bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase III trial in progress comparing tislelizumab plus concurrent chemoradiotherapy (cCRT) with placebo plus cCRT in patients with localized esophageal squamous cell carcinoma (ESCC).
Authors: Wang Wei-Hu , Li Jiancheng , Li Tao , Zhao Kuaile , Yu Rong , Wang Wenqing , Chen Mingqiu , Liang Long , Zou Jiyan , Wang Yidi , Shen Wei , Wu Zhe , Xiao Zefen
Published: February 2020

TPS475

Background: In China, esophageal cancer (EC) ranks as the eigth most common cancer and the sixth most common cause of cancer related death. The predominant histological subtype of EC is ESCC. At first diagnosis, more than half of patients (pts) with ESCC are unfit for surgery. An alternative to surgery is cCRT; however, many pts experience local failure or distant metastasis after cCRT. As such, innovative therapies are needed. Tislelizumab, an investigational humanized monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. In previous studies, tislelizumab, as a monotherapy and in combination with chemotherapy, was generally well tolerated and had antitumor activity in pts with ESCC. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT03957590) is designed to compare the efficacy of tislelizumab versus placebo in combination with cCRT. Patients with histologically confirmed localized ESCC for whom cCRT is suitable and surgery is unsuitable/declined are being enrolled. Approximately 316 Chinese pts will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo (IV Q3W) in combination with cisplatin (25 mg/m2 IV on Days 1-3 of each 3-week cycle) plus paclitaxel (135 mg/m2 IV Q3W) and radiotherapy at a total dose of 50.4 Gy. An Independent Data Monitoring Committee will be established to assess the safety/tolerability of tislelizumab plus cCRT in the first 20 enrolled pts; monitoring across the study will occur at regular intervals thereafter. Progression-free survival (PFS), assessed by a Blinded Independent Review Committee per RECIST v1.1, is the primary endpoint. Secondary efficacy endpoints include overall response rate, duration of response, and overall survival. Incidence and severity of adverse events (CTCAE V5.0) and HRQoL are additional secondary endpoints. Exploratory endpoints include PFS rate at Years 1 and 2, pharmacokinetic profile, and predictive biomarker analyses. Clinical trial information: NCT03957590.
Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.
Authors: George Thomas J. , DeRemer David L. , Parekh Hiral D. , Lee Ji-Hyun , Markham Merry Jennifer , Daily Karen Colleen , Kaye Frederic J. , Staal Stephen , Jones Dennie V. , Stechmiller Bruce K. , Allegra Carmen Joseph , Hromas Robert A.
Published: February 2020

TPS591

Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks on treatment. Enrollment continues to a maximum of 47 evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347.

[Table: see text]
Phase I study of a new concept cancer vaccine composed artificial intelligence (AI)-designed shared-antigen peptides plus combined synergistically activating antigen-specific CTL reaction (CYT001) in patients with advanced hepatocellular carcinoma (CRESCENT 1).
Authors: Ogasawara Sadahisa , Kanzaki Hiroaki , Koroki Keisuke , Kanayama Kengo , Maruta Susumu , Kobayashi Kazufumi , Kiyono Souichiro , Nakamura Masato , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Tawada Akinobu , Chiba Tetsuhiro , Arai Makoto , Nakada Hiroyuki , Yamaguchi Nobuko , Hanaoka Hideki , Kato Naoya
Published: February 2020

TPS595

Background: CYT001 (CYTLIMIC Inc.) is a novel cancer vaccine involving artificial intelligence (AI)-designed shared-antigen peptides and optimal combined adjuvants that boost the cancer-immunity cycle. The two multi-HLA reactive peptides heat shock protein 70 (HSP70) and glypican 3 (GPC3) were screened by an AI-based prediction system according to the proteome, mRNA, and histopathology data fromhuman samples. These immunogenic peptides were confirmed to show cross-reactivity to HLA-A 24:02, 02:01, and 02:06. Poly-ICLC (Oncovir Inc.) binds to Toll-like receptor 3 (TLR3) and melanoma differentiation antigen 5 (MDA5) on antigen-presenting cells (APCs)and activates APCs. LAG-3Ig (Immutep Inc.) binds to the major histocompatibility complex (MHC) class II molecules of APCs and activates APCs. Both poly-ICLC and LAG-3Ig synergistically activate antigen-specific CTL reactions as effective combination adjuvants. The present study aims to evaluate the safety and tolerability of CYT001 (mixture of HSP70 peptide [2.0 mg], GPC3 peptide [2.0 mg], poly-ICLC [1.0 mg], and LAG-3Ig [1.4 mg]) in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single-center, phase 1, open-label, single-arm, investigator-initiated clinical trial of CYT001 for advanced HCC patients with no eligible standard systemic therapy, Child–Pugh A liver disease, and HLA-A 24:02, 02:01, or 02:06. Enrolled patients will receive CYT001 as a subcutaneous injection on days 1, 8, 15, and 21 in the 1st and 2nd cycles, days 1 and 15 in the 3rd and 4th cycles, and day 1 in the 5th cycle or later of 28-day cycles. The primary endpoint is dose-limiting toxicity, and the secondary endpoints are safety and the response rate. The transition of the CTL reactions of both the HSP70 and GPC3 peptides will be evaluated using blood samples of the subjects. Exploratory analyses include investigation of candidate biomarkers for treatment efficacy using liver tumor biopsy samples (baseline and after the 1st cycle) and blood samples (baseline and every days of administration). Clinical trial information: jRCT2031190072.
FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
Authors: Javle Milind M. , Shaib Walid Labib , Braun Stephan , Engelhardt Marc , Borad Mitesh J. , Abou-Alfa Ghassan K. , Boncompagni Andrea , Friedmann Silke , Gahlemann Christoph Georg
Published: February 2020

