Combo Group Research Articles

Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study

IntroductionSintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here. MethodsIn this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers. ResultsAs of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45–0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime “immune deserts” to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19–0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20–0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting. ConclusionsThe addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.

Combined Oral Administration of Analgesia and Anxiolysis for Pain Associated with Bone Marrow Aspiration and Biopsy

▪BackgroundBone marrow aspiration and biopsy (BMAB) is a painful procedure, and the commonly adopted local infiltration anesthesia (LIA) with lidocaine is unable to relieve the pain during the most uncomfortable phases, or the anticipatory anxiety related to pain recalling thereafter. As there are no formal guidelines for adding a sedoanalgesic premedication before beginning the BMAB, many combinations have been adopted by several authors.AimsOur randomized and patient blinded trial aimed to evaluate, as primary end point, the efficacy and safety of opioid and benzodiazepine agent combination plus LIA in patients who underwent BMAB for hematological malignancies. Two secondary end points were: 1) to define if patients who already underwent to BMAB without LIA prefer sedoanalgesia; 2) to demonstrate if sedoanalgesia can influence the quality of the biological specimen harvested.MethodsPatients were randomly assigned into two arms for receiving either placebo plus LIA (standard group, 48,6%) or oral fentanyl citrate 200 mcg plus oral midazolam 5 mg in addition to LIA (combo-group, 51,4%) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numered Rating Scale (NRS: 0-10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b, and T3) and evaluating discomfort grade during each moment of procedure in both groups. Cognitive function was measured before and 30 minutes after the procedure. Possible side effects were recorded, as well as the adequacy of tissue samples harvested. A telephone interview was performed 24 hours later. A total number of one-hundred-sixteen (n =116) were enrolled in the study. Nine (n = 9) patients did not meet inclusion criteria and were excluded. Fifty-two (n = 52) patients were randomized and assigned to standard group and fifty-five (n = 55) to combo group (Figure 1).ResultsAt T2b and T3 (corresponding to the biopsy time and time after the biopsy, respectively) there was a significantly lower (p < 0.05) perception of pain in the patients who received sedoanalgesia (combo-group) compared to those who did not (standard group). Moreover, 100 % of the patients in combo group who had previously undergone this procedure without premedication reported that they would prefer sedoanalgesia for the subsequent procedures, thus confirming the effectiveness of this combination also in relieving anticipatory anxiety. Finally, the histological specimen was found to be high in quality, as defined by standards.ConclusionsAdministration of oral analgesia and anxiolysis is a safe and feasible option to be used in outpatient setting; sedoanalgesia is very effective in reducing pain during the biopsy and it diminishes the anticipatory anxiety related to a painful procedure. Patients should have the possibility to choose between local anesthesia alone or sedoanalgesia plus local anesthesia. [Display omitted] DisclosuresPane:Novartis: Honoraria, Speakers Bureau.

Acetyl-L-Carnitine Ameliorates Metabolic and Endocrine Alterations in Women with PCOS: A Double-Blind Randomized Clinical Trial.

Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder and the main cause of infertility in women of reproductive age. Affected women suffer from insulin resistance and present with an intense stress response. Treatment with insulin sensitizers alone and in combination is used to ameliorate the signs and symptoms associated with the disease. This study was designed to compare the endocrine and metabolic parameters as well as subjective and objective measures of stress in women with PCOS before and after treatment with acetyl-L-carnitine (ALC) and metformin plus pioglitazone. A total of 147 women with PCOS were randomly assigned into two groups: the combo group (n = 72) received a combination of metformin, pioglitazone, and ALC (500mg, 15mg, and 1500mg, respectively), twice daily; the Met + Pio group (n = 75) received metformin plus pioglitazone (500mg, 15mg, respectively) and placebo (citric acid plus calcium carbonate), twice daily for 12weeks. Medications were discontinued when pregnancy was confirmed. The Perceived Stress Scale (PSS14) and Profile of Mood States (POMS) were employed as subjective measures of stress. The endocrine and metabolic functions of women with PCOS were assessed by measuring insulin, leutinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and adiponectin levels in fasting blood samples. Insulin resistance was calculated by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Women at baseline had significantly elevated circulating concentration of insulin and low level of adiponectin. Treatment decreased insulin in both groups; however, the combo group showed a significant decrease (p = 0.001). Serum adiponectin level was raised significantly after treatment in both groups (p < 0.001). HOMA-IR also decreased in both groups (both p < 0.001). Testosterone, FSH, and LH significantly improved in both groups. LH also decreased in both groups; however, the change was significant only in the combo (metformin plus pioglitazone plus ALC) group (p = 0.013). Interestingly, there was a significant improvement in body circumference (p < 0.001) in the combo group. The PSS scores of the patients improved significantly (p < 0.001) in the combo group. Interestingly, regular menstrual cycles were found (97.2%) in the carnitine group, but in only 12.9% of the other group. We conclude that addition of ALC therapy is superior to metformin plus pioglitazone in ameliorating insulin resistance, polycystic ovaries, menstrual irregularities, and hypoadiponectinemia in women with PCOS. Trial registration: clinicalTrial.gov NCT04113889. Registered 3 October, 2019. https://clinicaltrials.gov/ct2/show/NCT04113889 .

