bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients with metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (MCRPC).
Authors: Autio Karen A. , Klebanoff Christopher Austin , Schaer David , Kauh John S. , Slovin Susan F. , Blinder Victoria Susana , Comen Elizabeth Anne , Danila Daniel Costin , Hoffman David M. J. , Kang Suhyun , McAndrew Philomena , Modi Shanu , Morris Michael J. , Rathkopf Dana E. , Sanford Rachel Ann , Tate Sonya C. , Yu Danni , McArthur Heather L.
Published: May 2019

2548

Background: Tumor-associated macrophages (TAM) correlate with increased invasiveness, growth, and immunosuppression. Activation of CSF-1R results in proliferation, differentiation, and migration of monocytes/macrophages. CSF-1R inhibition with LY3022855 (LY), a human immunoglobulin G subclass 1 (IgG1) monoclonal antibody (mAB), may have favorable anti-tumor effects. We evaluated the safety and clinical response of LY monotherapy. Methods: Patients (pts) with advanced refractory MBC and MCRPC received LY intravenously in 6-week cycles in cohorts: A) 1.25 mg/kg every 2 weeks [Q2W]; B) 1.0 mg/kg on Weeks 1, 2, 4, and 5; C) 100 mg once weekly; D)100 mg Q2W. MCRPC pts were enrolled in cohorts A and B; MBC pts were enrolled in all cohorts. Anti-tumor activity was assessed using RECIST v1.1 by radiological imaging every 6 weeks. Results: Thirty-four pts (22 MBC; 12 MCRPC) received ≥1 dose of LY. Median age was 57.0 years (range: 32.0–81.0) for MBC pts and 72.5 years (range: 58.0–84.0) for MCRPC pts. Baseline Eastern Cooperative Oncology Group performance status was 0 (n = 13, 38.2%), 1 (n = 18, 52.9%), or 2 (n = 3, 8.8%). MBC pts were hormone receptor (HR) positive (n = 20), HR negative (n = 1), or unknown (n = 1); 3 MBC pts received concurrent hormone therapy. Common treatment-related adverse events of any grade were fatigue (38.2%), decreased appetite (26.5%), nausea (26.5%), increased lipase (23.5%), and increased creatine phosphokinase (20.6%). No complete or partial response was observed. Stable disease (SD) was observed in 5/22 MBC pts (duration 82–302 days) and 3/7 evaluable MCPRC pts (duration 50–124 days). Two MBC pts (9%; Cohort A) had durable SD > 9 months and 1 pt had palpable reduction in a nontarget neck mass. Circulating CSF1 and IL-34 increased at Day 8 suggestive of target engagement. Pharmacokinetics of LY were consistent with other IgG1 mAbs. Conclusions: LY3022855 was well tolerated and showed evidence of target engagement. Clinically meaningful SD > 9 months was observed in 2 MBC pts. Tumor biomarker analyses are underway. Clinical trial information: NCT02265536.
An open label, multicenter phase II study combining imprime PGG (PGG) with pembrolizumab (P) in previously treated metastatic triple-negative breast cancer (mTNBC).
Authors: O'Day Steven , Borges Virginia F. , Chmielowski Bartosz , Rao Ruta D. , Abu-Khalaf Maysa M. , Stopeck Alison , Nikolinakos Petros , Telli Melinda L. , Xie Bin , Shaheen Montaser F. , Mattson Paulette , Gargano Michele Anne , Cox Joanna , Karantza Vassiliki , Chisamore Michael Jon , Osterwalder Bruno , Bose Nandita , Uhlik Mark T. , Graff Jeremy
Published: May 2019

2550

Background: Checkpoint inhibitor (CPI) monotherapy shows limited clinical response in previously treated mTNBC patients (pts) (Table). Agents are needed that extend this benefit to more mTNBC pts. PGG is a novel, IV administered PAMP that, in pts with 20ug/ml anti-beta glucan antibody (ABA+), activates innate immune cells. Preclinically, PGG reprograms myeloid cells to repolarize the immunosuppressive tumor microenvironment & enhance antigen presentation, driving T cell activation- the mechanistic basis to explore PGG + P in mTNBC patients. Methods: 44 mTNBC pts ( 1 line of chemotherapy [Tx] for metastatic disease, ABA) received PGG (4 mpk IV weekly) + P (200 mg IV q3w) until PD or intolerable toxicity. 1° endpoints were ORR by RECIST v1.1 & safety. 2° endpoints included OS & DCR. CT scans (q6 wks) were reviewed locally. Tumor biopsies (pre & 6 wks on Tx) & blood samples were assessed for PGG-mediated immune activation. Results: Table shows IMPRIME 1 clinical response data (Keynote086, PCD4989g shown for context). Confirmed response was also evident in pts with liver or visceral metastases, high LDH. 10 IMPRIME 1 pts were originally ER/PR+, received hormonal Tx and progressed to TNBC. Of these, 5 are confirmed PR, 4 SD (3 still on Tx), 1 PD. No unexpected safety signals were observed. Conclusions: These are the first clinical data to suggest that PGG provides added clinical benefit for pts with previously treated mTNBC and support further development of PGG + P for mTNBC. Clinical trial information: NCT02981303. [Table: see text]
Assessment of the Fanconi anemia repair pathway as a predictor of clinical activity of pembrolizumab (PEM).
Authors: Villalona-Calero Miguel Angel , Diaz John Paul , Diaz Zuanel , Duan Wenrui , Schroeder Eric Douglas , Aparo Santiago , Gatcliffe Troy Antony , Alonso Alfredo Pedro , Cuitiva Sebastian , Albrecht Federico , Venkatappa Siddhartha A. , Guardiola Victor , Troner Michael B. , Garrido Sara M. , Walker Gail , Rubens Muni , De Zarraga Fernando I. , Vuong Hao
Published: May 2019