TPS597

Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In iCCA, FGFR genetic aberrations include FGFR2 fusions and, less commonly, FGFR2 M/A. iCCA prognosis is poor, and chemotherapeutic and targeted treatment options are limited. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 M/A is less well defined. Derazantinib (DZB) is an investigational, oral small-molecule kinase inhibitor with activity against FGFR1, 2 and 3, which demonstrated antitumor activity in patients with unresectable iCCA with FGFR2 fusions. Based on preliminary efficacy data demonstrating durable responses of > 6 months and a clinically meaningful progression-free survival in a subset of iCCA patients harboring FGFR2 M/A (NCT01752920), the multicenter, multicohort open-label phase 2 study FIDES-01 is evaluating the effect of DZB in separate cohorts of iCCA patients with FGFR2 fusions or FGFR2 M/A. Methods: The new cohort evaluates 300 mg once daily dosing of DZB in patients with unresectable iCCA with FGFR2 M/A per liquid or tissue biopsy-based next generation sequencing and at least one previous systemic therapy. Treatment will continue until progressive disease, intolerance, withdrawal of informed consent, or death. Using a Simon’s two-stage design, the primary endpoint to assess the antitumor activity of DZB is the proportion of patients with PFS at 3 months (PFS3; per RECIST 1.1 central review). Secondary objectives are evaluation of median PFS, objective response rate, duration of response, safety profile, quality of life (incl., QLQ-C30, QLQ-BIL21, EQ-5D), and symptom response from baseline. Current status: The study was initiated in July 2019 with planned enrollment of 43 patients with confirmed FGFR2 M/A. Clinical trial information: NCT03230318.
The impact of early palliative care on the quality of life of patients with advanced pancreatic cancer: The IMPERATIVE study.
Authors: Lelond Stephanie , Chochinov Harvey , Daeninck Paul Joseph , Goldenberg Benjamin Adam , Lix Lisa , McClement Susan , Kim Christina
Published: February 2020

TPS777

Background: Pancreatic cancer is lethal. Chemotherapy can improve survival by months; however, many patients experience an overwhelming burden of cancer-associated symptoms and poor quality of life (QOL). Early palliative care (EPC) alongside standard oncologic care results in improved QOL and survival in patients with lung cancer. Although international guidelines recommend EPC for patients with advanced pancreatic cancer (PANC), the benefit is not known. Objectives: The primary objective is to test for change in QOL between baseline (BL) and 16 weeks (wk). Secondary objectives are to test for change between BL and 16 wk in (a) symptom control; and (b) depression and anxiety. Methods: This prospective case-crossover study of patients with PANC provides EPC plus standard oncologic care. Primary oncology clinics refer patients to an EPC team led by a palliative care physician and a clinical nurse specialist. BL questionnaires are completed prior to initial EPC assessment, then every 4 wk until wk 16. EPC visits are every 2 wk for the first month, every 4 wk until wk 16, and then as needed. QOL, symptom control, anxiety and depression are measured using the FACT-Hep tool, ESAS-r, HADS and PHQ-9, respectively. A generalized linear model will test for statistically significant change in scores between BL and 16 wk; chemotherapy (yes/no) is included as a confounding covariate; model fit will be assessed. A sample size of 20 patients provides 80% power after controlling for covariate effects. 40 patients will be enrolled to account for missing data. To date, 28 patients have enrolled and 17 have completed the intervention. Significance: The benefit of EPC for patients with PANC is not known, however, EPC is increasingly recognized internationally by patients and stakeholders as a critical intervention which may improve both QOL and satisfaction with care. The Canadian Partnership Against Cancer’s report on the patient experience states “the best possible patient experience means all people with cancer have equitable access to high-quality person-centered palliative care”. This study offers access to EPC and provides an environment in which the benefit of an integrated approach is evaluated.
A phase II, open-label pilot study evaluating the safety and activity of Nal-IRI in combination with 5-FU and oxaliplatin in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study) (NCT03483038).
Authors: Parekh Hiral D. , Cioffi Jessica L. , Hitchcock Kathryn , Lee Ji-Hyun , Fan Z. Hugh , Allegra Carmen Joseph , Hughes Steven J. , Trevino Jose Gilberto , DeRemer David L. , George Thomas J.
Published: February 2020

