccines with anti-PD1 in mCRPC patients but with lower immunogenicity than in localised prostate cancer patients. However, an encouraging response rate, as measured the reduction in PSA levels by 50%, was observed in this trial and options for enhancing immunogenicity and efficacy further will be discussed.
    • Updated integrated analysis of the efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small-cell lung cancer

      Dziadziuszko, R.; Krebs, Matthew G; De Braud, F.; Siena, S.; Drilon, A.; Doebele, R. C.; Patel, M. R.; Cho, B. C.; Liu, S. V.; Ahn, M. J.; et al. (2021)
      Purpose: Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in ROS1 fusion-positive NSCLC. Methods: The efficacy-evaluable population included adults with locally advanced or metastatic ROS1 fusion-positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety. Results: In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found. Conclusion: Entrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion-positive NSCLC, including patients with CNS metastases.
    • Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study

      Abbosh, C.; Frankell, A.; Garnett, A.; Harrison, T.; Weichert, M.; Licon, A.; Veeriah, S.; Daber, B.; Moreau, M.; Chesh, A.; et al. (2020)
      Introduction Minimal residual disease (MRD) detection in solid tumors describes isolation of circulating tumor DNA (ctDNA) molecules in plasma following definitive treatment of a cancer. Detection of MRD following surgical tumor excision categorizes patients as high risk for disease recurrence. Establishing an MRD approach to treating early-stage NSCLC will facilitate escalation of standard of care (SoC) treatment only in patients destined to relapse from their cancer and overcome challenges associated with conventional adjuvant drug-trial design. Here, we present data from the lung TRACERx study where patients with early-stage NSCLC underwent phylogenetic ctDNA profiling following resection. Methods Patient specific anchored-multiplex PCR (AMP) enrichment panels were generated for 78 lung TRACERx patients who underwent surgery for stage I-III NSCLC; 608 plasma samples were analyzed. Extensive patient-specific cfDNA enrichment panels targeted a median of 196 (range 72 to 482) clonal and subclonal variants detected in primary tumor tissue by multi-region exome sequencing. A novel MRD-caller controlled and estimated background sequencing error to maximize ctDNA detection at low mutant allele frequencies (MAFs). Analytical validation experiments benchmarked assay performance. Results Analytical validation of a 50-variant AMP-MRD assay demonstrated a sensitivity of 89% for mutant DNA at a MAF of 0.008% (with 25ng of DNA input into the assay), specificity was 100% experimentally and 99.9% (95% CI: 99.67 to 99.99%) modelled in-silico. 45 patients suffered relapse of their primary NSCLC; ctDNA was detected at or before clinical relapse in 37 of 45 patients. In these 37 patients the median ctDNA lead-time (time from ctDNA detection to clinical relapse) was 151 days (range 0 to 984 days) and the median time to relapse from surgery was 413 days (range 41 to 1242 days). In 10 of 10 patients who developed second primary cancers during follow-up no ctDNA was detected, reflecting specificity of the MRD assay toward the primary tumor. In 23 patients who remained relapse-free during a median of 1184 days of study follow-up, ctDNA was detected in 1 of 199 time-points analyzed. Analysis of SoC adjuvant surveillance imaging (CT, PET-CT or MRI, 220 encounters) revealed examples of MRD positive patients where SoC radiological surveillance was negative for impending relapse. Through application of large cfDNA enrichment panels targeting up to 483 variants per patient we observed dynamic changes in clonal composition and copy-number status prior to NSCLC relapse, categorized relapse as monoclonal or polyclonal and identified distinct subclonal dynamics during systemic intervention for disease recurrence. Conclusions ctDNA is an adjuvant biomarker capable of both detecting MRD following surgery and defining the clonality of relapsing disease. These data pave the way for clinical trials predicated on escalation of adjuvant standard of care in NSCLC patients who exhibit MRD positive status following surgery.
    • The EurOPDX Research Infrastructure: Supporting European and worldwide cancer research with patient-derived xenografts