2555

Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM was given every 3 weeks and computed tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.
Fatal adverse events associated with pembrolizumab in cancer patients: A meta-analysis.
Authors: Golshani Gol Minoo , Sher Amna Falak , Wu Shenhong
Published: May 2019

2561

Background: Pembrolizumab, an immune checkpoint inhibitor (ICI) against programmed cell death-1(PD-1) protein has emerged as an effective treatment for many cancers. Although better tolerated than chemotherapy, it has unique immune related adverse event and little is known about its risk of fatal adverse events (FAE). Therefore, we conducted a meta-analysis of clinical trials to determine the incidence and risk of fatal adverse events with pembrolizumab. Methods: A systematic search for phase I-III clinical trials of pembrolizumab was conducted using databases from PUBMED, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October 2018. Eligible studies included prospective clinical trials of pembrolizumab with available data on FAE. Data on FAE was extracted from each study and pooled for calculations. Incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated by employing fixed or random-effects models. Results: A total of 11 clinical trials of pembrolizumab, with 3713 patients were included for analysis. The overall incidence of FAE with pembrolizumab was 1.2% (95% CI: 0.5-2.8%).The incidence of FAE significantly varied among different tumor types (P=0.02), ranging from 0.2% in melanoma to 3.1% in breast cancer.The incidence of FAE was significantly higher (P<0.001) with chemotherapy plus pembrolizumab (7.0%, 95%CI: 4.9-10%) as compared to pembrolizumab alone (0.7%, 95% CI: 0.4-1.2, p=<0.001). There was no significant difference in the risk of FAEs when pembrolizumab was compared with chemotherapy with RR=1.24 (95% CI: 0.8-1.89, P=0.31). Conclusions: Pembrolizumab is similar to chemotherapy in the risk of fatal adverse events in cancer patients. Combination of pembrolizumab with chemotherapy increased the risk of FAE in comparison with pembrolizumab alone. Further studies are needed to identify risk factors. [Table: see text]
Characteristics of patients receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ.
Authors: Rubinstein Wendy S. , Chen Li , Komatsoulis George Anthony , Stepanski Edward , Jun Monika , Zhi Jizu , Lau Denise , Roberts Jeremy , Miller Robert S. , Walker Mark S. , Fukushima Ryan , Hyde Brigham , Khozin Sean
Published: May 2019

2566

Background: ICI’s have demonstrated significant clinical benefit since the first FDA approval in 2011 of ipilimumab for metastatic melanoma. Five additional ICI therapies have since been approved across several indications. The objectives of this study were to describe the clinical and demographic features of patients receiving ICI treatment along with utilization patterns in real-world settings. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database, which now contains EHR data from 49 diverse oncology practices in the U.S. Adult patients diagnosed with any cancer type who received ≥1 dose of an ICI (see Table) and had ≥2 clinical visits were eligible for inclusion. Patients were excluded if they received an ICI prior to its first FDA approval date to avoid inclusion of clinical trial patients. Descriptive statistics were used to examine treatment patterns and clinical characteristics of patients receiving ICIs. Results: This analysis included 12,712 patients who received an ICI. Median patient age was 67.4 years [IQR 59.3, 75.3]; 58% were male. White race made up the highest percent (83%) of ICI patients, followed by Black race (9%) and Other (8%). The most common primary cancers at the start of treatment were lung cancer (36%), melanoma (8%), urothelial cancer (2%) and renal cell carcinoma (2%). Of the 8,444 patients with known disease stage, 5,446 (64%) had Stage IV cancer. Breakdown of ICI treatment patterns can be found in the accompanying table. Uptake of ICIs was the most rapid for nivolumab, which had the highest use (49%), followed by pembrolizumab for rapid adoption and use (30%). Conclusions: This analysis gives insights into patient characteristics and real-world treatment patterns for ICIs. ICIs were used most widely in males, lung cancer patients and patients with advanced disease. These baseline characteristics inform our analyses of ICI use in patients with autoimmune disease, also reported herein.[Table: see text]
Cardiovascular complications of immune checkpoint inhibitor therapy.
Authors: Master Samip R. , Robinson Arelis , Mills Glenn Morris , Mansour Richard P
Published: May 2019

