Partial Response Patients Research Articles

Abstract LB-076: Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy - results of a randomized phase II clinical trial (NSCLC-TKD/IL-2) (Eudra-CT Number 2008-002130-30)

Abstract Membrane-bound heat shock protein 70 (mHsp70) is indicative for high-risk tumors with negative prognosis but also serves as a target for NK cells that are stimulated with Hsp70 peptide TKD and low dose IL-2 (TKD/IL-2). Herein, the efficacy of ex vivo TKD/IL-2 activated, autologous NK cells was tested in a randomized, investigator initiated phase II clinical trial in patients with mHsp70 positive advanced stage NSCLC after radiochemotherapy (RCT, 60-70 Gy, platinum-based chemotherapy). The interventional (INT) group received 4 cycles TKD/IL-2 activated, autologous NK cells every 2-6 weeks subsequent to standard RCT and the control (CTRL) group received best supportive care. The primary objective of the study was to examine whether the adjuvant treatment of NSCLC patients with TKD/IL-2 activated NK cells is feasible and effective with respect to progression-free survival (PFS). Secondary objectives were the assessment of treatment and biological responses, toxicity, quality-of-life (QoL, QLQ-LC13). Eight patients were randomized into the INT and eight into the CTRL arm. None of the patients died between randomization and final tumor assessment 18 months after randomization. In the INT group one patient had complete response (CR), one patient partial response (PR), two patients stable disease (SD) and one patient progressive disease (PD) at the last documented visit, whereas in the CTRL group only 2 patients showed clinical responses (PR, SD) and five patients had PD. The clinical response of patients in the INT group appeared to be mediated by activated NK cells whereas in the CTRL group by CD8+ T cells. The NK cell therapy after RCT was well tolerated, no differences in QoL were observed between both study groups. Citation Format: Gabriele Multhoff, Stephanie E. Combs, Sophie Seier, Stefan Stangl, Wolfgang Sievert, Maxim Shevtsov, Christiane Blankenstein, Martin Hildebrandt, Konrad Kokowski, Matthias Hautmann, Hubert Hautmann, Claus Roedel, Rainer Fietkau, Rudolf M. Huber, Bernhard Haller, Christina Ertl, Michal Devecka, Robert Offner, Norbert Ahrens. Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy - results of a randomized phase II clinical trial (NSCLC-TKD/IL-2) (Eudra-CT Number 2008-002130-30) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-076.

Abstract CT136: Phase I study with rapamycin combined with irinotecan, the SFCE RAPIRI I trial, a new way to target tumor hypoxia in pediatric refractory cancers

Abstract Background: Hypoxic environment is a pejorative prognostic factor in pediatric solid tumors (ST). It is favoring neoangiogenesis, tumor progression and resistance to treatments through the activation of mTor and HIF-1α pathways. Those hypoxic markers can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a dose-escalation phase I trial combining both drugs to inhibit tumor hypoxic mechanisms present in several pediatric refractory/relapsing ST. Procedure: Patients were enrolled in this 3+3 escalation trial with ten dose levels. The primary endpoint was to determine the maximum tolerated dose (MTD) of rapamycin when combined with irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day) and associated biweekly with intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics (PK), efficacy analyses and pharmacodynamics (UGT1A1 status, cytokines/chemokines assessment, MRI markers and proteins' expression) were evaluated. Results: 42 patients were treated and had mild to moderate reversible toxicities. No MTD was present up to the tenth level. The PK were highly variable. Nevertheless, the usually targeted concentrations of rapamycin over time were reached at 1.5 mg/m2/day dose. When looking to the 2 partial responses (PR) and 19 stable diseases (SD) in 31 assessable patients, the mean irinotecan AUC was 363 min.mg/L and the mean D8 rapamycin AUC was 9.3 min.mg/L. No significant relationship was observed between dose escalation and response, but progressive tumors' subgroup (PD) had slightly lower mean irinotecan AUC (321 min.mg/L) and D8 rapamycin AUC (6.5 min.mg/L). The two main tumor groups were brain tumors (BTs) and sarcomas. A high proportion of those patients experienced tumor responses (3/4 ependymomas, 2/3 medulloblastomas, 1 rhabdoid tumor, 2/3 high-grade gliomas and 5/6 osteosarcomas). In all 17 assessable patients for immunohistochemistry, the two targeted proteins, mTor and HIF-1α, were expressed, but the resistance to this double strategy was significantly linked to the HIF-2α protein hyperexpression. In the BTs, lower ADC values in MRI were also a prerequisite for tumor responsiveness. Cytokine analyses, distinguished specific proinflammatory and angiogenic signatures during first course of treatment: PR patients had an increase of TNF, associated to a stable PIGF and a decrease of VEGF-C; the SD subgroup had a significant increase of VEGF-D and a stable or increase of sFLT1 and PD group had a constant increase of IL8 and VEGF-D. Conclusion: Despite no MTD, we can propose a next phase II trial with rapamycin dose of 1.5 mg/m2/day associated with 125 mg/m2 irinotecan in STs not expressing HIF-2α protein. A precise PK follow-up will be used to reach an irinotecan AUC up to 360 min.mg/L and a D8 rapamycin blood concentration of 10 µg/L. The cytokine evaluation will help us to predict during first cycle the potential tumor response. Citation Format: Sarah Jannier, Veronique Kemmel, Consuelo Sebastia, Agathe Chammas, Amelia-Naomi Sabo, Erwan Pencreach, Françoise Farace, Benoit Lhermitte, Birgit Geoerger, Isabelle Aerts, Didier Frappaz, Pierre Leblond, Nicolas Andre, Yves Perel, Nadège Corradini, Anne Isabelle Bertozzi, Florence Vincent, Natacha Entz-Werle. Phase I study with rapamycin combined with irinotecan, the SFCE RAPIRI I trial, a new way to target tumor hypoxia in pediatric refractory cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT136.