TPS790

Background: Neoadjuvant treatment for borderline resectable pancreatic cancer (PCa) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Irinotecan liposomal injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PCa. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with borderline resectable PCa without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive FOLFNal-IRINOX regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038 . [Table: see text]
Phase II study of nivolumab and relatlimab in advanced mismatch repair deficient (dMMR) cancers resistant to prior PD-(L)1 inhibition.
Authors: Bever Katherine M. , Wang Hao , Durham Jennifer N. , Petrie Susan , Hoare Jessica , Wilt Cara , Sharfman William Howard , Azad Nilofer Saba , Laheru Daniel A. , Anders Robert A , Pardoll Drew M. , Topalian Suzanne Louise , Jaffee Elizabeth M. , Le Dung T.
Published: February 2020

TPS839

Background: Cancers deficient in DNA mismatch repair (dMMR) are highly immunogenic tumors exhibiting high rates of response to immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) interaction. These tumors are characterized by high levels of microsatellite instability (MSI-H) and an exceptionally high tumor mutation burden, thought to underlie responsiveness to immunotherapy, with higher predicted immunogenicity of mutation-associated neoantigens. However, primary and acquired resistance are observed and diversity in responses is not fully explained by variations in mutation burden. Other immune checkpoints may be acting in parallel with PD-1/PD-L1. In particular, lymphocyte activation gene 3 (LAG3) mediates exhaustion of activated T cells and may have a role in resistance to PD-(L)1 inhibitors (PD-(L)1i); therefore, we hypothesized that the addition of LAG3 inhibitor (relatlimab) to the PD-1i nivolumab may overcome resistance in these tumors. Methods: Patients with advanced dMMR/MSI-H cancer who have progressive disease (by RECIST 1.1) during or within 6 months of PD-(L)1i containing therapy, and after at least 12 weeks of therapy, and meet other eligibility will be enrolled. All patients will receive nivolumab 480mg + relatlimab 160mg every 4 weeks until intolerance or progression, or up to a maximum of 2 years. The primary endpoint is objective response rate. Key secondary endpoints include safety, progression free and overall survival, and other response endpoints as measured by RECIST 1.1 and iRECIST criteria. Exploratory objectives will include analysis of the tumor microenvironment on biopsies obtained at baseline and on-treatment, analysis of T cell populations in the tumor and in the periphery and functional characterization of mutation-associated neoantigen-specific T cells. Studies of the microbiome will be conducted on stool and oral wash samples. Enrollment of 21 patients is planned. Clinical trial information: NCT03607890.
First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer.
Authors: Cole Christopher Browning , Annunziata Christina M.
Published: February 2020

1

Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 106 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for >6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.
AABH (aspartyl [asparaginyl] β-hydroxylase) as a serum biomarker for breast cancer.
Authors: Moshiri Kiarash
Published: February 2020

2

Background: Breast cancer accounts for 27% of female cancers. One in every eight women will develop breast cancer in their lifetime. More than 220,000 new cases of breast cancer will be diagnosed in the United States in 2020. Five-year survival rates for breast cancer are 98% for localized disease, 83% for regionally spread and 26% for distantly spread cancer. However, 25% of all metastases occur more than 5 years after the initial diagnosis and thus survival rates decrease as time goes out to 10 years due to disease recurrence. Current detection methods rely on imaging modalities, including mammography and MRI. No serum bio-markers have been approved for either breast cancer screening or monitoring for disease recurrence, yet. In asymptomatic women in remission from breast cancer the guidelines of the major oncologic organizations only suggest annual mammography for detection of new primary tumors. Methods: We have investigated the utility of aspartyl (asparaginyl) β-hydroxylase (AABH) as a serum bio-marker for cancer. AABH has been detected by immunohistochemical staining (IHC) in a broad range of cancers including breast cancer. It has been detected by IHC in > 99% of tumor specimens tested (n > 2000) but is absent in adjacent non-affected tissue, and in tissue samples from non-affected individuals. This led to the development of a sandwich ELISA that reliably measures AABH in serum. Results: In the current study we have utilized the assay to quantify AABH levels in the sera of patients diagnosed with Breast Cancer compared to women free of disease. Increased levels of AABH were found in the serum of 99% of patients with breast cancer (n = 189). In women not known to have cancer, AABH was essentially undetectable in serum (n = 65, specificity = 96%). Serum from several women currently in remission subsequent to treatment for breast cancer were also analyzed and found to be negative for AABH. Conclusions: Thus, measurement of serum AABH levels has great promise as a diagnostic tool for breast cancer with potential application in monitoring for disease recurrence. Elevated serum AABH in conjunction with mammography and MRI may greatly facilitate earlier diagnosis of both primary and recurrent Breast Cancer.
Results of a phase Ib trial of encapsulated rapamycin in prostate cancer patients under active surveillance to prevent progression.
Authors: Kemp Bohan Phillip M. , Cindass Jessica L. , Chick Robert Connor , Vreeland Timothy J. , Hale Diane F. , Hickerson Annelies , Clifton Guy Travis , Peoples George Earl , Liss Michael
Published: February 2020