2568

Background: Cardiac toxicity has largely been underestimated toxicity of checkpoint inhibitors. There have been several cases of myocarditis and fatal heart failure reported in patients treated with checkpoint inhibitors. We did a retrospective analysis of data of adverse effects of drugs that has been made available to public by the FDA. Methods: The FDA has made the data on adverse effects of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the cardiac toxicities of various immune check point inhibitor therapies available at FDERS for the years 2017-2018. Results: The reviewed the reported side effects of pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab and ipilimumab from FDA data. A total of 36,848 toxicities from immunotherapies were reported. Out of that, 2316(6.2 %) were cardio toxicities and 816 were fatal. The most common cardiac complications were as follows: myocarditis (15%), atrial fibrillation (13%), pericardial disease including pericardial effusion (13%), cardiac failure (17%) and coronary artery disease (19%). Approximately 50%, 43%, 40% 22% and 15 % of cases with myocarditis, ischemic heart disease, cardiac failure, atrial fibrillation and pericardia disease were fatal. Conclusions: Out of the reported cases of adverse reaction to check point inhibitor, 6.2% were cardio toxicities. 35% of cardio toxicities were fatal. Half of the cases who developed myocarditis died. There was no statistical difference in rate of cardiotoxicities caused by PD1, PDL1 or CTLA 4 inhibitors.
Immunomodulation by HDAC inhibition: Results from a phase Ib study with vorinostat and pembrolizumab in metastatic urothelial, renal, and prostate carcinoma patients.
Authors: Pili Roberto , Quinn David I. , Albany Costantine , Adra Nabil , Logan Theodore F. , Greenspan Andrew , Budka Justin , Damayanti Nur , Green Mark A , Fletcher James W. , Tann Mark , Edwards Sara I , Burney Heather , Liu Hao , Hahn Noah M.
Published: May 2019

2572

Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that HDAC inhibitors have synergistic antitumor effects in combination with PD-1 inhibition in tumor models by inhibiting the function of Tregs and MDSCs. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial, renal and prostate carcinoma. Methods: The primary objective was to evaluate the safety and tolerability of this combination strategy. The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and one week OFF) and a fixed, standard dose of pembrolizumab (200 mg IV every 21 days). Patients were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve urothelial and renal cancer pts = 15), Cohort B (previously treated, anti-PD1/PD-L1 resistant urothelial and renal cancer pts = 14), and Cohort C (prostate cancer pts = 14). Results: Dose levels 1 (4 enrolled, 3 evaluable) and 2 (4 enrolled, 3 evaluable) were completed without DLTs and 200 mg was the Phase II recommended dose for vorinostat. The most common resolved grade 3/4 toxicities were acute kidney injury (n = 1), anemia (n = 1), diarrhea (n = 1), and hypothyroidism (n = 1) in the dose expansion cohorts. We have enrolled 43 pts (37 evaluable) in the dose expansion cohorts. For Cohort A, B, and C the median PFS were 2.8 months, 5.2 months, and 3.5 months. Two PR were observed including the dose escalation phase. Two PCA pts have achieved undetectable PSA. We have performed several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells, PDL-1 staining and PSMA PET scans in a subset of pts. Conclusions: The results from this phase Ib suggest that the combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint resistant UC/RCC pts and immune checkpoint naïve PCA pts. Clinical trial information: NCT02619253.
Immune-mediated colitis after resumption of immune checkpoint inhibitor therapy.
Authors: Abu-Sbeih Hamzah , Ali Faisal , Naqash Abdul Rafeh , Owen Dwight Hall , Patel Sandip H. , Otterson Gregory Alan , Kendra Kari Lynn , Ricciuti Biagio , Chiari Rita , Giglio Andrea De , Sleiman Joseph , Funchain Pauline , Beatriz Wills , Zhang Jiajia , Naidoo Jarushka , Philpott Jessica , Gao Jianjun , Subudhi Sumit Kumar , Wang Yinghong
Published: May 2019

2577

Background: Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the recurrence rate and risk factors for IMDC after ICI resumption. Methods: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between 1/2010 and 11/2018. Univariate and multivariate logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. Results: Of the 167 patients in our analysis, 32 resumed an anti-CTLA-4 agent and 135 an anti-PD-1/L1 agent. The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136). IMDC recurred in 57 (34%) patients overall (44% of those resuming an anti–CTLA-4 and 32% resuming an anti–PD-1/L1 agent); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC (Table). The median duration from ICI resumption to IMDC recurrence was 53 days (IQR 22-138). On multivariate logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45, 95%CI, 1.59-7.69; P<0.01). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95%CI, 1.08-9.62; P=0.02) or had longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95%CI, 1.00-1.03; P=0.03). Risk of IMDC recurrence was lower for those who resumed anti–PD-1/L1 therapy than for those who resumed anti–CTLA-4 therapy (OR, 0.30; 95%CI, 0.11-0.81; P=0.02). Conclusions: One-third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. IMDC recurrence was less frequent after resumption of anti–PD-1/L1 than after anti–CTLA-4. Characteristics of recurrent IMDC based on resumed ICI therapy. [Table: see text]
High prevalence of IBD-associated genetic variants in patients (pts) with immune checkpoint inhibitor (ICI) enteritis/colitis.
Authors: Grover Shilpa , Srivastava Amitabh , Friedman Sonia , Buchbinder Elizabeth Iannotti , Hodi F. Stephen , Rahma Osama E.
Published: May 2019