Abstract CT118: Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients

Abstract Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including PDAC. Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and that combining FAK and PD-1 inhibitors with gemcitabine achieves a maximal response. This suggests the need for a cytotoxic agent to bolster antigen presentation. Defactinib is an orally available, well-tolerated, potent FAK inhibitor. Methods: This study included a dose escalation phase (all solid tumors) and dose expansion phase (metastatic PDAC). A 3+3 design with five dose levels was used in the dose escalation phase. For the expansion phase, 10 PDAC patients with stable disease on front-line gemcitabine/nab-paclitaxel were enrolled in the Maintenance cohort (A), while 10 patients who progressed on at least one line of therapy were enrolled in the Refractory cohort (B). Pre and on-treatment biopsied were collected from all PDAC patients. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints included safety, toxicity, objective response rate, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints included developing a molecular and immune profile for treatment response. Results: In dose escalation, the common low grade (G1/2) treatment-emergent adverse events included fatigue, anorexia, nausea and vomiting. No DLTs were seen. The RP2D was defactinib 400mg twice daily, gemcitabine 1000 mg/m2 days 1, 8 and pembrolizumab 200mg day 1 of a 21-day cycle. Safety and toxicity results in the escalation cohort were reported at the 2018 ASCO Annual Meeting. Among 8 evaluable PDAC patients enrolled on the dose escalation phase, we observed 1 (13%) partial response (PR), 3 (38%) stable disease (SD), 4 (50%) progressive disease (PD). In the Maintenance cohort, 1 (10%) PR, 6 (60%) SD, and 3 (30%) PD were observed. Two patients in the Maintenance cohort remain on study, and the median time on treatment was 4.6 months. In the Refractory cohort, 5 (50%) had SD, 4 (40%) PD, 1 not evaluable; median PFS was 2.9 months and median OS was 7.6 months. Interestingly, two confirmed PR patients both have MSS disease. Paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decrease with treatment. Conclusions: The combination regimen was well tolerated. Encouraging efficacy signals were observed in both Maintenance and Refractory cohorts. Updated outcomes and correlative analyses are forthcoming. Citation Format: Andrea Wang-Gillam, Robert McWilliams, A. Craig Lockhart, Benjamin R Tan, Rama Suresh, Kian-Huat Lim, Katrina S. Pedersen, Nikolaos Trikalinos, Olivia Aranha, Haeseong Park, Lee Ratner, Nicholas Boice, David G. Denardo. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT118.

Effect of genomic and transcriptional alterations in first-line chemotherapy on subsequent immunotherapy in non-small cell lung cancer (NSCLC) patients.