P285 A retrospective observational study on the effectiveness and safety of vedolizumab with or without budesonide induction therapy among patients with moderate-to-severe Crohn’s disease

Abstract Background The α4β7 integrin monoclonal antibody vedolizumab (VDZ) has been shown to be efficacious for patients with moderate-to-severe Crohn’s disease (CD). This study aimed to analyse the added value of budesonide in combination with VDZ as an induction treatment for this indication. Methods A multicentre, retrospective chart review study was conducted in Belgium, Israel, and Switzerland. Adult patients with moderately to severely active CD (defined as an abdominal pain [AP] score of ≥2 and/or a mean daily loose stool frequency [LSF] score of ≥4 for the previous 7 days) who initiated induction therapy with either VDZ monotherapy (mono) or a combination therapy (combo) of VDZ with budesonide (index date) between 1 January 2015 and 31 January 2019 were included. Patients who received VDZ by IV infusion at weeks 0, 2, 6, 10 (only some patients received VDZ during week 10), and 8 weeks thereafter were assessed for time to patient-reported outcome (PRO) clinical remission (Kaplan-Meier curves), defined as an average daily composite score of AP ≤1 and LSF ≤31 within 14 weeks. Regression models were used to assess differences and associations. Results Overall, 123 patients were included (mono, n=73; combo, n=50). Patients initiating combo presented with more severe disease at index date than patients initiating mono. PRO clinical remission rates were estimated at 71.4% (50/70) in the mono and 68.0% (34/50) in the combo groups, with a similar median time to PRO remission of 91 days (95% CI: 70–98) and 95 days (95% CI: 70–98), respectively (Figure 1). Figure 2 shows the mean % change in AP and LSF from baseline to week 14, which was comparable for mono and combo. The variables associated with mean % change were moderate and severe AP scores for AP and being a current smoker for LSF. One patient in each group discontinued VDZ before week 14 (due to lack of effectiveness [mono] and adverse event [AE; combo]); 68.0% of patients in the combo group discontinued budesonide by the end of the follow up period. The reasons for discontinuation were routine treatment regimen (8 weeks 9 mg/day+subsequent tapering-off) in 85.3% of the patients, lack of effectiveness in 5.9% and AEs in 2.9% (5.8% other reasons). Safety event rates were similar among the groups for overall AEs (mono, 23.3%; combo, 26.0%), with the majority designated as mild to moderate in severity, and 83.3% resolved within the follow-up period. Conclusion Comparable effectiveness and safety outcomes were observed with mono and combo therapy in patients with CD; however, disease state among patients receiving combo was more refractory/severe at baseline. Further evidence is needed to corroborate these findings. Reference

Comparison of time to failure of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy: A consecutive analysis of NSCLC patients with high PD-L1 expression.

9061 Background: There are two types of pembrolizumab-containing strategies for patients with non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥50%): the early combination of pembrolizumab plus chemotherapy, and chemotherapy after pembrolizumab failure. Which strategy is superior, however, remains unclear. Comparing progression-free survival (PFS) or progression after the next therapy line (PFS2) in previous clinical trials has not allowed any conclusions regarding superiority to be made. Instead, the time to failure of strategy (TFS), which represents the time until disease exacerbation when the same number of drugs has been used, should be used to compare the two strategies. Methods: We consecutively reviewed the efficacy and safety of first-line, pembrolizumab-containing regimens administered between December 2017 and November 2020. We divided the patients who received pembrolizumab as a first-line treatment into two groups according to whether they received chemotherapy: a pembrolizumab plus chemotherapy group (combo group), and a pembrolizumab monotherapy group (mono group). TFS was defined as the PFS in the combo group and the PFS2 in the mono group. We used the propensity score matching (PSM) method to reduce the bias. Results: Of the 964 patients with advanced NSCLC who underwent first-line treatment, 126 with a PD-L1 TPS ≥50% were eligible for inclusion in this analysis (89 in mono group, 37 in combo group). PSM matched 36 people from each of the two groups. The median follow-up period was 16.2 months (range, 0.1-34.3 months). The patient backgrounds were similar. The overall response rate (ORR) of the combo group was higher than that of the mono group (69.4% vs. 50.0%). The median PFS (mPFS) in the combo group was longer (11.4 months vs. 6.0 months). However, the median TFS (mTFS) of the two groups was almost the same (11.4 months vs. 11.7 months). At the time of the analysis, the median overall survival had not been reached. The frequency of all immune-related serious adverse events (irSAE) was similar, however, that of all SAE and AE leading to treatment discontinuation were larger in the combo group. Conclusions: The ORR of the combo group was higher than that of the mono group; however, the TFS was similar. We suggest that pembrolizumab plus chemotherapy, which can increase toxicity, might be of value in patients, producing a clinically meaningful increase in the ORR.[Table: see text]

Abstract PS13-28: Pre-treating TNBC with docetaxel and il-12 enhances anti-PD1 efficacy

Abstract Introduction: Amongst all breast cancers, Triple Negative Breast Cancer (TNBC) account for 15-20% of all the cases. TNBC affect younger patients, and is more prevalent in African-American women. The poor prognosis for this very aggressive tumor subtype is exacerbated by the lack of specific targeted therapy against the disease. Although TNBC initially respond very well to chemotherapy, paradoxically the disease-free survival is very short. It has been showed that TNBC have higher rates of CD8+ T-cells infiltration, and express high level of PD-L1. Together, these data provide a strong rationale for the combination of chemotherapy and immunotherapy to treat TNBC patients. In this study, we investigated the response to pre-priming the tumor with one round of docetaxel and IL-12, followed by anti-PD1 maintenance in mouse E0771 and 4T1 TNBC syngeneic models. We hypothesized that docetaxel will promote the release of neo-antigens, while IL-12 will activate immunity specific to these antigens and anti-PD1 therapy prevent the exhaustion of those T-cells. Materials/Methods: Mouse TNBC E0771 and 4T1 cell lines were injected in the mammary fat pad of C57BL/6, and Balb/c mice respectively. On day 1, the mice received a single dose (20mg/kg) of docetaxel and one intratumoral injection (1.25x109) of mAdv.IL-12, a replication defective adenoviral vector containing mIL-12 (mouse) cDNA under the transcriptional control of Rous sarcoma virus long terminal repeat (provided by Dr. Chen, HMRI). Anti-PD1 (InVivoMab anti-mouse PD-1 CD279) was administered 3 times a week (2 cycles) starting 5 days post docetaxel and Il-12 treatment. At the end of the study, IFN-gamma levels were measured from blood and tumor samples; tumor sizes were compared between treatment groups (Control/mAdv.IL-12/anti-PD1/and various Combination), as well as survival curves. The metastatic burden to the lungs (H&amp;E), as well as the apoptosis in the tumor (TUNNEL) were assessed by IHC. Results: In both 4T1 and E0771 tumor models, triple combination of docetaxel + IL-12 followed by anti-PD1 significantly reduced tumor size compared to both single agents, and double combination. In the Triple Combo group, 1 mice had lung metastasis vs all of them in the other treatment groups. IHC data indicate a higher level of TILs in the treatment groups, with a statistically significant difference in the combination groups compared to single agents. There was more apoptosis in the triple combo group as indicated by TUNNEL. Conclusion:Our preliminary data strongly supports that treating TNBC models with docetaxel and mAdv.IL-12 followed by anti-PD1 significantly slows down tumor growth, and decrease lung metastasis incidence. We are actively investigating the mechanism through which the response is achieved. Citation Format: Ann Cassany Anselme, Wei Qian, Jianying Zhou, Roberto R. Rosato, Jenny C. Chang. Pre-treating TNBC with docetaxel and il-12 enhances anti-PD1 efficacy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-28.