2582

Background: Colitis is a frequent toxicity of ICI therapy but there is paucity of data on risk factors. Specific serological markers and genetic polymorphisms have been associated with inflammatory bowel disease (IBD) (ulcerative colitis, Crohn’s disease). However, the prevalence of these markers in pts with ICI colitis is unknown. We performed a pilot study to determine the prevalence of IBD-associated genetic and serologic biomarkers in pts with ICI colitis. Methods: Cancer pts with histologically confirmed ICI enteritis/colitis and no history of IBD underwent commercial IBD panel testing. The panel included 4 genetic markers ( ATG16L1, NXK2–3, ECM1, STAT3), 8 serological markers (anti-A4-Fla2, anti-A4-FlaX, anti-CBir1, anti-OmpC, ASCAIgA, ASCA-IgG, pANCA, ANCA), and 5 inflammatory markers (vascular endothelial growth factor [VEGF], intracellular adhesion molecule 1[ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], C-reactive protein, serum amyloid A [SAA]). Clinical testing on serum samples was performed by Prometheus Laboratories (San Diego, CA). Results: Of 15 cancer pts with biopsy confirmed ICI colitis, 10 (67%) were homozygous for 1 or more of 4 genetic markers. The remaining 5 pts were all heterozygous for two or more of the genetic markers. One or more serologic markers associated with IBD were elevated in 7/15 (47%) pts. Serum reactivity was noted for ASCA-IgA (1/15, 7%), ASCA-IgG (1/15, 7%), anti-OmpC (3/15, 20%), anti-CBR IgG (2/15, 13%), anti-A4-FlaX (1/15, 7%), and ANCA (2/15, 13%). One or more inflammatory markers were elevated in 13/15 (88%) pts. Elevations in VEGF, VCAM-1, ICAM-1, and SAA were noted in 2 (13%), 8 (53%), 8 (53%), and 11 (73%) pts, respectively. Only 6 (40%) pts had elevations in CRP levels despite the presence of active inflammation on biopsy. The IBD panel was reported as being consistent with Crohn’s disease in 2 pts, ulcerative colitis in 1 pt and inconclusive for type but consistent with IBD in 1 pt. Conclusions: In this pilot study, all patients with ICI colitis, were either homozygous or heterozygous for two or more high risk IBD alleles. If validated, such testing may prospectively identify pts at risk for developing ICI colitis.
Overcoming genetically based resistance mechanisms to PD-1 blockade.
Authors: Torrejon Davis Yuri , Abril-Rodriguez Gabriel , Tsoi Jennifer , Champhekar Ameya , Kalbasi Anusha , Campbell Katie Marie , Parisi Giulia , Puig-Saus Cristina , Cheung-Lau Gardenia , Wohlwender Tom , Berent-Maoz Beata , Grasso Catherine , Comin-Anduix Begoña , Hu-Lieskovan Siwen , Ribas Antoni
Published: May 2019

2584

Background: Mechanism-based strategies to overcome resistance to anti-PD1 therapy are urgently needed. Using CRISPR/Cas9 genome editing tools, we developed acquired resistant models through JAK1/2 and B2M loss of function (LoF) mutations in human melanoma cell lines and in the murine MC38 colon carcinoma, known for high mutational load and good response to anti-PD-1. We hypothesized that the downstream activation of the IFN-receptor pathway or the activation of natural killer (NK) cells would overcome this resistance. Methods: We studied signaling changes in four human cell lines (parental and LoFs) exposed to IFN-gamma using RNAseq. In addition, we analyzed the in-vivo antitumor activity in MC38 variants with anti-PD1 and characterized the tumor microenvironment using mass cytometry (CyTOF). Finally, we tested strategies to overcome resistance mechanisms with SD-101 (TLR-9 agonist) and bempegaldesleukin (NKTR-214, CD-122 biased agonist) with the extent of CD8 and NK1.1 depletion. Results: RNAseq differential gene expression analysis showed that the IFN-gamma induced increased expression of antigen presenting machinery, IFN-gamma signaling and chemokines (CXCL9/10) was lost in JAK1/2-LoF human melanoma cell lines. The significant antitumor activity of anti-PD-1 against MC38 parental cell line was lost in JAK1/2 and B2M LoF sublines, and CyTOF analysis revealed that anti-PD-1 therapy was unable to increase tumor CD8+ T-effectors in these LoF tumors. The intratumoral administration of SD-101 (50 μg/injection q4dx3wks) was able to overcome local resistance even in non-injected sites in JAK1/2 and IFNAR-type-I LoF tumors, and systemic administration of bempegaldesleukin (0.8 mg/kg, q9dx2, i.v.) was able to overcome resistance in B2M LoF with significantly increased survival (Table). Depletion studies showed complete abrogation of anti-tumor response with anti-NK1.1 in JAK1 LoF and B2M LoF, and partial abrogation with anti-NK1.1 or anti-CD8 in JAK2 LoF tumors. Conclusions: Even in the extreme setting of genetic resistance to PD-1 blockade by JAK1/2 LoF, resistance can be overcome by SD-101, a TLR9 agonist, while resistance of B2M LoF can be overcome by bempegaldesleukin (NKTR-214), a CD-122 biased agonist. Our findings support the testing of these rational mechanistic strategies in patients with a-PD1 resistance. [Table: see text]
Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
Authors: Zhu Jason , Pabla Sarabjot , Labriola Matthew , Gupta Rajan T. , McCall Shannon , George Daniel J. , Dressman Devin , Glenn Sean , George Saby , Morrison Carl , Zhang Tian
Published: May 2019