34

Background: At low doses, rapamycin inhibits cell proliferation and angiogenesis while augmenting CD8 T-cell responses, cumulatively producing an antitumor effect. Oral rapamycin is limited by variable bioavailability. Encapsulated rapamycin (eRapa) incorporates submicron rapamycin particles into a pH-sensitive polymer, improving bioavailability and allowing for consistent and lower dosing. Here, we present results of a phase Ib trial evaluating safety and treatment effects of eRapa in patients with low-grade prostate cancer (PCa). Methods: PCa patients with Gleason ≤7 (3+4) under active surveillance were enrolled in a 3+3 study with 3 dosing cohorts (0.5mg weekly, 1mg weekly, and 0.5mg daily) to determine the optimal dosing. Patients were treated for 3 months (m) and followed for 6m. Safety, labs (including PSA), pharmacokinetics, immune response, and quality of life (QOL) were assessed for each cohort. Results: 14 patients were enrolled; 3 in cohort 1, 3 in cohort 2, and 8 in cohort 3. 2 patients withdrew for non-dose limiting toxicity (DLT) (grade 1-2) adverse events (AEs) in cohort 3, leaving 6 evaluable. A single grade 3 DLT (neutropenia) occurred in cohort 3. No AEs > Grade 1 occurred in cohorts 1/2. Peak serum rapamycin concentration ([Rapa]) was 7 ng/mL after a 1 mg dose (2h after administration). Stable trough levels (2 ng/mL) were established after 48 hrs and persisted to 13wks. Central memory CD8 T cells and CD3+/CD56+ NK cells were more prevalent in cohort 3 than other cohorts at 1m (p = 0.027 and p = 0.041) and 3m (p = 0.023 and p = 0.049). There was no significant change in PSA level; no patients clinically progressed on therapy. In cohort 3, there were no differences between baseline and 3m QOL assessments but there was a suggestion of withdrawal effects at 6m. Conclusions: Treatment with low dose eRapa is safe and well-tolerated. The dose of 0.5mg daily produced stable serum [Rapa] through the duration of treatment and resulted in a positive immune impact. Further investigation with low dose and/or intermittent dosing of eRapa as a preventive agent in PCa and other indications will be required to establish clinical benefit. Clinical trial information: NCT03618355.
Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T).
Authors: Dummer Reinhard , Gusenleitner Daniel , Campbell Catarina D. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Ana , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Gasal Eduard , Brase Jan C. , Long Georgina V.
Published: February 2020

39

Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part [p] 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P< .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P< .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Immunogenomic signatures to predict outcome in ovarian and endometrial cancers: Potential strategies in targeting the tumor immune microenvironment to improve response to immunotherapy.
Authors: Mahdi Haider , Ni Ying
Published: February 2020

4

Background: Ovarian and MSS endometrial cancers are characterized by immunosuppressive microenvironment (TME) and low response to immunotherapy with checkpoint inhibitors (CPI). Targeting immunosuppressive factors within TMErepresents an attractive approach to enhance response to CPI. Therefore, we sought to investigate different immunogenomic signatures and immune cells within TME and correlate them with survival. Methods: We used whole transcriptome sequencing of matched tumor-normal samples from 38 uterine serous cancer and TCGA data of ovarian (n = 374) and endometrial cancers (n = 541). Immunogenomic signatures focusing on Transforming Growth Factor (TGFβ), 18-genes IFN-γ and myeloid signatures (CD47 and B7H4 expressions) and immune cell abundance were investigated. Gene expression score was calculated by averaging the normalized and log transformed individual gene read counts. The optimized score cut off was selected to best separate the survival in the pilot cohort. Then the score was tested in TCGA RNAseq datasets. Population abundance of tissue-infiltrating immune cells were estimated using MCPcounter R package from bulk transcriptome data. Results: Higher IFN-γ and lower TGF-β signatures predicted better survival for endometrial and ovarian cancers (p < 0.05). The impact of TGF-β was higher in MSI-H vs. MSS cancers (p = 0.013 vs. 0.09). High CD47 predicted poor survival in endometrial cancer. Combined IFN-γ and TGF-β signatures predicted survival in the ovarian and endometrial cohorts (p < 0.001). Combined IFN-γ and CD47 expression predicted survival in endometrial cancer (p = 0.033). Analysis of immune cell abundance revealed enrichment of monocytic lineage and neutrophils but paucity of cytotoxic T-cells, NK cells, dendritic cells and B-cells. Immune cell abundance is being correlated with survival. Conclusions: Our data support the role of immunogenomic markers in predicting survival. We are evaluating these markers in predicting response to CPI in a pilot cohort. Immunogenomic markers represent the tumor microenvironment, can potentially guide rationale combination immunotherapy.
Tumor inflammatory signature as a biomarker of response to immunotherapy in lung cancer.
Authors: Pabla Sarabjot , Van Roey Erik , Conroy Jeffrey M. , Glenn Sean , Wang Yirong , Nesline Mary , Burgher Blake , Giamo Vincent , Andreas Jonathan , Lenzo Felicia L. , Morrison Carl
Published: February 2020