9614 Background: Recent studies have demonstrated that first-line immunotherapy has better therapeutic response than second-line immunotherapy in NSCLC patients. However, the mechanism behind this observation has not been elucidated. The aim of this study is to investigate the mechanism of unfavorable influence that the first-line chemotherapy exerts on subsequent immunotherapy. Methods: 29 NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET) mutations were enrolled in this study. Paired cancer tissues before and after chemotherapy were collected, and NGS-based WES and mRNA sequencing were performed. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: We found that the total number of SNV/INDEL mutations and the tumor mutational burden (TMB) decreased significantly following chemotherapy. The decrease of mutation burden correlated well with therapeutic response: patients with partial response (PR) exhibited significant decrease while patients with stable disease (SD) or progression of disease (PD) did not. Meanwhile, a sharp decrease in common mutations before and after chemotherapy was observed in PR and PD patients, but not SD patients, suggesting that mutational change reflected the therapeutic response. The change in copy number variations (CNVs) exhibited similar trends and correlation with therapeutic response. Subsequent analysis on mRNA levels revealed a sharp decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant to immunotherapy response. Pathway enrichment analysis showed that the genes with decreased expression mainly represented immune-related signaling pathways or biological processes. Conclusions: Our study revealed a possible mechanism underlying unsatisfactory multiple-line immunotherapy following chemotherapy, and indicated that first-line chemotherapy may influence the tumor microenvironment to exert unfavorable influence on subsequent immunotherapy.

A Potential Biomarker from Diffusion Weighted Imaging and Parametric Response Map Analysis for Treatment Response Prediction in Nasopharyngeal Cancer

Diffusion-weighted imaging (DWI) is an MRI technique which provides functional information of tissue by detecting microscopic motion of water molecules. The change of apparent diffusion coefficient (ADC) derived from DWI was used as an imaging biomarker for treatment response prediction in cancers [1]. However, it was based on whole-tumor analysis which did not reflect heterogeneity within the tumor. To overcome this limitation, a new method called parametric response map (PRM) analysis was proposed to evaluate response by quantifying voxel-wise changes in ADC [2]. Here we investigated the use of PRM analysis on ADC from DWI as an imaging biomarker for treatment response prediction in nasopharyngeal cancer (NPC) patients. We collected thirteen patient datasets including ten complete response (CR) patients and three partial response (PR) patients at King Chulalongkorn Memorial Hospital where one patient dataset consisted of DWI and ADC data acquired before (i.e. pre-treatment) and at five weeks after (i.e. mid-treatment) initiation of chemoradiation therapy. For each dataset, we compared pre-treatment ADC image with co-registered mid-treatment ADC image, and calculated the percentage of voxels with increased ADC values with respect to total voxels within the tumor ROI, defined as PRM+. To validate the feasibility of the PRM biomarker, we computed the mean and standard deviation (SD) of percentage change in tumor volume (%AVol ) and in ADC (%AADC) and PRM+ across CR and PR patients, where tumor response was from 6-month follow-up data using RECIST1.1 guideline. The results showed that %AVol as well as %AADC between both groups was not significantly different. In contrast, PRM+ was significantly different between both groups (p < 0.05, 82.7±7.8% in CR vs 66.7±6.5% in PR). Our results implied that the proposed PRM+ biomarker could be a potential biomarker for early treatment response prediction in NPC patients.

New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor.

838 Background: While the introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal tumor (GIST), the response evaluation criteria have not been optimized. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib. Methods: We retrospectively reviewed 55 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups; active MR (morphologic response) (+) group and active MR (-) group, judging from the morphological features including the sharpness of the outline and the attenuation of target lesion. We investigated the association between the presence of active MR and clinical outcomes. Similarly, clinical outcomes classified by response evaluated by RECIST and Choi criteria were analyzed respectively. Results: Thirty-two patients had active MR (+). The median Progression-free survival(PFS) was 7 months vs 31 months (active MR(-) vs active MR(+), P = 0.013) and the median overall survival (OS) was 58 months vs 91 months ( P = 0.086), respectively. Although PFS of RECIST PD (progression disease) or Choi PD patients was shorter than that for PR (partial response) or SD(stable disease) patients ( P = 0.0037 for RECIST, P = 0.0058 for Choi), the number of PD patients was very small (N = 3, both in RECIST and Choi). Conclusions: The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with inoperative GIST.