Maintenance of Sustained Low Disease Activity or Remission in Patients With Rheumatoid Arthritis Treated With Etanercept Monotherapy: Results from the Corrona Registry.

ObjectiveThe purpose of this study was to evaluate maintenance of remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) who achieved remission/LDA with etanercept (ETN) plus a conventional synthetic disease‐modifying antirheumatic drug (csDMARD) and to compare patients who discontinued csDMARD to receive ETN monotherapy (Mono) with those remaining on combination therapy (Combo).MethodsPatients from the Corrona RA registry between October 1, 2001, and August 31, 2017, were eligible. The index date for the Mono cohort was the csDMARD discontinuation date; the index visit for the Combo cohort was estimated from time between ETN initiation and csDMARD discontinuation in the Mono cohort. The main outcome calculated was maintenance of remission/LDA. Patients were censored if they switched to or added a biologic DMARD, discontinued ETN, when a csDMARD was reintroduced (Mono), or if methotrexate increased more than 5 mg/d (Combo). Trimming was used to balance demographic and clinical characteristics between groups. Cox regression models were adjusted for the remaining differences across groups.ResultsWe identified 182 Mono and 403 Combo patients; 120 Mono and 207 Combo patients remained after trimming. Most patients (approximately 80%) were biologic medication–naive before initiating ETN. At 24 months postindex, modeled percentages of patients remaining in remission/LDA were 75% for Mono and 86% for Combo (overall adjusted P = 0.057). More patients were censored for therapy change in Mono than in Combo groups (37% versus 5%), largely due to reintroduction of csDMARDs in the Mono group.ConclusionMany patients with RA who achieved remission/LDA on combination therapy maintained remission/LDA with ETN monotherapy for 2 years after csDMARD discontinuation. ETN monotherapy may be a viable option for patients who discontinue csDMARDs after achieving LDA/remission.

Abstract 2221: Combining irreversible electroporation with TLR7 and CD40 agonists confers systemic anti-tumor immunity in a murine pancreatic cancer model

Abstract Introduction: Pancreatic Cancer (PC) has a highly immunosuppressive microenvironment with a low mutational burden and has so far been resistant to immunotherapy. Irreversible electroporation (IRE) is a non-thermal method of inducing tumor cell death, without damage to adjacent blood vessels, that is being used clinically for selected patients with locally advanced PC. Despite local control rates greater than 90%, most IRE patients develop distant recurrence, emphasizing the need for better methods to treat micrometastatic disease. Using an immunocompetent mouse model of PC, we have previously shown that IRE induces complete regression in 25-33% of subcutaneous tumors, and complete responders are protected from a tumor rechallenge. However, IRE alone did not produce significant therapeutic immunity (abscopal effects) against concomitant distant tumors. We hypothesized that combination of IRE with innate immune stimulators would also enhance the adaptive immune response. Methods: We used a cell line generated from a genetically engineered (KPC) mouse establish bilateral flank tumors. The “primary” tumor was treated with IRE alone or in combination with local delivery of a toll-like receptor 7 (TLR7) agonist (1V270) and CD40 agonistic antibody (CD40Ab). 15 parameter procartaplex (Thermo) was used for cytokine analysis and RNA-Seq was performed using an Illumina MiSeq 1000 platform with total RNA from excised tumor all on day 7 post procedure. Results: We observed complete regression in 8/10 tumors treated with the combination (Combo) of IRE, 1V270 and CD40Ab compared to 3/10 in IRE alone. However, the combo was much more effective than IRE alone at inducing regression of the untreated secondary flank tumor, including complete regression of 7/10 untreated tumors. CD40Ab alone had minimal effect on local or secondary tumor growth. Analysis of systemic cytokines using multiplex analysis showed 112 fold increase in IFNy levels in plasma with the Combo compared to untreated mice (P&amp;lt;0.001) and a 39 fold increase compared to IRE alone (P&amp;lt;0.001). Other factors of Th1 response such as IP-10 and IL12-P70 were also significantly (P&amp;lt;0.001) higher in the Combo group compared to IRE alone along with TNFa (elevated 3.2 fold vs IRE). RNA-Seq of the whole tumor followed by gene set enrichment analysis showed significant elevation in Type II interferon, (P&amp;lt;0.0001), IL2 (P&amp;lt;0.0001), and apoptosis (P=0.0001) pathways in the Combo group. Both IRE alone and the Combo group complete responders were protected from tumor growth after immediate rechallenge (14 days) and delayed rechallenge (180 days). However, flow cytometric analysis of the splenocytes revealed that the combo group had more CD44+CD62L+CD8+ central memory T-cells (16%) in contrast to IRE alone (11%). Conclusion: These data suggest that local delivery of CD40Ab and TLR7 agonists augment the systemic immune effects of IRE and have the potential to improve the overall survival of patients undergoing IRE for locally advanced PC by reducing distant recurrence. Citation Format: Jayanth Surya Narayanan Shankara Narayanan, Diego Vicente, Partha Ray, Thomas Whisenant, Rebekah White. Combining irreversible electroporation with TLR7 and CD40 agonists confers systemic anti-tumor immunity in a murine pancreatic cancer model [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 2221.