      Vinolo, E.; Arribas, J.; Bertotti, A.; Bruna, A.; Byrne, A. T.; Clarke, Robert B; Conte, N.; de Jong, S.; Decaudin, D.; Dudova, Z.; et al. (2020)
      Counteracting high failure rates in oncology drug development and improving therapeutic management of cancer patients requires preclinical models that can account for the complexity and heterogeneity of human tumors. Patient-derived cancer xenografts (PDXs) maintain histopathological features and genetic profiles of the original patient tumors and are increasingly recognized as reliable models to predict treatment efficacy and discover sensitivity and resistance biomarkers with immediate clinical relevance.Launched in 2013, the EurOPDX Consortium now gathers 18 academic research institutions throughout Europe and in the US (www.europdx.eu). The goal of the Consortium is to maximize exploitation of PDXs and other patient-derived models for cancer research by: (i) integrating institutional collections into a multicentre repository; (ii) defining common standards to improve the quality and reproducibility of oncology preclinical data; (iii) sharing models within and outside the consortium to perform collaborative precision oncology “xenopatient” trials. Building on its first successes, EurOPDX is now teaming up with other key academic and SME partners in a four-year project to build the “EurOPDX Distributed Infrastructure for Research on patient-derived Xenografts" (EDIReX project, Horizon 2020 grant no. 731105).This new cutting-edge European infrastructure offers access to PDX resources for academic and industrial cancer researchers through 6 state-of-the-art installations or “nodes”. We will present the specific objectives of the project, including our work towards standardization and optimization of biobanking, quality control and data tracking, and the performance of in vivo drug efficacy experiments. Access to the resource, including the distribution of cryopreserved samples from established models, the structured biobanking of user-developed models and the performance of drug efficacy studies, is offered through a grant application system which last deadline is planned mid-June 2020. Selection of the models by users and browsing of PDXs annotation data is made possible thanks to the newly-developed EurOPDX Data Portal (dataportal.europdx.eu), which will display approximately 1,000 models by April 2020 (including 700+ models of colorectal cancer, 80+ gastric and 80+ breast cancer models).We aim to improve preclinical and translational cancer research and promote innovation in oncology by integrating a European PDX repository and facilitating access to this much-needed resource for European and worldwide researchers.
    • Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer

      Skwarski, M.; McGowan, D. R.; Belcher, E.; Di Chiara, F.; Stavroulias, D.; McCole, M. G.; Derham, J.; Chu, K. Y.; Teoh, E.; Chauhan, J.; et al. (2021)
      Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). Patients and methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was perf0rmed. Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. Conclusions: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
    • Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers

      Marcinkute, R.; Woodward, E. R.; Gandhi, A.; Howell, Sacha J; Crosbie, E. J.; Wissely, J.; Harvey, J.; Highton, L.; Murphy, J.; Holland, C.; et al. (2021)
      Background: Women testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers. Methods: Women were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk. Results: In total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01-24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO-10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%. Conclusion: Over a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.
    • Improving prostate cancer care through the 'outlier process': a national quality improvement workshop

      Nossiter, J.; Morris, M.; Parry, M.; Sujenthiran, A.; Aggarwal, A.; Cathcart, P.; Payne, H.; Clarke, Noel W; van der Meulen, J.; Clinical Effectiveness Unit, Royal College of Surgeons of England, London (2020)
      Background The National Prostate Cancer Audit (NPCA) reports publicly performance indicators for all hospitals in England and Wales providing radical prostate cancer treatment, identifying those with results that fall outside the ‘accepted range’ as ‘potential negative outliers’. Hospitals with outlying results are requested to provide a formal response. This ‘outlier process’, targeting a limited number of hospitals, mirrors a ‘high-risk approach’ of preventing poor quality care in contrast to a ‘population approach’ that would target all hospitals. We invited clinicians to a national workshop to learn how the outlier process contributes to quality improvement. Methods The workshop started with presentations on reducing the ‘toxicity’ of radical prostate cancer treatment. Then, clinicians from three hospitals identified as outliers shared their experience of the process and the changes in practice they had made as a result. We collected data in three ways. First, an online platform was used to gather comments from participants during the workshop. Second, a number of participants were interviewed about the outlier process as a means to improve quality of care. Third, feedback was sought after the workshop from all participants. Responses were collated and analysed for themes. Results Sixty-nine clinicians attended including urologists, oncologists, radiographers and nurses, representing a spread of hospitals across England and Wales. There were 6 interviews, 21 online comments and 31 responses after the workshop. The clinicians representing outlying hospitals highlighted the negative (stigma, work load, negative impact on reputation) and the positive impact (detailed review of procedures, implementation of targeted approaches) of the outlier process. Participants felt that sharing experiences of outlying hospitals helps others to improve. They also suggested a ‘buddy system’ between better and worse performing hospitals. Many highlighted the importance of ‘networks’ to share experiences, either good or bad, as a vehicle for improving practice. Discussion The outlier process was generally accepted as a possible mechanism to improve practice. However, participants indicated that effective dissemination is key to ensuring that identifying poor outcomes in some hospitals (e.g. high-risk approach) can stimulate country-wide quality improvement (population approach).
    • SARS-CoV-2 infection and adverse events in patients with cancer receiving immune checkpoint inhibitors: an observational prospective study