The Five-Year Survival Rate of Patients with Nasopharyngeal Carcinoma Based on Tumor Response after Receiving Neoadjuvant Chemotherapy, Followed by Chemoradiation, in Indonesia: A Retrospective Study

Introduction: Nasopharyngeal cancer (NPC) is a common malignancy in Southeast Asia with a high mortality rate. Previous studies have shown that the patient survival rate is <80% worldwide. At the Dharmais Cancer Hospital, NPC is the first of the top 10 diseases with the highest rate of stage III cancer progression. Objective: This study aims to determine the 5-year survival rate of patients with NPC based on tumor response and their prognostic factors after receiving neoadjuvant chemotherapy, followed by chemoradiation. Methods: The records of 261 patients between January 2009 and December 2013 were retrospectively analyzed. All patients with NPC who received neoadjuvant chemotherapy, followed by chemoradiation, at the Dharmais Cancer Hospital from 2009 to 2013 were identified. Patients with metastasis were excluded. The primary endpoint of this study was overall survival, which was defined as the time from the date of treatment to the date of death. The survival curve was analyzed using the Kaplan-Meier method. The Cox proportional hazard model was used for the multivariate analysis of prognostic factors. Results: The tumor response rates for patients with complete response (CR), partial response (PR), and progressive disease (PD) were 33.7, 45.2, and 21.2%, respectively. The 5-year overall survival rate was 38.6%. The 5-year survival rates based on tumor response among CR, PR, and PD patients were 71.0, 30.4, and 10.6%, respectively. The significant independent prognostic factors were tumor response, educational background, job, alcohol consumption, clinical stage, and prompt treatment. Conclusion: The survival probability of patients with NPC receiving neoadjuvant chemotherapy, followed by chemoradiation, was higher in the CR group than in the PR and PD groups. This confirms that early detection can improve the patient’s survival. Long-term follow-up is required to determine the factors influencing tumor response in NPC.

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study

Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab+ trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab+ trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab+ trastuzumab, n= 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n= 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n= 1/1, PFS 18.5 months), and high TMB (atezolizumab, n= 1/1, PFS 5.5+ months). No unexpected toxicity occurred. Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

Composite Copy Number Variation in CDK4, CDKN2A and RB1 Predisposes Mantle Cell Lymphoma to Expansion of PD1+ Tumor Cells and Resistance to CDK4/6 Inhibitor Therapy as Revealed by Integrative Longitudinal scRNA-seq

Composite Copy Number Variation in CDK4, CDKN2A and RB1 Predisposes Mantle Cell Lymphoma to Expansion of PD1+ Tumor Cells and Resistance to CDK4/6 Inhibitor Therapy as Revealed by Integrative Longitudinal scRNA-seq

P109 - The durability of complete response and partial response in patients with genitourinary cancer treated with PD-1/PD-L1 inhibitors

P109 - The durability of complete response and partial response in patients with genitourinary cancer treated with PD-1/PD-L1 inhibitors

Benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis.

Recent insights showed the possibility of using JAK inhibitors for the treatment of alopecia areata (AA). Most of the previous articles evaluated the overall efficacy of existing JAK inhibitors rather than evaluating one of them alone. Currently, the benefit and risk profile of tofacitinib for the treatment of AA is still not clear. To estimate the safety and efficacy of tofacitinib in patients with AA based on summarizing the clinical outcomes. The systematic review and meta-analysis was performed according to PRISMA guidelines. ROBINS-I (Risk of Bias in Non-randomized Studies-of Interventions) was used for quality assessment. We enrolled 14 studies including six clinical trials and eight observational studies with 275 patients. The result of meta-analysis showed that tofacitinib has reasonable effectiveness in patients with AA. The pooled good/complete hair regrowth rate of tofacitinib treating patient with AA was 54.0% (95% CI: 46.3%-61.5%), and the pooled rate of partial response in patients with AA taking tofacitinib was 26.1% (20.7-32.2%). Approximately a quarter of patients had experience of relapse, most of which was reported due to discontinuation of tofacitinib. In terms of toxicity, reported adverse effects included only mild symptoms. Upper respiratory infection, headache and acne were the most common adverse events. Tofacitinib seems to be a promising drug for the treatment of AA with only mild adverse effects. More thorough larger sized randomized clinical trials are required to further assess the safety and clinical efficacy of tofacitinib for the treatment of AA.