Abstract 20: Fluvastatin inhibits the development of breast cancer in SV40C3Tag mouse model of triple negative breast cancer

Abstract Introduction: Primary prevention of breast cancer that is effective at preventing both HR- and HR+ tumors, remains an important clinical need and repurposing of existing low toxicity drugs represents a low cost, efficient strategy for meeting this goal. Cholesterol pathway activation is associated with poor prognosis across all subtypes of breast cancer patients. Relevant to breast cancer prevention, the breast epithelium in women with atypical hyperplasia, a known high risk state, is known to have increase in cholesterol levels and an increase in oxidative products of cholesterol. Additionally, cholesterol pathway genes such as HMG Co A reductase (HMGCR) are deregulated in transformed cells and drive the initiation and progression of breast cancer. These observations suggest a role for the cholesterol pathway early in tumorigenesis, thus making it an attractive target for prevention. Methods: Using SV40C3 tag mice, a transgenic mouse model of TNBC, we targeted the cholesterol pathway by fluvastatin. Fluvastatin is a cholesterol lowering drug that blocks the cholesterol pathway activation through inhibition of HMGCR, a rate limiting enzyme of the pathway. Ten mice each were treated with fluvastatin (10mg/kg body weight/ day) alone, in combination with aspirin, AMPK activator, or vehicle control for 16 weeks starting at the age of about 6 weeks. Starting at the age of 10 weeks, mice were regularly examined for the presence of mammary tumors and any palpable mass of 0.3mm or bigger was considered as a lesion. At the end of 16 weeks of treatment, all mice were euthanized and mammary glands were excised, weighed and divided in 2 parts- one was fixed in formalin for any histochemical analyses and the other half was snap frozen for RNA extractions. Results: Fluvastatin treatment for 16 weeks reduced the tumor incidence and average tumor burden by 50%. Additionally, in animals that developed tumors, fluvastatin delayed the onset of palpable tumors by 2.5 weeks and inhibited tumor size, as indicated by a 4- fold lesser tumor weight in the fluvastatin treated group relative to vehicle control group. To our surprise, the combo group (fluvastatin and aspirin) did not inhibit tumor incidence or size. We found the growth inhibitory effects of fluvastatin to be mediated by increased programmed cell death. Conclusions: In line with NCI's emphasis to repurpose low toxicity drugs for prevention of cancer, our pre-clinical data supports efforts to test the efficacy of fluvastatin for prevention of TNBC in clinical trials. Citation Format: Anjana Bhardwaj, Matthew D. Embury, Raniv D. Rojo, Constance Albarracin, Isabelle Bedrosian. Fluvastatin inhibits the development of breast cancer in SV40C3Tag mouse model of triple negative breast cancer [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 20.

Abstract 927: Deep proteomic profiling of CD4+ and CD8+ T cell-depleted tumor models in PD-1 treatment

Abstract Background Immunotherapies targeting the PD-1/PD-L1 axis have been shown to be effective in only around 20% of cancer patients and the mechanism of action (MOA) underlying the differences between responders and non-responders remains poorly understood. It is therefore critical to understand the roles of different lineages of immune cells play mediating PD-1 response, while gaining an overall understanding of the interplay between tumor microenvironment (TME) and immune cell populations. To address this, tumor-bearing syngeneic mice were treated with an anti-PD-1 antibody in combination with targeted CD4+ or CD8+ T cell depletion. Tumor tissues were subsequently investigated with an unbiased proteomics workflow based on data-independent acquisition (DIA) mass spectrometry to provide insights into TME in different treatment contexts. Methods T cell subpopulations were depleted in two subcutaneous murine syngeneic models (MC38, and Hepa 1-6) followed by anti-PD-1 treatment (10mg/kg). The depletion of CD4+ and CD8+ T cells were accomplished with anti-CD4 (GK1.5) and anti-CD8 (2.43). The effectiveness of each depletion was assessed by tumor growth, followed by flow cytometry analysis of tumor infiltrating lymphocytes. FFPE tumor tissue samples, taken at the end of study (17-20 days), were digested using standard procedures and analyzed using 4h gradients on a C18 column coupled to a Thermo Scientific Q Exactive HF-X mass spectrometer. Data were extracted using Spectronaut™ (Biognosys) with a sample specific library. Results Consistent with expectation, depletion of CD8+ T cells significantly attenuated the antitumor effects of anti-PD-1 treatment in both tumor models, confirming the crucial roles of CD8+ T cells in tumor cell killing and inhibition of growth. However, depletion of CD4+ T cells showed opposing effects in the two models tested with a significant enhancement of anti-PD-1 efficacy in MC38 tumors and a reduction of anti-PD-1 efficacy in Hepa1-6 tumors. These effects were further studied by a deep proteome analysis (&amp;gt;9'000 proteins quantified. Statistical analysis showed large differences on proteome level between the two models (&amp;gt;3,000 proteins differentially expressed). We observed a strong upregulation of IFNγ inducible proteins upon anti-PD-1 therapy in the MC38 model, which is boosted upon CD4+ depletion, while many IFNγ pathway related markers were downregulated in the combo group of anti-PD-1 and anti-CD4 in Hepa 1-6. The data of the proteome analysis will be correlated to additional data from RNAseq analysis. Conclusions This study shows an unequivocal role of CD8+ T cells in anti-PD-1 induced tumor growth inhibition whereas the role of CD4+ T cells depends on the specific tumor type and TME. In our study we demonstrate how a deep proteome analysis improves the understanding of the interdependency of immune cells and the TME. Citation Format: Jan Muntel, Ying Jin, Haochen Yu, Nicholas Dupuis, Yongli Shan, Annie X. An, Wubin Qian, Davy Ouyang, Kristina Beeler, Roland Bruderer. Deep proteomic profiling of CD4+ and CD8+ T cell-depleted tumor models in PD-1 treatment [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 927.