      Mandala, M.; Lorigan, Paul C; De Luca, M.; Bianchetti, A.; Merelli, B.; Bettini, A. C.; Bonomi, L.; Nahm, Sharon; Vitale, M. G.; Negrini, G.; et al. (2021)
      Background: In ambulatory patients with cancer with asymptomatic or pauci-symptomatic SARS-CoV-2 infection, the safety of targeted therapies (TTs), chemotherapy (CT) or immune checkpoint inhibitors (ICIs) therapy is still unknown. Material and methods: From the start of the first epidemic wave of SARS-CoV-2 in Bergamo, Italy, we have prospectively screened all consecutive outpatients who presented for treatment to the Oncology Division of the Papa Giovanni XXIII Hospital, Bergamo for SARS-CoV-2 antigen expression. We identified patients treated with ICIs and compared these to patients with the same cancer subtypes treated with TTs or CT. Results: Between March 5 and May 18, 293 consecutive patients (49% melanoma, 34% non-small cell lung cancer, 9% renal cell carcinoma, 8% other) were included in this study: 159 (54%), 50 (17%) and 84 (29%) received ICIs, CT or TTs, respectively. Overall 89 patients (30.0%) were SARS-CoV-2 positive. Mortality of SARS-CoV-2-positive patients was statistically significantly higher compared with SARS-CoV-2 negative patients (8/89 vs 3/204, respectively, Fisher's exact test p=0.004). All deaths were due to COVID-19. Serious adverse events (SAEs) were more frequent in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative cases (Cochran-Mantel-Haenszel (CMH) test p=0.0008). The incidence of SAEs in SARS-CoV-2 positive compared with SARS-CoV-2 negative patients was similar in ICI and CT patients (17.3% and 3.7% for positive and negative patients in ICIs and 15.4% and 2.7% in CT, Breslow-Day test p=0.891). No COVID-19-related SAEs were observed in the TTs patients. Conclusions: The incidence of SAEs was higher for SARS-CoV-2-positive patients treated with ICIs and CT, mostly in advanced disease. No SAEs were observed in patients treated with TTs. SAEs were COVID-19 related rather than treatment related. Treatment with ICIs does not appear to significantly increase risk of SAEs compared with CT. This information should be considered when determining treatment options for patients.
    • A phase II study (TACTI-002) of eftilagimod alpha (a soluble LAG-3 protein) with pembrolizumab in PD-l1 unselected patients with metastatic non-small cell lung(NSCLC) or head and neck carcinoma(HNSCC)

      Krebs, Matthew G; Majem, M.; Felip, E.; Forster, M.; Doger, B.; Clay, T.; Carcereny, E.; Peguero, J.; Horn, L.; Bajaj, P.; et al. (2020)
      Background Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment may lead to stronger anti-tumor responses in combination with pembrolizumab than observed with pembrolizumab alone. We report results from stage 1 of all parts of the study (NCT03625323). Methods Patients (pts) with unselected PD-L1 expression were recruited into 3 cohorts: part A; 1st line, immunotherapy naïve NSCLC; part B; 2nd line, immunotherapy refractory NSCLC and part C; 2nd line immunotherapy naive HNSCC. The study uses a Simon’s 2-stage design, with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Fifty-eight (58) pts were recruited into stage 1. Up to additional 51 pts will be recruited if a pre-specified ORR threshold is met for the respective part. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles; pembrolizumab is administered at 200 mg intravenous infusion every 3 wks for up to 2 yrs. The study was approved by ethic committees and institutional review boards. Results Between Mar 2019 and Jul 2020 88 pts were enrolled. The median age was 67 yrs (range 53-84) and 70% were male. ECOG PS 0:1 was 42% and 58% respectively. Pts from all PD-L1 tumor expression subgroups were recruited. Pts received a median of 4 (1-25) pembrolizumab and 5.5 (1-22) efti administrations. The most common (≥ 15%) treatment emergent adverse events (TEAEs) were asthenia (28%), cough (27%), decreased appetite (22%), dyspnea (21%), fatigue (18%) and diarrhea (15%). Three (3) pts discontinued due to treatment related AEs. The ORR (acc. to iRECIST) of the 58 patients enrolled into stage 1 is shown in (table1). PK profiles after the first or repeated efti dosing were in line with previous studies, with a mean Cmax at7 ng/ml reached ≤ 24h. Circulating TH1 biomarkers 2 weeks after the last efti administration were increased (3 months vs. baseline) by a mean 61% and 209% for CXCL10 (Student paired t-test, p=0.02, n=31) and IFN-γ(p= 0.02, n=19), respectively. Conclusions Efti plus pembrolizumab is safe and shows encouraging antitumor responses in NSCLC and HNSCC patients
    • AMG 757,a half-life extended bispecific t-cell engager (bite (r)) immune therapy against DLL3 in SCLC: phase 1 interim results