438O - METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours

BackgroundPRMT5 is an enzyme that methylates arginines in proteins important for tumor growth and development. GSK3326595 is a potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. METEOR-1 is a phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of GSK3326595 in adults with solid tumors. MethodsEligible participants (pts) were >18 years with advanced or metastatic solid tumors. Pts were enrolled in a modified toxicity probability interval design. Safety, tolerability, PK, PD, and efficacy data were used to identify the recommended phase 2 dose (RP2D). ResultsFifty-four pts with a median age of 60 (range 21 – 81) received at least one dose of drug. The most common tumor types were adenoid cystic carcinoma (ACC; n=14 [26%]), colorectal cancer (n=9 [17%]), and breast cancer (n=3 [6%]). Dosing proceeded from 12.5mg to 600mg once daily (QD), and from 50mg to 200mg twice daily. Median time on treatment was 1.8 months (range 1day to 18.7 months). Overall, 48 pts (89%) experienced at least one adverse event (AE) that was deemed treatment-related. The most common related AEs were fatigue (n=21 [39%]), anemia (n=17 [31%]), nausea (n=17 [31%]), alopecia (n=15 [28%]), and dysgeusia (n=14 [26%]). Grade 3/4 related AEs included anemia (n=8 [15%]), thrombocytopenia, neutropenia, and fatigue (each n=4 [7%]). There were no Grade 5 related AEs. Twenty-two pts (41%) had ≥1 dose reduction. GSK3326595 Cmax and AUC were dose-dependent after single and repeat dosing. PD analyses showed robust target engagement, as measured by dimethylated arginine in plasma and tumor samples. Clinical activity was observed in several tumor types, with partial responses in patients with HPV+ cervical cancer (1 response/1 subject) and ACC (3 responses/14 subjects). Durable stable disease was achieved in bladder cancer and other tumors. 400mg QD was selected as the RP2D. ConclusionsThis is the first study evaluating a PRMT5 inhibitor. Overall, AEs were common but manageable. Patients with multiple tumor types responded to therapy. Part 2 of the study is open for subjects with predefined solid tumors and non-Hodgkin’s lymphoma. Clinical trial identificationNCT02783300. Legal entity responsible for the studyGlaxoSmithKline. FundingGlaxoSmithKline. DisclosureL.L. Siu: Advisory / Consultancy: Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (compensated), Morphosys (compensated), Roche (compensated), GeneSeeq (compensated), Loxo (compensated), Oncorus (compensated), Symphogen (compensated), Seattle Geneti; Research grant / Funding (institution): Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks; Shareholder / Stockholder / Stock options, Spouse: agios. D.W. Rasco: Research grant / Funding (institution): gsk. S. Postel Vinay: Research grant / Funding (institution): Boehringer Ingelheim, Roche and Merck KGaA; Advisory / Consultancy: Merck KGaA; Travel / Accommodation / Expenses: AstraZeneca; Leadership role, Principal/sub-investigator of clinical trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol. P. Martin Romano: Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies, Drug supplied: AstraZeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche; Non-remunerated activity/ies, Courses, trainings for: AstraZeneca, Roche. J.L. Egger: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S.A. Gorman: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. R. Parasrampuria: Full / Part-time employment: GlaxoSmithKline. K. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. B.E. Kremer: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. M.M. Gounder: Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Epizyme, Tracon, Amgen, Daiichi Sankyo, Springwork Therapeutics, Bayer, Karyopharm. All other authors have declared no conflicts of interest.

CLINICAL SIGNIFICANCE OF PLASMA MIR-21, MIR-141, MIR-29C, AND MIR-BART7 IN PATIENTS WITH LOCALLY ADVANCED NASOPHARYNGEAL CANCER AND THEIR ALTERATIONS AFTER CHEMORADIATION THERAPY