47

Background: Tumor Inflammation signatures (TIS) comprising multiple immune genes have been shown to enrich for response to ICI. To study this immune phenotype in a large cohort of clinically evaluated patients, we studied gene expression data for a stable pan-cancer tumor inflammation profile and clinical response to ICI. Methods: 1323 FFPE tumors from 35 histologies were tested by RNA-seq, PD-L1 IHC and DNA-seq for TMB. Unsupervised analysis of the RNA-seq data revealed a cluster of 160 genes which separated inflamed from non-inflamed tumor microenvironments (TME). A TIS, algorithmically defined as the mean mRNA expression of the 160 genes was developed with each tumor assigned into a weak, moderate or strong inflammation group. PD-L1 IHC was performed using DAKO 22C3 antibody and considered positive if TPS ≥1%. TMB > 10 mut/Mb was considered high. The TIS, PD-L1 and TMB were independently applied to 110 NSCLC cases for association with ORR to ICIs by RECIST criterion. Results: Unsupervised clustering identified 3 inflammation clusters in the 1323 samples; inflamed (n = 439; 33.2%), borderline (n = 467; 35.3%) and non-inflamed (n = 417; 31.5%). 160 genes are over-represented by T & B-cell activation, IFNg, chemokine, cytokine and interleukin pathways. The TIS algorithm results in an inflammatory score that leads to 3 distinct groups of strong (n = 384; 29.0%), moderate (n = 354; 26.8%) and weak (n = 585; 44.2%) inflammation. Strongly inflamed tumors are over-represented by PD-L1+ tumors (240/384) whereas weakly inflamed tumors are significantly under-represented by PD-L1+ tumors (369/585; p = 1.02e-14). Strongly inflamed tumors presented with improved ORR to ICI in NSCLC (36.6%; 16/44; p = 0.051). Similar results were observed for overall survival for strongly inflamed tumors (median = 16 months; p = 0.0012) vs. weakly inflamed tumors (median = 8 months). ORR for PD-L1+ 33.96% (p = 0.026) and TMB high 21.43% (p = 0.83) were observed. Conclusions: Concurrent measurement of multiple markers led to a comprehensive, stable TIS that predicts host immune response. A strongly inflamed TIS was associated with higher ORR versus single biomarker PD-L1 and TMB in NSCLC.
Pemetrexed (Pem) with pembrolizumab (Pembro) maintenance: A post hoc subgroup safety analysis of KEYNOTE-189.
Authors: Aerts Joachim , Garon Edward B. , Wang Chunxiao , Muehlenbein Catherine , Kim Jong Seok , Gadgeel Shirish M.
Published: February 2020

51

Background: KEYNOTE-189 showed that Pembro+Pem and platinum (Plat) followed by Pembro+Pem improved survival vs Placebo(Plac)+Pem+Plat followed by Plac+Pem in nonsquamous metastatic non-small cell lung cancer. Real-world data suggest Pem is being discontinued after the first 4 cycles with Plat (data on file), perhaps due to toxicity concerns. This study evaluated changes in toxicities and renal impairment in patients (pts) receiving Pem maintenance. Methods: Using KEYNOTE-189 patient data, pts receiving ≥5 cycles of Pem (including the first 4 cycles with Plat) were selected, and a subgroup with renal adverse events were identified by system organ class and preferred term (MedDRA 20.1). Pts with treatment-emergent adverse events (TEAEs) and changes in serum creatinine (sCR) were summarized every 4 cycles. Results: 310 pts in the Pembro+Pem+Plat arm and 135 in the Plac+Pem+Plat arm received ≥5 cycles of Pem. 30 and 5 pts experienced renal events in each arm, respectively. Table shows pts with Gr. 3-5 TEAEs in each period of 4 cycles. Gr. 3-5 TEAEs generally decreased after cycle 4. Pts with renal events had increasing maximum sCR changes from baseline with every 4 cycles. Conclusions: The percentage of pts with renal and Gr. 3-5 TEAEs did not increase with prolonged treatment with Pembro+Pem. Toxicity increased moderately with Pembro+Pem vs Plac+Pem in later cycles. The incidence of Gr. 3-5 renal toxicity was consistently low across the cycles. These data support the safety of prolonged Pem and Pembro in pts after 4 cycles of Pembro, Pem, and Plat along with careful monitoring of renal function. Clinical trial information: NCT02578680 . [Table: see text]
A network meta-analysis of immunotherapy-based regimens for first-line treatment of advanced non-squamous non-small cell lung cancer.
Authors: Agg Himani , Ndirangu Kerigo , Muehlenbein Catherine , Winfree Katherine B. , Zhu Yajun Emily , Thom Howard , Tongbram Vanita
Published: February 2020