      Borghaei, H.; Boyer, M.; Johnson, M.; Govindan, R.; Rodrigues, L. P. A.; Blackhall, Fiona H; Boosman, R.; Champiat, S.; Hummel, H. D.; Lai, W. V.; et al. (2020)
      Background Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in small cell lung cancer (SCLC) and minimally expressed in normal tissues.1 AMG 757, a half-life extended BiTE® immune therapy, binds to DLL3 on tumor cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. We report initial safety and efficacy from the ongoing phase 1 study of AMG 757 in patients with SCLC. Methods AMG 757 was administered intravenously every two weeks (with/without step dose) at doses of 0.003–3.0 mg. Eligible patients had SCLC that progressed or recurred following ≥1 platinum-based regimen. Antitumor activity was assessed using modified RECIST 1.1. The study was approved by the Ethics Board at participating institutions. Results As of 1 June 2020, safety and efficacy data are available for 31 patients enrolled at the first seven dose levels (DL) with median age, 63 (44–74) years; ECOG PS: 0–1, n=30 (96.8%); median prior lines, 2.0 (1–6); and previous PD-1/PD-L1 treatment: n=12 (38.7%). Median treatment duration was 6.1 (0.1–59.4) weeks. Treatment-emergent adverse events (AEs) were reported for 30 (96.8%) patients. AMG 757-related AEs occurred in 25 (80.6%) patients, including 5 (16.1%) that were grade ≥3 and one (3.2%) grade 5 (pneumonitis in DL5 [0.3 mg]). Three AEs (dyspnea, pneumonitis, fatigue) led to treatment discontinuation. The most common AE was cytokine release syndrome (CRS), which was reported in 11 (35.5%) patients. CRS AEs were grade 1–2, consisted mainly of fever with/without hypotension, and occurred mostly within 24 hours of the first or second dose of AMG 757. CRS events were reversible, did not lead to treatment interruption or discontinuation, and were managed with supportive care, corticosteroids, and/or anti-IL 6 therapy. The MTD for AMG 757 has not yet been reached. AMG 757 exhibited dose proportional increase in exposures. Response to AMG 757 is shown (figure 1). Confirmed partial response was reported in 5 (16.1%) patients (1/12 [8.3%] in DL5, 1/8 [12.5%] in DL6, 3/7 [42.9%] in DL7), and stable disease in 8 (25.8%) of all treated patients. Most responses occurred after 8 weeks on treatment. All responders remain on treatment with duration of response ranging from 2.0+ to 7.4 months+.
    • Generalizability of potential biomarkers of response to CTLA-4 and PD-1 blockade therapy in cancer