Internal Load In Football Players: Can The Mind See What The Heart Says?

Rating of perceived exertion (RPE) is a simple, validated, measure of physical effort, largely reflecting heart rate (HR). However, RPE is being replaced by continuous HR monitoring to quantify internal loads which maximize performance and enhance recovery. PURPOSE: Primary aim: assess relationships between RPE (athlete and coach) versus HR during football practice. Secondary aims: quantify internal load via HR assessments of training impulse (TRIMP) and recovery. METHODS: Data represents pre-season testing, in an ongoing study. Twenty-nine collegiate male football players (age=20±2years; body mass index= 34±6kg/m2; weight=118±20kg) and 3 coaches volunteered to participate. Each athlete was pre-assigned a HR monitor for the first 7 days of football camp. All participants underwent a 3-minute quick recovery test (QRT). HR monitors were then worn during practice. Athlete HR, TRIMP, %heart rate reserve (%HRR), %heart rate max (%HRmax) were recorded and visible only to researchers. Immediately following practice, all athletes and coaches were asked to assess RPE for the entire training session (sRPE) using the Borg CR-10 scale. %HRmax and %HRR were transformed to scale from 1-10, to match the Borg CR-10. Significance set at p<0.05. RESULTS: Training sessions over this 7-day period, lasted 145.8±33.7 minutes. When weekly data were combined, significant overall correlations (pairwise;N=187) were noted between %HRR versus: %HRmax (r=0.84;p<0.0001), athlete sRPE (r=0.30;p<0.0001) and head coach RPE (r=0.30;p<0.0001). Athlete sRPE was correlated with one coach sRPE (r=0.30;p<0.0001). Athletes were then subdivided into Big, Combo, and Skill position groups. Two-way ANOVA for sRPE between athletes, coaches and %HRR demonstrated a significant interaction effect (F=15.2;p<0.0001;22.8%), time effect (F=36.4;p<0.0001;13.6%), and position effect between groups (F=26.1;p<0.0001;6.5%). TRIMP decreased over time, with a significant time effect (F=23.7;p<0.0001;33%) and position effect (F=5.4;p=0.005;2.5%). Trend for QRT to dip on Day 2, then increase over time. CONCLUSIONS: Athletes and one coach significantly predicted training effort (HR) during practice. However, the variance was small (9%) and sRPE remained steady despite decreased training load and increased QRT scores (trend) over time.

AB0337 TOFACITINIB MONOTHERAPY OR COMBINED WITH METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS SHOW SIMILAR RETENTION OVER FOUR YEARS. REPORT FROM RHUMADATA ®

Background:Since the introduction of biologic agents around the turn of the century, the scientific evidence shows that the majority of agents, independent of the therapeutic target, have a better outcome when used in combination with methotrexate (MTX). In 2014, tofacitinib (TOFA), an agent targeting Janus kinase 1 and 3, has reached the Canadian market with data showing that the combination with MTX may not be necessary [1,2].Objectives:To evaluate the efficacy and retention rate of TOFA in real-world patients with rheumatoid arthritis (RA).Methods:Two cohorts of patients prescribed TOFA was created. The first cohort was formed of patients who were receiving MTX concomitantly with TOFA (COMBO) and the other of patients using TOFA in monotherapy (MONO). MONO patients either never use MTX or were prescribed MTX post-TOFA initiation for at most 20% of the time they were on TOFA. COMBO patients received MTX at the time of TOFA initiation or were prescribed MTX post-TOFA initiation for at least 80% of the time. For all those patients, baseline demographic data definitions. Disease activity score and HAQ-DI were compared from the initiation of TOFA to the last visit. Time to medication discontinuation was extracted, and survival was estimated using Kaplan-Meier calculation for MONO and COMBO cohorts.Results:Overall, 194 patients were selected. Most were women (83%) on average younger than the men (men: 62.6 ± 11.0 years vs. women: 56.9 ± 12.1 years, p-value=0.0130). The patient’s assessments of global disease activity, pain and fatigue were respectively 5.0 ± 2.7, 5.2 ± 2.9, 5.1 ± 3.1 in the COMBO group and 6.2 ± 2.5, 6.5 ± 2.6, 6.3 ± 2.8 in the MONO group all differences being significant across groups. HAQ-DI at treatment initiation was 1.3 ± 0.7 and 1.5 ± 0.7 in the COMBO and MONO groups, respectively, p-value=0.0858. Similarly, the SDAI score at treatment initiation was 23.9 ± 9.4 and 25.2 ± 11.5, p-value=0.5546. Average changes in SDAI were -13.4 ± 15.5 (COMBO) and -8.9 ± 13.5 (MONO), p-value=0.1515, and changes in HAQ -0.21 ± 0.63 and -0.26 ± 0.74, p-value 0.6112. At treatment initiation, DAS28(4)ESR were 4.4 ± 1.4 (COMBO) and 4.6 ± 1.3 (MONO), p-value 0.5815, with respective average changes of -1.06 ± 2.07 and -0.70 ± 1.96, p-value=0.2852. The Kaplan-Meier analysis demonstrated that the COMBO and MONO retention curves were not statistically different (log-rank p-value=0.9318).Conclusion:Sustainability of TOFA in MONO or COMBO are not statistically different as are the changes in DAS28(4)ESR and SDAI. Despite this result, some patients may still benefit from combination with MTX.