Introduction:&#x0D; Plasma microRNAs (miRNAs) are biological markers that have been extensively studied in cancer, including nasopharyngeal cancer (NPC). The clinical significance of miRNA in NPC patients in Indonesia has never been studied.&#x0D; Objective: &#x0D; This study was aimed to know the expression of plasma miRNAs in NPC patients (miR-21, miR-29c, miR-141dan miR-BART7) and their relationship with clinicopathological characteristics and treatment response.&#x0D; Method: &#x0D; This was a cohort, longitudinal study among locally advanced NPC patients (stage IIB-IVB) in Dharmais Cancer Hospital, Jakarta. miRNA expression was assayed using quantitative real-time polymerase chain reaction (qRT-PCR) technique. Four miRNAs were evaluated, i.e., miR-21, miR-29c, miR-141, and EBV-miR-BART7. The results were normalized against a reference gene, miR-16.&#x0D; Result: &#x0D; A total of 52 patients and 10 normal subjects were enrolled in this study; 17 of them completed treatment. Patients’ mean age was 45.1+12.53 (14-68) years. The ratio between men and women was 3:1. MiR-21 and miR-29c could be detected in all subjects; miR-141 was detected in 22 (42.3%) and EBV-miR-BART7 in 26 (50%) subjects. There was no significant difference between miR-21 or miR-29c expression between before and after therapy. However, miR-21 expressions tend to decrease in a patient with complete response (CR) (4.13+3.65 vs. 2.74+3.23; p=0.650) and tend to increase in patients with partial response (PR) (3.00+5.86 vs. 8.77+8.43; p=0.465). There was no difference of miR-29c expression between CR and PR patients.&#x0D; Conclusion: &#x0D; Our study shows that not all miRNA can be detected in the plasma of NPC patients. Levels of miRNA expressions in these locally advanced patients are similar. Expression of miR-21 is potentially used as a biomarker of evaluating treatment response in NPC patients.

Investigation of Using Diffusion-Weighted Magnetic Resonance Imaging (DWI) Combined with CT and Esophagogram to Evaluate the Therapeutic Effect of Esophageal Squamous Cell Carcinoma (ESCC) Treated with Chemoradiotherapy

To investigate the application value of using DWI combined with CT and esophagogram evaluating the therapeutic effect of ESCC treated with chemoradiotherapy (CCRT). From January 2004 to December 2015, 529 patients with ESCC underwent CCRT were enrolled. Therapeutic effect was evaluated based on the maximal esophageal wall thickness measured by CT, hyperintense expression in DWI and tumor shape changes in esophagogram. Prognosis analysis was also performed. A total of 529 patients were evaluated by esophagogram and CT -based evaluation criteria, 132 patients were in complete response (CR) and 385 in partial response (PR) after CCRT. Overall survival (OS) and local control (LC) rates of patients in CR were significantly higher than those in PR, with the 5-, 10-year OS at 37%, 30% versus 21%, 19%, respectively (P<0.001). The median survival time was 5 months for 12 patients in none response (NR). Of all enrolled patients, 83 patients received DWI examination before and after CCRT. A total of 48 patients had no hyperintense expression in DWI (defined as CR) after CCRT and 35 still had hyperintense expression (defined as PR). OS and LC rates of patients received DWI examination in CR were significantly higher than those in PR (P=0.013, 0.001). In contrast, there was a trend towards increased uncontrolled and recurrent rate of patients in PR versus CR (P<0.05). According to the evaluation criteria based on DWI combined with CT and esophagogram, OS and LC rates of patients in CR were significantly higher than those in PR, with the 5-year LC at 62% versus 33% and 5-year OS at 48% versus 16%, respectively (P=0.018, 0.002). The esophagogram and CT -based evaluation criteria can accurately evaluate the therapeutic effect and predict prognosis in patients with ESCC. The expression of hyperintense in DWI at the end of treatment may indicate a high risk of recurrence. The therapeutic effect evaluated by DWI combined with CT and esophagogram maybe more objective and more accurate.

The Impact of First Complete Remission by PET-CT and Time to Next Treatment on Survival of Follicular Lymphoma Patients