2595

Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high Teffhigh/PD-L1+ are more likely to respond to ICI. Here, we use two gene panels as well as other inflammation markers in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 86 patients (pts) with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing for Teff status. Two gene panels were analyzed: a Teff Gene Panel (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1) and a 5-Gene panel (FOXP3, CCR4, KLRK1, ITK, and TIGIT) based on the gene expression pattern of tumors in our cohort. Objective response rates (ORRs, defined as CRs and PRs) were correlated with PD-L1 status (positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay), and TMB (0-10, 10-20, ≥20 mut/Mb), and tumor inflammation (high CD8 expression compared to a large reference population). Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, Teff gene panel, 5-gene panel, PD-L1 status, and TMB were associated with ORR and tested using a chi-squared test with Yates’s continuity correction. Results: ORR was 50% (4/8) for PD-L1 positive pts and 14% (9/65) for PD-L1 negative pts (p = 0.042). The majority of tumors (95%, 82/86) had TMB < 10 mut/mb. 43 pts (50%) were classified as Teffhigh and 43 pts were classified as Tefflow. ORR was 23% (10/43) in the Teffhigh cohort and 12% (5/43) in the Tefflow cohort (p = 0.256). ORR was 31% (14/45) in the 5-Gene high cohort and 2% (1/41) in the 5-Gene low cohort (p = 0.001). Conclusions: TMB and tumor inflammation based on CD8 did not reliably predict for objective responses in this study of mRCC pts treated with ICIs. Gene expression signatures provide a more comprehensive evaluation of the tumor microenvironment and may lead to better predictive biomarkers for ICI response than individual biomarkers such as PD-L1, TMB, or CD8 expression.
Dynamic changes of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) during treatment with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
Authors: Russo Alessandro , Franchina Tindara , Ricciardi Giuseppina , Battaglia Alessandra , Schifano Silvia , Schifilliti Maurizio , Scimone Antonino , Toscano Giuseppe , Zanghì Mariangela , Adamo Vincenzo
Published: May 2019

2596

Background: ICIs have revolutionized the therapeutic landscape of NSCLC. However, with the exception of PD-L1 expression, predictive biomarkers are lacking. The aim of this study was to evaluate the dynamic changes of some markers of inflammation over time and the outcome of NSCLC patients (pts) treated with nivolumab (N) or pembrolizumab (P). Methods: All consecutive NSCLC pts treated with N or P between Aug. 2015-Dec. 2018 were analyzed. Laboratory results were collected at baseline, 6 weeks (6-wk), and 12 weeks (12-wk) and correlated with the outcome. NLR and PLR were defined as absolute neutrophil and platelet count divided by lymphocyte count, respectively. NLR ≥5, PLR ≥200, and LDH levels ≥ upper normal limit were considered high. Overall survival (OS) was defined as time from ICI start to death and Progression Free Survival (PFS) as time from treatment start to progression disease or death for any cause. OS and PFS curves were estimated using the Kaplan–Meier method and compared with the log-rank test. Results: We included 71 consecutive NSCLC pts treated with either N (75%) or P (25%). Baseline characteristics: median age 69 years (range 46-80), sex male 76%, squamous histology in 39%. PD-L1 expression (39/71): < 1% in 20%, 1-49% in 45%, and ≥50% in 35%. NLR ≥5 was associated with lower PFS and OS, with an increased predictive value over time ( p =0.01 and p =0.009 at baseline; p =0.007 and p <0.001 at 6-wk; p <0.001 and p <0.001 at 12-wk, respectively). PLR ≥200 at baseline and 12-wk was significantly associated with shorter OS ( p =0.05 and p =0.004, respectively), but no in terms of PFS at all the three time points. Finally, LDH ≥UNL at baseline was associated with shorter PFS and OS ( p =0.02 and p =0.03), as well as a reduction of LDH levels at 12-wk compared with baseline values ( p =0.006 and p =0.004). Conclusions: Baseline evaluation of NLR, PLR and LDH levels is significantly associated with outcome in NSCLC treated with single agent ICIs. Moreover, dynamic changes of LDH levels at 12 weeks significantly predicted outcome. These easy to determine parameters may have a place in the selection process of pts candidate for immunotherapy.
A dose-finding study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients with advanced solid malignancies.
Authors: Juergens Rosalyn A. , Chu Quincy S. , Renouf Daniel John , Laurie Scott Andrew , Purcea Daniela , McWhirter Elaine , Arndt Diane , Gelmon Karen A. , Hilton John , Gavillet Bruno , Ellis Peter Michael , Sawyer Michael B. , Kollmannsberger Christian K. , Andrews Wright Natalie , Rouits Elisabeth , Brichory Frank , Vuagniaux Gregoire , Szyldergemajn Sergio A. , Goss Glenwood
Published: May 2019