A novel TGF-beta targeted peptide HTPEP-001 enhances antitumor efficacy of anti-PD1 in mice models.

e15200 Background: With the emergence of immunotherapy in recent years, therapeutic antibodies against programmed death 1 (PD1) and its ligand (PDL1) have proven to be a huge success in multiple cancer types. However, these robust responses only occur in a subset of patients. Identifying mechanisms of responses and resistance is key to improve outcomes and setup new treatment strategies. Transforming Growth Factor-beta (TGF-beta) is an immunosuppressive cytokine and overexpression of TGF-beta in the tumor microenvironment is proven to be a key element of resistance to anti-tumor response. We have developed a novel peptide HTPEP-001 which blocks TGF-beta signaling in both cellular and fibrosis animal models (ATS-2020 abstract). In this study, we explored the antitumor effect and mechanism of HTPEP-001 when administered together with anti-PD1 antibody in mice models. Methods: Animal models: 1. C57BL/6 mice were inoculated subcutaneously with 5*105 MC38 cells. 2. BALB/c mice were inoculated on the right mammary fat pad with 1*105 EMT-6 cells. Treatment groups: A. HTPEP-001 (60 mg/kg, intravenously, qd); B. isotype IgG; C. rat anti-mouse PD1 (10 mg/kg, intraperitoneally, twice a week); D. Coadminstration of HTPEP-001 and anti-PD1 (combo). Treatments were initiated 4-5 days after inoculation and lasted for 10 days. ELISA, immunofluorescence and flow cytometry analysis of dissected tumors were performed. Results: Compared to anti-PD1 group, mice treated with both HTPEP-001 and anti-PD1 exhibited additional reductions in tumor size and 13% higher inhibition of tumor growth (59% in Anti-PD-1 vs 72% in combo) in MC38 model. In the EMT6 model, coadministration of HTPEP-001 and anti-PD1 also showed additional reduction in tumor burdens. Coadmistration of HTPEPE-001 and anti-PD-1 significantly decreased active TGF-beta1 and phosphorylated Smads expression in tumors in both MC38 and EMT6 models. Furthermore, immunofluorescence and flow cytometry analysis of CD8+ lymphocytes in tumor mass revealed markedly elevated number of cytotoxic tumor infiltrating lymphocytes in combo group compared to HTPEP-001 and anti-PD1 groups. Conclusions: This study showed that HTPEP-001 enhanced the anti-tumor activity of anti-PD1 via suppressing TGF-beta signaling and promoting infiltration of cytotoxic lymphocytes in two syngeneic tumor models. We will continue to develop HTPEP-001 as an add-on therapy to checkpoint inhibitors with a goal to improve the outcomes of current immunotherapy.

Preseason Screen Cannot Predict Injury over Three Years of College Football.

This study aimed to investigate if the Functional Movement Screen (FMS) total score, individual component test scores, or number of asymmetries can predict noncontact injury risk over three consecutive seasons of National Collegiate Athletic Association Division I football. Because football teams comprise individuals with vastly different physical characteristics and playing responsibilities, we divided the subjects into three homogeneous groups based on position (big, combo, and skill). Each FMS score was assessed with regard to the total team score and by individual position groups. For our injury analysis, we also controlled for exposure. Two hundred and eight National Collegiate Athletic Association Division I athletes participated over three consecutive seasons, yielding a total of 343 observations. There was no significant relationship between total FMS score and likelihood of injury when analyzed by the total team or by position group. These findings were the same for all groups, for both the total number of injuries and injuries weighted by injury exposure. The only significant findings occurred when we considered individual test item scores to injury by position group. We only found a significant relationship in the expected direction with push-up stability in the combo group. FMS was not a good predictor of noncontact injury.

Effect of Probucol and/or Cilostazol on Carotid Intima Media Thickness in Patients with Coronary Heart Disease: A Randomized, Multicenter, Multinational Study.

Aim: In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time.Methods: Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints.Results: Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; −0.12 ± 0.36 mm vs. probucol; −0.11 ± 0.32 mm vs. combo; −0.16 ± 0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p = 0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions.Conclusion: Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.

PRIME-HF: Novel Exercise for Older Patients with Heart Failure. A Pilot Randomized Controlled Study.

OBJECTIVESTo test the hypothesis that (1) older patients with heart failure (HF) can tolerate COMBined moderate‐intensity aerobic and resistance training (COMBO), and (2) 4 weeks of Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) before 4 weeks of COMBO will improve aerobic capacity and muscle strength to a greater extent than 8 weeks of COMBO.DESIGNProspective randomized parallel open‐label blinded end point.SETTINGSingle‐site Australian metropolitan hospital.PARTICIPANTSNineteen adults (72.8 ± 8.4 years of age) with heart failure with reduced ejection fraction (HFrEF).INTERVENTIONParticipants were randomized to 4 weeks of PRIME or COMBO (phase 1). All participants subsequently completed 4 weeks of COMBO (phase 2). Sessions were twice a week for 60 minutes. PRIME is a low‐mass, high‐repetition regime (40% one‐repetition maximum [1RM], eight strength exercises, 5 minutes each). COMBO training involved combined aerobic (40%‐60% of peak aerobic capacity [VO2peak], up to 20 minutes) and resistance training (50‐70% 1RM, eight exercises, two sets of 10 repetitions).MEASUREMENTSWe measured VO2peak, VO2 at anaerobic threshold (AT), and muscle voluntary contraction (MVC).RESULTSThe PRIME group significantly increased VO2peak after 8 weeks (2.4 mL/kg/min; 95% confidence interval [CI] = .7‐4.1; P = .004), whereas the COMBO group showed minimal change (.2; 95% CI −1.5 to 1.8). This produced a large between‐group effect size of 1.0. VO2 at AT increased in the PRIME group (1.6 mL/kg/min; 95% CI .0‐3.2) but not in the COMBO group (−1.2; 95% CI −2.9 to .4), producing a large between‐group effect size. Total MVC increased significantly in both groups in comparison with baseline; however, the change was larger in the COMBO group (effect size = .6).CONCLUSIONTraditional exercise approaches (COMBO) and PRIME improved strength. Only PRIME training produced statistically and clinically significant improvements to aerobic capacity. Taken together, these findings support the hypothesis that PRIME may have potential advantages for older patients with HFrEF and could be a possible alternative exercise modality.