We retrospectively analyzed the impact of initial positron emission tomography and computed tomography (PET-CT) complete remission (CR) and time to next treatment (TTNT) on patient outcome in follicular lymphoma. Between 2002 and 2014, 150 patients could be evaluated for treatment response and long-term outcome. The CR after first line treatment with either rituximab-cyclophosphamide, oncovin, and prednisolone (R-COP) or rituximab-cyclophosphamide, doxorubicin, oncovin, and prednisolone (R-CHOP) was 89% and partial response (PR) was 7%. The 5- and 10-year survival rates were 86.0% and 62.6%, respectively. In five years, 11% of patients had died of lymphoma and 3% from other causes. Forty-seven patients (31%) underwent a second line of treatment comprising 19 (40%) with a TTNT shorter than 24 months and 28 (60%) longer than 24 months. There was no difference in overall survival (OS) between R-COP (86%) and R-CHOP (77%) at 5 years, but there were more next treatment events in the R-COP compared with the R-CHOP group on longer follow-up (60% versus 35% at 8 years). For PET-CT response, there was a significant OS difference between initial CR and PR patients (88% versus 70%, p < 0.01), and a longer TTNT was seen in initial CR patients. Patients with a TTNT longer than 24 months had better OS compared with patients with a shorter TTNT (93% versus 54% at 5 years, p < 0.01). In conclusion, patients with initial PET-CT CR and TTNT longer than 24 months had better OS compared with those achieving only PR and shorter TTNT. PET-CT CR should be considered the treatment goal during initial treatment, and more aggressive treatment should be considered for patients with a TTNT of less than 24 months.

Response to Immunosuppressive Therapy in Acquired Aplastic Anaemia: Experience of a Tertiary Care Centre from Eastern India.

The current study was conducted to assess response to immunosuppressive therapy (IST) in acquired aplastic anaemia (AA). It was a retrospective and prospective observational study. Patients were diagnosed as per standard international guidelines and IST was started as per standard protocol. Patients were followed up at 3months and 6months for assessment of response as per published standard guidelines. Total 76 cases were included in the study. The median age of the study population was 36years with a range of 6-66years with a male to female ratio of 2.04:1. Most common clinical presentation was pallor followed by bleeding. Commonest type of disease in the study group was severe AA. Among total 76 patients, 32 patients received Atgam and 44 patients received Thymogam. Within 3months of ATG administration, 4 patients died and 1 patient was lost to follow up. At 3months, 2 (2.63%) patients were on complete response (CR), 32 (42.10%) patients were in partial response (PR) and 37 (48.68%) patients were on no response (NR). Overall response (OR) at 3months was 44.73%. At 6months 5 (6.57%) patients were in CR, 43 (56.57%) patients in PR and 23 (30.26%) patients in NR; the OR was 63.14%. Overall response at 3months was 44.73% and overall response at 6months was 63.14%. The study revealed better overall survival for patients with ATGAM treatment than THYMOGAM treatment arm.

Blockade of VEGFR and PD-L1 Inhibits Alveolar Soft-Part Sarcoma.

Combined treatment with axitinib and pembrolizumab achieved partial responses in patients with ASPS.

CD45RA+CCR7\u2212 CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab

BackgroundCheckpoint inhibitors have become standard care of treatment for non-small cell lung cancer (NSCLC), yet only a limited fraction of patients experiences durable clinical benefit, highlighting the need for markers to stratify patient populations.MethodsTo prospectively identify patients showing response to therapy, we have stained peripheral blood samples of NSCLC patients treated with 2nd line nivolumab (n = 71), as well as healthy controls, with multiplex flow cytometry. By doing so, we enumerated 18 immune cell subsets and assessed expression for 28 T cell markers, which was followed by dimensionality reduction as well as rationale-based analyses.ResultsIn patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.ConclusionsThis study demonstrates that high numbers of peripheral CD8 T cells expressing differentiation markers and lacking co-stimulatory receptors at baseline are associated with response to nivolumab in NSCLC patients.