2599

Background: Second mitochondria-derived activator of caspase (SMAC) mimetics regulate apoptosis and modulate NFκB signaling which drives the expression of genes involved in immune and inflammatory responses. In patient (pt) tumors, Debio 1143 increased PD-1/PD-L1 expression and tumor infiltrating lymphocytes. In pre-clinical models, it synergizes in vitro and in vivo with PD1/PD-L1 checkpoint inhibitors (CPIs). Methods: In a phase I study, using a mCRM model, avelumab (10 mg/kg i.v. on D1&15 q4w) was combined with escalating doses of Debio 1143 (100 mg/d to 250 mg/d orally, D1-10 & D15-24 q4w) to define the RP2D. Consenting adult pts with advanced solid tumors, normal organ function, and PS-ECOG = 0-1 were eligible provided none received prior CPI. Dose-limiting toxicities (DLTs), efficacy, safety, PK, PD and biomarkers were assessed. Results: As of DEC’18, 16 pts were treated; M/F: 8/8; ECOG = 0 in 6 (38%); median age = 58 (28-79); 5 pts had NSCLC, 2 MPM, 2 ovarian and 7 had other tumors (n = 1 each). Common AEs were: nausea (69%); fatigue (62%); vomiting (50%); cough, dyspnea, myalgia (44% each); diarrhea, anorexia (38% each); pruritus and constipation (31% each). These were generally grade 1-2, occasionally grade 3. One pt had a DLT at 250 mg/d dose: a grade 3 AST/ALT increase. No treatment-related AEs grade 4 or higher occurred. No dose-relationships for laboratory abnormalities were observed, except for ALT/AST increases, which at 200 mg/d were all grade 1 and asymptomatic. Maximal tolerated dose was not reached and there were no dose reductions. In 15 evaluable pts, 1 PR (NSCLC) and 5 SD (RECIST v1.1) were observed. Tumor shrinkage > 15% was seen in 2 other NSCLC pts. PK showed high interpatient variability and dose-proportional increase. TNFα and IFNγ peaked in plasma following Debio 1143 dose on D1 after 8 hrs, and on D17/22, in a dose-proportional manner. Four pts developed anti-avelumab antibodies. Conclusions: Debio 1143 at 200 mg/d can be safely combined with avelumab. Toxicity was predictable and mild. Clinical activity was observed in NSCLC pts. PK was linear; no drug interaction was suspected. PD and biomarker analysis is ongoing. Expansion at this RP2D is ongoing in NSCLC. Clinical trial information: NCT03270176.
First-in-human (FIH) trial evaluating immune activation and safety of PIN- 2 administered intravenously to patients with advanced solid tumors.
Authors: Bier Colin , Millward Michael , Kotasek Dusan , Gorelick Kenneth J , Goldberg Joshua Brian
Published: May 2019

2600

Background: Innate immunity is an integral component necessary to initiate systemic anti-tumor immunity in patients with progressive malignancy. PIN-2 is a novel immunomodulating agent derivatized from a transactivator (Tat) protein that stimulates innate immunity in vivo by promoting differentiation of peripheral blood monocytes into activated APC’s linking the innate and adaptive immune systems resulting in endogenous T-cell priming against a multitude of tumor associated antigens unique to the individual. Methods: A FIH clinical trial was conducted in patients (pts) with extensively pretreated solid tumors to evaluate the pharmacodynamics (PD) and safety of PIN-2. 8 pts (2 men), mean age 62.7 (±7.9) years, and a median of 4.5 prior treatment lines, were enrolled in 2 Australian centers. 2 pts received 1 cycle of treatment and 6 received 2 cycles. Pts were given 300 µg of PIN-2 IV 3 times/wk for 2 wks followed by a 1 wk rest period. A 2nd cycle of treatment was offered based on pt and investigator preference. Plasma was collected at 6 and 24H post-infusion 1 to evaluate immune activation. Th1 cytokines (TNF-α, IFN-γ, IL-12, CSF-2) were analyzed to assess PD activity. Results: A significant increase in TNF-α was seen 6H following PIN-2 infusion (p = 0.0142), demonstrating rapid onset of immune activation. There were no clear changes in the other parameters evaluated. PIN-2 was rapidly cleared from plasma, with mean T1/2 = 24.0 (8.07) min, Tmax = 1.06 (0.665) min, Cmax= 77,500 (61,600) pg/mL, and AUC0-inf = 690,000 (493,000) pg•min/mL. 3 pts discontinued treatment, 2 for adverse events (1 gr 2 infusion reaction, 1 unrelated SAE of abdominal pain) and 1 for disease progression on day 12. Treatment related AEs were grade 1 and 2, and readily managed. There was a single unrelated gr 3 event (anemia) and no AEs > gr3. 2 pts developed anti-drug antibodies; however, these did not result in changes in the immuno-PD profile. Conclusions: PIN-2 was generally well tolerated with an acceptable safety profile. PIN-2 caused an early increase in TNF-α, consistent with PD activity predicted by preclinical data. Further study alone and in combination with other agents in pts with advanced solid tumors is warranted. Clinical trial information: ACTRN12617001597381.
Safety profile of INT230-6, a novel intratumoral (IT) formulation, during injections into a variety of refractory deep and superficial tumors with evidence of tumor regression and immune activation.
Authors: El-Khoueiry Anthony B. , Thomas Jacob Stephen , Hanna Diana L. , Siu Lillian L. , Azad Nilofer Saba , Whalen Giles Francis , Bender Lewis H. , Walters Ian B. , Olszanski Anthony J.
Published: May 2019