Abstract A20: Enhancing checkpoint inhibitor therapy with ultrasound stimulated microbubbles

Abstract Checkpoint inhibitor (CI) therapies are playing an increasingly prominent role in the treatment of cancer but are only effective and durable in subsets of patients. This has prompted the investigation of combining multiple CIs or their use in conjunction with conventional therapies such as chemotherapy to achieve complementary effects. A significant consideration with combinatorial approaches is the associated increase in toxicity. This provides a compelling motivation to couple CI therapy with locally applied physical methods such as radiotherapy or therapeutic ultrasound. Therapeutic ultrasound is undergoing rapid development for oncological applications and can elicit therapeutically relevant effects through ablation or impacting vascular function. It is also known to evoke immune responses, though their use in combination with immunotherapy remains to be established. One therapeutic ultrasound approach is to acoustically stimulate systemically injected “microbubbles” to undergo violent oscillations in targeted tumor regions to shut down the vasculature. We have previously shown that this approach can potentiate the antitumor effects of a range of chemotherapeutic agents. In the present study, we investigate if this form of “antivascular” ultrasound can enhance the efficacy of anti-antagonistic PD-1 (aPD-1) therapy. To test this paradigm, we used a mouse colorectal cancer line (CT26.wt), which was initiated subcutaneously in the right hind limb of 8- to 12-week-old female Balb/c mice. Mice were split into four groups: MBs (control), aPD-1 (drug group), US (ultrasound plus microbubbles group) and US + aPD-1 (combo group). Experiments were initiated on mice when tumors were in the range of 50-100 mm3. The immunotherapy drug used in this study is an anti-mouse PD-1 (clone: RMP1-4, Bioxcell). The drug aPD-1 was administered intraperitoneally at a dosage of 200 μg to respective groups prior to treatment and subsequently administered every 3 days for a total of 5 doses. Longitudinal studies were done where tumor growth was monitored every 3 days until animals reached endpoint (tumor size&amp;gt;1000 mm3). Acute experiments were done, which included flow cytometry and ELISPOT to assess how T-cell populations/activity changed with each respective treatment. Longitudinal experiments (n=5-6) showed that US + aPD-1 treatment significantly inhibited tumor growth relative to MB-only, US-only group and aPD-1 group at Day 6 (p&amp;lt;0.0001, p&amp;lt;0.01, p&amp;lt;0.01, respectively) and at Day 9 (p&amp;lt;0.0001, p&amp;lt;0.01, p&amp;lt;0.05, respectively). This inhibition of tumor growth with combinatorial treatment translated to longer survival times compared to MBs (p&amp;lt;0.01), US (p&amp;lt;0.01) and aPD-1 (p&amp;lt;0.005). Flow cytometry (n=5-7) and ELISPOT (n=6) data did not clearly show a T cell-dependent mechanism for the inhibition of tumor growth. In conclusion, these results demonstrate the ability of “antivascular” US therapy to enhance CI therapy, while the specific mechanisms of enhancement remain to be elucidated. Citation Format: Sharshi Bulner, Aaron Prodeus, Jean Gariepy, Kullervo Hynynen, David E. Goertz. Enhancing checkpoint inhibitor therapy with ultrasound stimulated microbubbles [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A20.

Combined Oral Fentanyl Citrate and Midazolam as Premedication for Bone Marrow Aspiration and Biopsy in Patients with Hematological Malignancies: A Randomized, Controlled and Patient-Blinded Clinical Trial

Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA (sedoanalgesia) in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 μg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0–10), dividing the time of the procedure into five intervals (T0, T1, T2a, T2b and T3) and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested.

P1622Cancer drugs induce functional and structural impairment in adult cardiomyocytes

Abstract Introduction The addition of anti-human epidermal growth factor receptor 2 (HER2; ErbB2) monoclonal antibody Trastuzumab (TRZ) to Doxorubicin (DOXO) chemotherapy is associated with a synergistic increase in cardiac toxicity. While previous studies have addressed the toxicity of both agents on isolated cardiomyocytes (CMs), little is known regarding this process in vivo, especially with respect to electrophysiological changes. Purpose To investigate electrical and structural changes in LV and RV CMs using an in vivo rat model of DOXO/TRZ cardiotoxicity. Methods Rats received 6 IP injections of either DOXO or TRZ over a 2-week period, or 6 doses of DOXO followed by 6 doses of TRZ (COMBO), or saline as a control. In-vivo echocardiography was performed. Electrical activity and Ca2+ handling were assessed in LV and RV CMs from rat hearts. Single cell patch-clamp and field stimulation experiments were performed. Spontaneous sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks) were recorded at x100 magnification in line-scan mode (sampling rate 0.7 kHz) from 2 μM Fluo4-AM loaded CMs. To assess T-tubular disarray, CMs were incubated with di-3-ANEPPDHQ and periodic component was quantified by Fast Fourier Transform (FFT) analysis of confocal microscopy images. Results DOXO, and to a greater extent COMBO treatment was associated with significant increases in both LV end-systolic and end-diastolic volumes, and decreases in LVEF and fractional shortening. By contrast, TRZ alone merely increased LV end-systolic volume. Electrophysiological studies showed increases in action potential duration (APD), beat-to-beat variability of repolarization (BVR), delayed after depolarizations (DADs), and Ca2+-sparks in both DOXO and COMBO groups. Stimulated intracellular Ca2+ transients (1,2 and 4 Hz) showed significant changes with respect to time to peak, tau decay, amplitude, and fractional release in the DOXO group. These changes were associated with a significant downregulation of sarco/endoplasmic reticulum Ca2+ ATPase pump (SERCA) expression. From a structural viewpoint, these changes were associated with T-tubular disarray in the DOXO and COMBO groups. Conclusions DOXO, and to a greater extent COMBO treatment (but not TRZ alone) cause LV dysfunction in vivo. Moreover, both DOXO and COMBO treatments, but not TRZ alone, induce electrophysiological abnormalities and both structural and functional changes in the sarcoplasmic reticulum. These findings provide novel insights into the cellular mechanisms of CM dysfunction and arrhythmias associated with combined DOXO/TRZ therapy. Acknowledgement/Funding Swiss League against Cancer