PF522 MUTATIONAL LANDSCAPE OF PRIMARY MEDIASTINAL B‐CELL LYMPHOMA (PMBCL) BY MEANS OF CIRCULATING TUMOR DNA ANALYSIS

Background:Primary mediastinal B‐cell lymphoma (PMBCL) is a rare subtype of non‐Hodgkin lymphoma that predominantly occurs in adolescents and young adults. Biologically, PMBCL shares many similarities with classical Hodgkin lymphoma, including constitutive activation of the JAK‐STAT and NF‐kB pathways. High‐throughput sequencing of circulating tumor DNA (ctDNA) in peripheral blood (“liquid biopsy”) has recently emerged as a promising noninvasive approach in different types of neoplasms, including lymphoma. This option could be helpful in PMBCL when a biopsy specimen of the tumor is not available for molecular analysis and can also provide an insight into the overall clonal heterogeneity and noninvasively assess the molecular changes over time and the genetic mechanisms of resistance.Aims:The aim of this study was to analyze the mutational profile at diagnosis and in the refractory/relapse settings in PMBCL patients using ctDNA and to compare, when available, with genotyping from tissue biopsy DNA.Methods:We included 9 patients (M/F 4/5, median age 29 years) diagnosed with PMBCL in a single institution between 2015 and 2018 according to the WHO criteria. All patients were treated with R‐CHOP. After initial treatment, 4 patients achieved complete remission (CR), 2 partial response (PR), 3 were refractory. ctDNA extraction was performed from 1–2 mL of plasma collected in PAXgene Blood ccfDNA tubes (Qiagen). Samples were obtained both at diagnosis and at relapse/progression after chemoimmunotherapy. Tumor genomic DNA (gDNA) was isolated from formalin‐fixed paraffin‐embedded (FFPE) diagnostic tissue biopsies. Libraries were constructed with 10–30 ng of ctDNA and 150 ng of gDNA, using molecular‐barcoded library adapters and a hybridization capture based method (SureSelectXT‐Agilent Technologies). Mutation profiles were generated using a custom hybridization capture‐based panel of 115 genes and sequenced in a MiSeq instrument (Illumina, San Diego, CA).Results:ctDNA was obtained from all patients at diagnosis and from 4/5 patients in PR or who were refractory after treatment. Median amount of ctDNA at diagnosis was 46 ng (range: 10–74 ng). In all the cases, at least one mutation could be detected, with a median of 10 mutations per sample (range 1–22mutations). In 4 of the 5 cases with simultaneous tissue and peripheral blood samples, a similar number of mutations was detected with the same genes involved. The genes most frequently mutated at diagnosis were B2 M, GNA13, SOCS1, STAT6, HIST1H1C, HIST1H1E, MFHAS1, NFKBIE (figure). In 3 of the 4 cases with a ctDNA sample at diagnosis and at progression, changes in the allelic frequency of the mutations could be observed, whereas in the remaining case no mutation at progression could be detected. Of note, none of the 3 patients with NFKBIE mutation achieved a complete remission after first line treatment.Summary/Conclusion:Preliminary data on the use of ctDNA in patients with PMBCL show a good correlation with the information obtained in the tissue. Therefore, it can be a real‐time method to evaluate the mutational landscape and the appearance of clones resistant to treatment.image

Treatment with tumor-infiltrating lymphocytes in the changing treatment landscape of metastatic melanoma.

e14024 Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has been shown to induce durable complete responses in patients with metastatic melanoma (MM) who are anti-PD-1 naïve. Whether progression on or after anti-PD-1 therapy affects the outcome of TIL therapy given as a subsequent treatment line is largely unknown. To elucidate this, we analyzed updated clinical data covering a decade of TIL trials carried out in Denmark. Methods: Data from three clinical trials were pooled and data from 55 treated patients were available (ClinicalTrials.gov Identifiers: NCT00937625 (n = 31), NCT02379195 (n = 12) and NCT02354690 (n = 12)). Survival curves were computed according to the Kaplan-Meier method. Clinical response rate (RR) was evaluated according to RECIST criteria. Results: Median overall survival in the pooled cohort was 15.9 months and progression-free survival (PFS) was 3.7 months. Six patients achieved a complete response (11%), of which four are ongoing. Fourteen patients achieved a partial response (26%), of which three are ongoing. Median overall survival of responders was not reached with a median follow-up time of 40 months. RR was not statistically different depending on prior anti-PD-1 therapy (42% no prior anti-PD-1 therapy vs. 32% with prior anti-PD-1 therapy). However, there was a trend towards a shorter duration of partial responses in patients previously treated with both anti-CTLA-4 monotherapy and anti-PD-1 monotherapy, compared to patients previously treated with anti-CTLA-4 but not anti-PD-1 (P = 0.06). The two groups were balanced in respect to number of prior treatment lines. Conclusions: After progression on anti-PD-1 therapy, partial responses following TIL therapy might be shorter, but durable complete responses can be induced despite progression on prior anti-PD-1 therapy. Thus, TIL therapy remains an important treatment strategy in MM. Clinical trial information: NCT00937625, NCT02379195, NCT02354690.