2602

Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells. In preclinical experiments, INT230-6 led to necrosis and recruitment of immune cells with high rates of complete responses of injected and bystander tumors. This abstract highlights the safety and early pharmacodynamic activity of this approach. Methods: Patients with solid tumors that progressed on all standard treatments were enrolled. Dose escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. INT230-6 was injected once every 2 weeks in multiple lesions for 5 sessions. Patients were monitored for safety and tolerability weekly. Pharmacokinetic(Pk) samples and peripheral blood were collected for flow cytometry and circulating cytokines. Pre and on study biopsies are ongoing. Results: 28 patients (14 unique cancer types) receiving a median of 3 prior treatments were enrolled. Doses from 0.3 ml up to-80 ml of INT230-6 were given into single lesions with some patients receiving a total of 120 mL ( = 9.7mg VIN exceeding the IV VIN dose) without significant systemic absorption or typical cytotoxic adverse events. Pk analysis suggests that systemic exposure of VIN or CIS is ~10% of injected. No DLT’s or drug-related SAE’s reported. The most frequent adverse event was grade 1 or 2 pain at injected site. Superficial tumors showed signs of response including flattening, areas of necrosis and ulceration. Tumor reduction, apparent in in both injected and bystander tumors, may indicate an abscopal effect. An increase > 30% in CD8 T-cells was seen in the blood of 3/9 evaluable patients. Conclusions: INT230-6 was safe and well tolerated in > 100 injections (28 patients) with encouraging activity and pharmacodynamic effects in advanced refractory tumors. Additional analysis of immune cells from on study biopsies will be presented. A new cohort will evaluate combination with an anti-PD1 antibody to understand if local tumor destruction can increase systemic antigen load, increase immune cell recognition and initiate a systemic immune response. Clinical trial information: NCT 03058289.
THOR-707: Using synthetic biology to reprogram the therapeutic activity of interleukin-2 (IL-2).
Authors: Milla Marcos E , Ptacin Jerod , Caffaro Carolina E. , Aerni Hans R. , Ma Lina , Koriazova Lilia , Joseph Ingrid B. , Shawver Laura K.
Published: May 2019

2603

Background: Recombinant interleukin-2 (rIL-2; aldesleukin) is an approved immunotherapy in melanoma and renal cell carcinoma based on complete durable remissions. The anti-neoplastic properties of IL-2 are mediated by interactions with the beta-gamma chain (IL-2Rβγ) on naïve CD8+ T cells, which lead to their expansion and differentiation into T effector and T memory cells directed against the tumor. However, the widespread use of IL-2 in oncology is limited by interaction with the high affinity IL-2 receptor alpha chain (IL-2R⍺) on regulatory CD4+ T cells (Tregs), which leads to immunosuppression, and on innate lymphoid cells in the vascular endothelium, which leads to eosinophilic recruitment and activation, and the sometimes fatal complication of vascular leak syndrome (VLS). A rIL-2 biased toward IL-2βγ affinity with no IL-2R⍺interaction could fill unmet needs in oncology. Methods: Using a synthetic biology platform, we have engineered THOR-707, a rIL-2 that contains a novel amino acid encoded in the IL-2 gene via a new DNA base pair (X-Y). The novel amino acid serves as a hook for site specific pegylation that extends half-life, blocks IL-2R⍺ engagement and binds to the IL-2Rβγ. Results: In non-human primates, THOR-707 can be dosed to maximize the level of cytotoxic CD8+ T lymphocytes without elevation of VLS-inducing eosinophils. In murine tumor models, THOR-707 induced the expansion of peripheral and intratumoral CD8+ T cells without expansion of suppressive Tregs. Single-agent dose-dependent anti-tumor efficacy was observed in two syngeneic mouse models. In combination with a PD-1 inhibitor, survival of tumor-bearing mice was longer than either agent as monotherapy. Efficacy in tumor models was durable, suggesting activation of CD8+ memory T cell populations. Conclusions: THOR-707 is a reprogrammed, site-directed, singly-pegylated rIL-2 that changes the pharmacologic profile of IL-2, potentially providing a favorable risk-benefit profile. First-in-human studies are expected to begin this year evaluating THOR-707 as monotherapy and in combination with a PD-1 inhibitor. Based on preclinical evidence to-date, THOR-707 may potentially address existing and emerging unmet needs across multiple solid tumors.
AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced tumors: Preliminary results from ongoing phase I studies.
Authors: Powderly John D. , de Souza Paul L. , Gutierrez Rodolfo , Horvath Lisa , Seitz Lisa , Ashok Devika , Park Adam , Walters Matthew J. , Karakunnel Joyson Joseph , Berry Wade , Rieger Aimee , Garofalo Amanda , Lai Dominic W. , Chaudhry Arvind
Published: May 2019