1841O - Second/third-line nivolumab vs nivo plus ipilimumab in malignant pleural mesothelioma: Long-term results of IFCT-1501 MAPS2 phase IIR trial with a focus on hyperprogression (HPD)

BackgroundThe phase IIR trial IFCT-1501 (MAPS2) tested nivo or nivo+ipi in pts with relapsed MPM as second/third-line. This trial reached its primary endpoint with 40% or more of pts with disease control in both arms. We now focus on long-term survivals and specific patterns of progression. Methods125 pts were randomized to receive Nivo 3mg/kg q2w or Nivo 3mg/kg q2w+Ipi 1mg/kg q6w, until progr or unacceptable toxicity. Median follow-up for OS is 32.5 months (Mar. 1st2019). HPD was defined by calculating the tumor growth rate before and during i.o. with determining the variation per month (ΔTGR) (Ferrara, JAMA Oncol 2018) or by measuring the tumor growth kinetics (TGK)on i.o. and on last treatment before, with TGK ratio (TGKr) calculation (Saâda-Bouzid, Ann. Oncol. 2017). HPD was defined as disease progression (assessed by BICR) with ΔTGR exceeding 50% or with a TGKr>2. ResultsMedian OS was 11·9mo. (6·7–17·4) in the nivo arm and 15·9mo. (10·7–22.2) in the nivo+ipilimumab arm. 52 (82%) /63 pts in the nivo group and 49 (79%)/62 patients in the combo group had died by data cutoff. 1 & 2-year survivals were 49·2% (36·4–60·8) & 25·4% (15·5–36·6) in the nivo arm, and 58·1% (44·8–69·2) & 31·7% (20·5–43·4) in the Nivo +Ipi arm. With ΔTGR method, 4 and 2 patients in Nivo and combo group had HPD respectively, while 7 and 4 patients had HPD by using TGKr. HPD pts with TGKr had a poorer OS than pts with standard progression only in the nivolumab arm (median OS=1.6mo [0.8-7.7] vs. 4.4mo [2.4-10.8], (p=0.02 in Cox model), while no difference was seen with ΔTGR definition.When both arms were analyzed together, only HPD pts defined with the TGKr had significantly worse survival: HR (progressive pts vs HPD): 0.37 [0.19-0.75], p=0.006, with HR (pts with DCR vs. HPD)= 0.12 [0.06-0.25], p<0.0001 and 2.6, 5.5 and 23.1 mos of median OS for HPD, progressive and pts with DCR respectively. All HPD patients with available IHC data (n=8/11) had PDL1-neg expression at 1% cut-off (p=0.001). ConclusionsThe durable efficacy of Nivo & Nivo+Ipi in MPM in confirmed, with 1/4 and 1/3 of pts alive at 2 yrs respectively. HPD pattern of progression did exist in both arms, associated with significantly worse survival when the TGKr definition of HPD is used. Clinical trial identificationNCT02716272. Legal entity responsible for the studyIFCT: French Cooperative Thoracic Intergroup. FundingBMS. DisclosureG. Zalcman: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Inventiva; Honoraria (self), Advisory / Consultancy: Merck (MSD); Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche-France; Travel / Accommodation / Expenses: AbbVie. J. Mazieres: Honoraria (institution), Research grant / Funding (self): Roche-France; Honoraria (institution): BMS; Honoraria (institution), Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. L. Greillier: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Non-remunerated activity/ies: Novartis; Honoraria (self), Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Pfizer; Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Boerhinger-Ingelheim; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: AbbVie; Honoraria (self), Non-remunerated activity/ies: MSD. S. Lantuejoul: Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (self), Non-remunerated activity/ies: Roche-Diagnostics; Honoraria (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: BMS. O. Bylicki: Honoraria (self), Non-remunerated activity/ies: MSD; Non-remunerated activity/ies: Roche. I. Monnet: Travel / Accommodation / Expenses: BMS. R. Corre: Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Audigier-Valette: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Boerhinger-Ingelheim; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Sysmex; Honoraria (self): MSD; Honoraria (self): Clovis Oncology; Honoraria (self): AbbVie. O. Molinier: Honoraria (self): BMS. F. Guisier: Honoraria (self), Non-remunerated activity/ies: 3MS; Honoraria (self): MSD US; Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Boerhinger-Ingeheim; Non-remunerated activity/ies: Chugai. D. Planchard: Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): BMS; Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. E. Amour: Full / Part-time employment: IFCT. F. Morin: Full / Part-time employment: IFCT. D. Moro-Sibilot: Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): Takeda; Honoraria (self): Leurquin Mediolanum. A. Scherpereel: Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Boerhinger Ingelheim. All other authors have declared no conflicts of interest.