      Bortone, D.; Vensko, S.; Entwistle, S.; Cogdill, A.; Monette, A.; Najjar, Y.; Sweis, R.; Tschernia, N.; Wennerberg, E.; Bommareddy, P.; et al. (2020)
      Background Multiple genomics-based biomarkers of response to immune checkpoint inhibition have been reported or proposed, including tumor mutation/neoantigen frequency, PD-L1 expression, T cell receptor repertoire clonality, interferon gene signature expression, HLA expression, and others.1 Although genomics associations of response have been reported, the primary studies have used a variety of data generation and processing techniques. There is a need for data harmonization and assessment of generalizability of potential biomarkers across multiple datasets. Methods We acquired patient-level RNA sequencing FASTQ data files from 10 data sets reported in seven pan-cancer PD-1 and CTLA-4 immune checkpoint inhibition trials with matched clinical annotations.2–7 We applied a common bioinformatics workflow for quality control, mapping to reference (STAR), generating gene expression matrices (SALMON), T cell receptor repertoire inference (MiXCR), extraction of immune gene signatures and immune subtypes,8 and differential gene expression analysis (DESeq2). We analyzed i) immunogenomics features proposed as biomarkers, and ii) gene expression signatures built from each trial for association with overall survival across the set of trials using univariable Cox proportional hazards regression. In all, we assessed 9 total immunogenomics features/signatures. P-values were adjusted for multiple testing using the Benjamini-Hochberg method. Results Of the 9 immunogenomics features assessed, cytolytic activity score and expression of the Follicular Dendritic Cell Secreted Protein gene (FDCSP) were associated with survival in two of seven studies, respectively (adjusted p < 0.05) (figure 1). No proposed biomarkers were significantly associated with survival in more than two studies. The sets of genes significantly associated with clinical benefit across the studies were highly disjoint, with only three genes significant in three studies and thirteen genes significant in two studies (figure 2). No genes were significantly associated with clinical benefit in more than three of seven studies
    • A PHII study of bemcentinib, a first-in-class selective axl kinase inhibitor, in combination with pembrolizumab in pts with previously-treated advanced NSCLC: updated clinical & translational analysis

      Spicer, J.; Helland, A.; Carcereny, E.; Arriola, E.; Gomez, M. D.; Perez, J. M. T.; Thompson, J.; Strauss, J.; Granados, A. L. O.; Felip, E.; et al. (2020)
      Background AXL is implicated in resistance to immunotherapy. Bemcentinib (BGB324), a first-in-class, oral, selective and potent AXL kinase inhibitor, enhances checkpoint inhibitor (CPI) efficacy in pre-clinical models through tumor-immune mechanisms. Methods BGBC008 is a PhII single-arm, 2-stage study with bemcentinib (200 mg/d) and pembrolizumab (200 mg/q3wk) for previously-treated stage IV lung adenocarcinoma comprising 3 cohorts: chemotherapy-pretreated IO-naïve patients (Cohort-A), patients progressing on prior IO therapy (Cohort-B) or chemotherapy/pembrolizumab combination (Cohort-C). Primary endpoint was ORR according to RECIST1.1 with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary endpoints included DCR, PFS, OS and safety. Exploratory endpoints include biomarker analysis and correlation with clinical endpoints, including composite (tumor and immune cell) cAXL score, PD-L1 TPS, and genome-wide mutational and transcriptome analyses. Results As of July 2020, enrollment in Cohort-A and-B (stage 1) is completed; a total of 66 NSCLC patients were dosed. Cohort-A (n=50) results were previously presented. All Cohort-B1 (n=16) patients received at least one prior line of therapy, the most recent including CPI; 4 patients had 1 and 12 had 2+ prior treatments. Of the Cohort-B1 patients, cAXL status was available for 13 patients: 8 cAXL-positive, 5 cAXL-negative. PD-L1 TPS was available for 13 patients: 5 TPS >50%, 5 TPS 1–49%, and 3 TPS <1%. Of patients who had previously undergone 1 line of CPI therapy (n=4), 75% were cAXL-positive and 25% were not evaluable for cAXL (median TPS of 20%). Patients who had previously undergone 2+ lines of therapy (n=12), 33% were cAXL-positive, 50% cAXL-negative, and 17% not evaluable for cAXL(median TPS of 50%). Of the treated pts, most common TEAEs (>25% of patients) were increased ALT (29%; 10% G3+), AST (29%; 5% G3+), and diarrhoea (29%; 1% G3+). All cases of treatment-related transaminase increase were reversible and managed with concomitant administration of steroids and treatment interruption. Of the 15 radiologically-evaluable patients in Cohort-B1, 1 PR was observed; 6/7 (86%) cAXL-positive patients (1 PR, 5 SD) achieved clinical benefit while none was observed in cAXL negative patients. mPFS was 4.7mo in cAXL-positive and 1.9mo in cAXL-negative patients. Ongoing transcriptional analysis of pre-treatment biopsies revealed a distinct gene profile correlating with clinical benefit from bemcentinib + pembrolizumab combination treatment. Conclusions Overall, bemcentinib in combination with pembrolizumab was well-tolerated and shows promising clinical activity in AXL-positive immunotherapy refractory disease. Updated survival and translation/biomarker data will be presented.