52

Background: Immunotherapy (IO) for initial treatment of patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC) has led to improved progression free survival (PFS) and overall survival (OS) vs chemotherapy. The objective of this network meta-analysis (NMA) was to compare the efficacy of IO-based therapies to chemotherapy in the first-line treatment until progression for advanced nsqNSCLC. Methods: A systematic literature review was conducted to identify randomized controlled trials reporting PFS and/or OS data in adult patients who received first-line treatment for stage IIIB or IV nsqNSCLC until progression. MEDLINE, EMBASE and Cochrane Central Register were searched from the start of databases to June 2018. The NMA used fixed-effects models to estimate hazard ratios (HRs) and credible intervals (Crl) for PFS and OS of IO therapies vs pemetrexed + platinum. A subgroup of patients with PD-L1 tumor proportion score (TPS) ≥50% was also analysed. Results: Evidence networks comprised of 18 studies for the overall population and 3 studies for the PD-L1 TPS ≥50% subgroup. In PFS analysis for the overall population, HRs were lower for atezolizumab + bevacizumab + paclitaxel + platinum (HR 0.62; 95% CrI 0.48, 0.8), ipilimumab + nivolumab (HR 0.55; 95% CrI 0.38, 0.8) and pemetrexed + pembrolizumab + platinum regimens (HR 0.52; 95% CrI 0.43, 0.63) vs pemetrexed + platinum. In the PD-L1 TPS ≥50% subgroup, PFS HRs were lower for pembrolizumab (HR 0.81; 95% CrI 0.67, 0.98) and pemetrexed + pembrolizumab + platinum (HR 0.36; 95% CrI 0.25, 0.52) vs pemetrexed + platinum. In the OS analysis for the overall population, pemetrexed + pembrolizumab + platinum had a lower HR (HR 0.5; 95% CrI 0.4, 0.64) vs pemetrexed + platinum. This difference in OS was magnified in the PD-L1 TPS ≥50% subgroup (HR 0.42; 95% CrI 0.26, 0.68). Conclusions: Among all IO-based therapies in this analysis, pemetrexed + pembrolizumab + platinum had the highest PFS and OS benefit vs pemetrexed + platinum in the first-line treatment until progression for advanced nsqNSCLC for both the overall population and high PD-L1 subgroup. These comparative efficacy data may inform clinicians in treatment selection.
Real-world outcomes for metastatic non-small cell lung cancer patients treated with checkpoint inhibitor immunotherapy in Canada.
Authors: Yusuf Dimas , Ko Jenny J. , Cho Hyokeun , Sheremeto Corey , Wang Ying , Juergens Rosalyn A. , Ellis Peter Michael , Billawala Alkarim , Kay Amin , Kulkarni Swati , Elfiki Tarek A. , Gupta Rasna , Naccarato Krista , Pennetti Alex , Patel Devalben , Smith Elliot Charles , Walton Ryan , Hurry Manjusha , Liu Geoffrey , Cheung Winson Y.
Published: February 2020

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Background: The majority of patients with non-small cell lung cancer (NSCLC) are diagnosed with incurable, metastatic disease. Immunotherapy (IO) agents have improved overall, long term survival. There is a need to better understand how these drugs are utilized and perform in the real world to further inform physicians and policymakers. Methods: In this retrospective study, we analyzed characteristics, treatment patterns, and outcomes of patients with metastatic NSCLC treated with checkpoint inhibitors nivolumab or pembrolizumab at five Canadian cancer centres, with a focus on patients who received these treatments in the 2nd (2L) or 3rd line (3L) setting. We excluded patients who were in blinded clinical trials, exposed to multiple IO drugs, or who had tumors with EGFR or ALK mutations. Primary endpoints were overall survival (OS) and progression free survival (PFS) from start of IO. Secondary endpoints included immune-related toxicities. Results: Across all sites, we screened 322 patients and included 230 who met criteria: 49 (21%) from Alberta; 60 (26%) from British Columbia; and 121 (53%) from Ontario. Patients were diagnosed with metastatic NSCLC from 2009 to 2018, but the majority were diagnosed after 2015. Median age at diagnosis was 66.6 years, 54% were female, and 86% were either current or former smokers and 67% had stage IV disease. About 88% received nivolumab; 87% (n=200) received IO in 2L (n=111) or 3L (n=89). The median OS from start of IO was 10.9 (8.7–15.6) months, and were similar for 2L vs 3L (9.3 vs 12.0 months, p = 0.2). Median PFS was 5.7 (4.4–8.1) months. Pneumonitis was the most frequently reported toxicity affecting 7% of patients. Thyroiditis was reported in 4%; colitis, while dermatitis and hepatitis were each reported in 3%, and nephritis in 1%. Conclusions: In the real world, IO for advanced NSCLC was well-tolerated and had outcomes that were comparable to landmark clinical trials.
DPX-Survivac, a novel T-cell immunotherapy, to induce robust T-cell responses in advanced ovarian cancer.
Authors: Dorigo Oliver , Fiset Stephan , MacDonald Lisa Diana , Bramhecha Yogesh , Hrytsenko Olga , Dirk Brennan , Rosu Gabriela Nicola , Stanford Marianne
Published: February 2020

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Background: Survivin has emerged as an attractive target for T cell-based immunotherapy because of its essential role in tumor biology and its tumor-specific expression in multiple tumor types. DPX-Survivac is a novel T cell immunotherapy that uses the DPX platform to elicit strong and sustained survivin-specific T cell responses against tumor cells. DPX is designed to extend the duration and robustness of targeted immune responses by requiring active uptake of antigens by antigen presenting cells at the injection site. DPX-Survivac incorporating survivin targets within the DPX platform is therefore a relevant approach for treatment of survivin-expressing cancers to generate strong T cell responses that infiltrate tumors and result in measurable anti-tumor responses. Methods: 121 patients with platinum sensitive or resistant, advanced ovarian, fallopian tube or peritoneal cancer were treated with DPX-Survivac with or without drug combinations. Data from 3 different clinical trials were analyzed for systemic immune responses, tumor immune infiltrates and clinical tumor responses. Patients were enrolled in both the maintenance (N = 56) and recurrent (N = 65) disease settings. Results: DPX-Survivac generated survivin-specific T cells in 80% of patients as demonstrated by IFN-γ ELISPOT of PBMCs. Paired pre- and post-treatment tumor samples were collected from 37 patients. Survivin-specific T cells were found in the tumor microenvironment post-treatment using TCR-β sequencing. Clinical anti-tumor responses were correlated with increased infiltration of T cells into tumors following treatment with DPX-Survivac. An increase in T cell signaling in post-treatment tumor tissue was shown by RNAseq along with upregulation of cytotoxic markers, NK and B cell markers. Importantly, the antigen-specific T cells retain their functionality throughout the duration of treatment. Conclusions: DPX-Survivac stimulates significant clinical anti-tumor responses by inducing strong and sustained survivin-specific T cell responses and increasing infiltration of target-specific T cells into tumors. Clinical trial information: NCT01416038; NCT03332576; NCT02785250.
Causal modeling of TCGA, NSCLC, and HNSCC data to identify network drivers of tumor immune subtypes.
Authors: Das Rahul K , Yan Raymond T. , Davis Craig B. , Maciejewski Mateusz , Mu Xinmeng Jasmine , Krishnakumar Aishwarya , Church Bruce W. , Khalil Iya
Published: February 2020

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Background: Immune checkpoint inhibitors have achieved unprecedented success in several cancer types, yet only a subset of patients derives clinical benefit. Better understanding of tumor-immune interactions is imperative to improve clinical outcomes. Bayesian causal machine learning was applied on real world data to elucidate the molecular drivers of immune subtypes of tumors. Methods: Using a Reverse Engineering Forward Simulation (REFS) platform, ensembles of causal models were built on genomics, transcriptomics, and clinical data from 681 non-small cell lung carcinoma (NSCLC), 328 lung adeno (LUAD) and 353 lung squamous cell (LUSC), and 413 head and neck squamous cell carcinoma (HNSCC) patients from TCGA. The outcomes modeled were six tumor immune subtypes (Thorsson et al., 2018): wound-healing, IFNγ dominant, inflammatory, lymphocyte-depleted, immunologically quiet, and TGFβ dominant. Causal drivers of immune subtypes were identified from average causal effect (ACE) of the variables, as computed from the counterfactual simulations. ACE was defined as median of posterior distribution of odds ratio (1 vs 0 for discrete; 95th vs. 5th %ile for continuous variables). Results: The models showed impressive k-fold cross validation predictive performance (AUC ~ 0.8-0.9) for the most prevalent immune subtypes in TCGA: wound-healing and IFNg dominant in both LUAD and HNSCC, as well as inflammatory in LUAD. The potential causal drivers of the tumor immune subtypes and their ACE are listed in Table. The findings suggest that macrophage activation and polarization, which is driven in part by metabolic reprogramming, is a primary driver of tumor immune subtypes. Conclusions: Bayesian causal modeling revealed literature-supported hypotheses regarding predictors of response (CXCL13) and resistance (STK11 mutation, mTOR pathway) to PD-(L)1 blockade therapy. The additional target pathways such as AKT1/mTOR may be actionable for altering immunogenicity of tumors. [Table: see text]
Tumor mutational burden (TMB) as a predictive biomarker of immune checkpoint blockade (ICB) in metastatic solid tumors.
Authors: Kao Chester , Powers Eric , Datto Michael B. , Green Michelle , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J. , Clarke Jeffrey Melson , Strickler John H. , Zhang Tian
Published: February 2020

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Background: TMB is a promising predictive biomarker for ICB, but recent studies have shown that TMB varies substantially between tumor types. We examined the association between TMB and clinical response to ICB in metastatic urothelial carcinoma (mUC), renal cell carcinoma (mRCC), and non-small cell lung cancer (mNSCLC). Methods: We conducted a single center retrospective study inclusive of 1444 consecutive patients (pts) initiating ICB prior to 1/2019, cross-referenced with pts with Foundation One testing with TMB (mut/Mb), resulting in 17 mUC, 10 mRCC, and 60 mNSCLC. PD-L1 status was determined by the Dako 22C3 antibody. Pts were divided into clinical responders (R) and non-responders (NR) based on clinical assessment per their oncologist. The primary outcome of the study was to describe the relationship between TMB and clinical benefit, including duration of clinical response and overall survival (OS). A t-test was performed between R groups. Kaplan Meier (KM) curves and Cox-Mantel log rank tests were performed for PFS/OS comparing high TMB (≥ median) to low TMB pts. Results: For mUC, 8/17 (47%) were R with median TMB 7.74 (Interquartile range or IQR 6.04-9.78) compared to 9 NR, median TMB 7.57 (IQR 3.78-11.41) [p = 0.36]. For mRCC, 4/10 (40%) were R with median TMB 1.75 (IQR 1.75-1.97), versus 6 NR with median TMB 5.79 (IQR 3.07-7.48) [p = 0.02]. For mNSCLC, 30/60 (50%) were R with median TMB 11.38 (IQR 9.65-16.24), significantly higher than 30 NR with median TMB 9.46 (IQR 7.65-13.87) [p = 0.05]. For mNSCLC, no difference in PD-L1 positivity was found between R (17/30, 56%) and NR (16/30, 53%), and concurrent chemotherapy with ICB was the same in both R (10/30 (33%)) and NR (10/30 (33%)). KM analysis showed equivocal results for duration of clinical response and OS between high TMB vs low TMB in the three solid tumors, except OS in mUC which favored high TMB (p = 0.03) [cutoff TMB: mUC 7.57, mRCC 2.63, mNSCLC 11.35]. Conclusions: Higher TMB was associated with a greater likelihood of clinical benefit to ICB in our cohort of NSCLC patients and mUC. This correlation was not detected among mRCC patients, although these data are limited by relatively small number of cases.
Real-world evidence data (RWED) of financial toxicity (FT) in patients (pts) receiving cancer immunotherapy treatments.
Authors: Vorobiof Daniel A. , Hasid Lior , Litvin Alon , Deutsch Irad , Malki Eliran
Published: February 2020

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Background: RWED denotes data accumulated via EHR as well as cutting edge technology paired with consumer mobile devices. We are reporting data on 105 pts, users of Belong.life, a worldwide mobile application, who received immunotherapy for their various cancers and were asked to reply to a short, targeted survey on their FT while on treatment. Methods: 105 pts anonymously and voluntarily replied to a survey which included 14 general information questions and those describing FT, its most common encountered causes and their personal financial coping strategies. Results: 79% of the pts were USA based. 21% of the pts were < 50 years of age (yoa), 32% were 51-60 yoa and 47% were > 61 yoa. Pts’s stages were Stage 3 in 23% and 4 in 62% with unknown in 15%. There were 36% males and 64% females. The most common cancer diagnosis was lung in 46% followed by kidney in 17%, malignant melanoma in 14% and colorectal in 10%. The prevalent immunotherapy drugs were nivolumab and pembrolizumab in 36% respectively, and ipilimumab in 14% and durvalumab in 10%. Frequently reported FTs were high medical copayments in 35% of the pts, loss of income in 33% and high drugs and treatments copayments in 21%. 41% of the pts were insured by Medicare and 25% by Medicaid and other HMOs. Only 48% of the pts were aware of possible financial difficulties as a result of their diagnosis and treatment, and 34% received pre-treatment financial advice from their doctors which reduced the reported FT from 48% to 30%. When asked about coping strategies, 39% used personal savings, 28% trimmed their private expenses, and 24% received financial support from their families and friends. Conclusions: 105 users of the Belong.life application reported on their FTs experienced while receiving cancer immunotherapy. FT was most prevalent in the older group ( > 61 yoa) due to high medical and treatment copayments. Nearly half of the pts was not aware of the possible FT and only 38% received advisory information from their doctors. Reduced FT prevalence (from 48% to 30%) was reported by those informed pts. Physicians should become aware of their pts’s possible risks for FTs, therefore appropriate advice should be given prior to immunotherapy initiation.