2604

Background: AB928, a selective, small-molecule A2aR/A2bR antagonist, potently blocks the immunosuppressive effects of high adenosine concentrations in the tumor microenvironment. Preclinically, combining adenosine receptor inhibition with either chemotherapy or anti-PD-1 resulted in greater tumor control, suggesting AB928 may have additive activity when paired with either of these agents in cancer pts. Methods: Three dose-escalation (3+3 design) studies are assessing the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of increasing doses of AB928 (75, 150, 200 mg orally once daily) in combination with: standard pegylated liposomal doxorubicin in triple-negative breast cancer (TNBC) and ovarian cancer (OC); standard mFOLFOX6 in gastroesophageal cancer (GEC) and colorectal cancer (CRC); and AB122 (240 mg every 2 weeks) in various advanced tumors. Following identification of the recommended phase 2 dose of AB928 in combination with chemotherapy or AB122 in dose escalation, the following tumor cohorts may be expanded (15-40 pts/cohort) to further test the combinations: TNBC and OC, GEC and CRC, and renal cell carcinoma. Results: As of 01Feb2019, 9 pts were treated across the 3 studies, and time on treatment ranged from 1-182 days (table). Overall, AB928 combination therapy was well tolerated. Two pts underwent post-baseline disease assessment; both had stable disease. Preliminary data indicate that AB928 PK and adenosine receptor coverage in cancer pts are similar to what was previously assessed in healthy volunteers. AB122 PK and PD-1 coverage are equally unaffected by AB928 co-administration. Updated data, including biomarker data, will be presented at the meeting. Conclusions: Early results showed a favorable safety profile of AB928 combination therapy. All 3 studies are actively recruiting pts. Clinical trial information: NCT03719326; NCT03720678; NCT03629756. [Table: see text]
2D and 3D thermally bioprinted human MCF-7 breast cancer cells: A promising model for drug discovery.
Authors: Campbell Aleli , Philipovskiy Alexander , Heydarian Rosalinda , Varela-Ramirez Armando , Gutierrez Denisse A. , Solis Luis H. , Furth Michael E. , Boland Thomas
Published: May 2019

2605

Background: Breast cancer (BC) is the second leading cause of cancer death following lung cancer. Bioprinting, the use of computer aided process to print biological living and non-living material to create patterns in 2D or 3D structures, is a novel technique that has been proposed to be used to develop tissue engineered solutions for a wide array of clinical applications, e.g., skin grafting. We investigate here if bioprinted breast cancer cells show some of the hallmarks of cancer tissues, and thus may represent good in vitro models for drug discovery. Methods: For this study, MCF-7 BC cells were cultured, stained, counted and turned into a bioink solution by suspending in phosphate buffered saline solution. The cells were bioprinted over a 96-well plate and pre-incubated for 18 hours in DMEM and RPMI media with 10% Fetal Bovine Serum and Charcoal Stripped Serum, respectively. After 18 hours of incubation the media was supplemented with Tamoxifen at 5µM, 10µM, 50µM, 90µM and 110µM concentrations. Cytotoxicity was measured 24 hours post-treatment using a differential nuclear staining assay and an INCell 2000 bioimager system. Results: Bioprinted cells exposed to high concentrations of Tamoxifen (90 µM and 110µM) exhibited a viability of 8.2% and 10.8%, respectively. Whereas viability of manually seeded cells at those concentrations was 0.11% and 0.05%. Viability of negative and positive controls was at 7.6% and 97.0% for the bioprinted samples and for the normally seeded cells was 4.9% and 98.8% respectively. Conclusions: In our study, we have established a novel 2D/3D breast tumor model applying bioprinting technology for drug discovery. The higher cell viability of MCF-7’s at high concentrations of Tamoxifen could be attributed to the hormesis effect and activation of chaperone proteins, e.g., HSP70 and HSP90, possibly caused by bioprinting. We hypothesize that bioprinted MCF-7 cells also show increased levels of chaperone proteins, which may in a way mimic their in vivo behavior. In this novel in vitro 2D/3D model, the bioprinted cells show a more biological relevant behavior than normally cultured cells. Insights into the cell behavior after bioprinting may elucidate how to build improved in vitro models for BC research.
Gut microbiota and clinical outcomes treated with nivolumab in Chinese non-small cell lung cancer.
Authors: Lu Shun , Jing Yueping , Xia Liliang , Li Ziming , Yao Chengcheng , Wang Ying
Published: May 2019

2614

Background: Gut microbiome affecting responses to immune checkpoint inhibitors (ICIs) against non-small cell lung cancer (NSCLC) has been investigated in western population. However, considering genetic variation, this phenomenon remains in vague in east-Asian NSCLC population. The study is designed to explore the relationships between gut microbiome and clinical outcomes treated with anti-PD-1 blockade in Chinese patients. Methods: 37 NSCLC patients received the treatment of Nivolumab were enrolled in the study from the clinical trials CheckMate870 (NCT03195491). Fecal samples were collected at the starting point, every time point performing clinical evaluation and that with disease progression. 16s sequencing was applied to assess the gut microbiota characteristics. Peripheral immune profiles were determined by multi-color flow cytometry in parallel. Results: When subgrouping patients into responders (R) and non-responders (NR) groups according to the clinical response assessed by RECIST1.1, patients in R group harbored higher diversity of gut microbiome at the starting point with consistent composition along the treatment. Analyzing progression-free survival (PFS) according to RECIST 1.1, patients with higher microbiome diversity had significantly prolonged PFS when compared to those with low diversity. Compositional difference was observed between two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium logum, Prevotella corpri in R group whereas Ruminococcus_unclassified in NR group. Analysis of systemic immune responses using multi-color flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had more frequencies of memory CD8+ T cell subset in the periphery in response to anti-PD-1 therapy. Conclusions: Our results report the strong correlation between the gut microbiome diversity and the responses to anti–PD-1 immunotherapy in Chinese NSCLC patients regardless of genetic variation between Western and Chinese population. Patients with a favorable gut microbiome (such as high diversity) have enhanced immune responses mediated by effector T cell function in the periphery. These findings thus provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC.