Increase In Median Overall Survival Research Articles

Downstaging of Pancreatic Adenocarcinoma With Either Neoadjuvant Chemotherapy or Chemoradiotherapy Improves Survival

Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan-Meier and Cox proportional hazards modeling. The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio[HR] 0.82; 95 % confidence interval, 0.71-0.95; p = 0.01) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.

Definitive local therapy to head and neck squamous cell carcinoma with distant metastasis.

ObjectivesData on the efficacy of including definitive local therapy to the primary site for head and neck squamous cell carcinoma (HNSCC) patients with synchronous distant metastasis are lacking. In multiple different solid tumor types, there has been benefit when using systemic therapy followed by local consolidative therapy (stereotactic ablative radiotherapy or surgery) directed at metastases. We proposed to retrospectively evaluate patients at our institution that received definitive treatment to the primary.MethodsSingle institution retrospective study evaluating 40 patients with metastatic HNSCC treated with definitive surgery (55%) or chemoradiation (45%) to the primary site from 2000 to 2020. The major endpoints were overall survival (OS) and progression‐free survival (PFS) for the total population and multiple sub‐groups. Some variables were evaluated with multiple covariates Cox model.ResultsThe median PFS was 8.6 months (95% CI, 6.4–11.6), and OS was 14.2 months (95% CI, 10.9–27.5). In 28% of patients that received induction therapy, there was a twofold increase in median overall survival to 27.5 months. In the 33% of patients that received anti‐PD‐1 mAb as part of their treatment course, the median OS was significantly increased to 41.7 months (95% CI, 8.7‐NR) versus 12.1 months (95% CI, 8.4–14.4) with a 5‐year OS of 39%. Multivariate analysis for OS showed significance for age at diagnosis, use of IO, and number of metastatic sites.ConclusionWe observed impressive survival outcomes in metastatic HNSCC patients treated with definitive local therapy to the primary site in addition to induction and/or immunotherapy. Further study is warranted.Level of Evidence: 3.

Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials

IntroductionNeoadjuvant therapy may improve survival compared with upfront surgery in patients with resectable and borderline resectable pancreatic cancer, but high-quality evidence is lacking. MethodsWe systematically searched for randomised trials comparing neoadjuvant therapy with upfront surgery for resectable and borderline resectable pancreatic cancer published since database inception until December 2020. The primary outcome was overall survival (OS) by intention-to-treat with subgroup analyses for resectability status. Meta-analyses using a random-effects model were performed. Certainty of evidence was assessed using the GRADE approach. ResultsSeven trials with 938 patients were included. All trials included a neoadjuvant gemcitabine-based chemo(radio)therapy arm. None of the studies used adjuvant FOLFIRINOX. Neoadjuvant therapy improved OS (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.52–0.85; P = 0.001; I2 = 46%) compared with upfront surgery. This represents an increase in median OS from 19 to 29 months. In the subgroup of resectable pancreatic cancer (i.e., venous contact ≤180°, no arterial contact), no statistically significant difference in OS was observed (HR 0.77, 95% CI 0.53–1.12; P = 0.18; I2 = 20%). In the subgroup of borderline resectable pancreatic cancer (i.e. venous contact >180°, any arterial contact), neoadjuvant therapy improved OS (HR 0.61, 95% CI 0.44–0.85; P = 0.004; I2 = 59%). The GRADE certainty of evidence was high for the outcome of OS. ConclusionsNeoadjuvant therapy improves OS compared with upfront surgery in patients with borderline resectable pancreatic cancer. More evidence is required on whether neoadjuvant therapy improves survival for patients with resectable pancreatic cancer.

Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

IL7R Targeting Using OSE-127 Shows Robust Anti-Leukemic Activity in B-Cell Precursor Acute Lymphoblastic Leukemia Xenografts

Despite the favorable prognosis of B cell precursor acute lymphoblastic leukemia (BCP-ALL), relapse remains a clinical challenge. Antibody-based immunotherapies like Blinatumomab have improved BCP-ALL outcome, yet these can quickly turn ineffective due to CD19 antigen escape. Therefore, novel targeted immunotherapy options are urgently needed.We previously showed that high IL7R expression associates with adverse outcome in BCP-ALL patients and that IL7R targeting using laboratory-grade blocking antibodies significantly reduced leukemic burden in E2A-PBX1 and BCR-ABL patient derived xenografts (PDX) (Alsadeq et al., Blood, 2017; Abdelrasoul et al., Nat. Commun., 2020). Here we used the humanized monoclonal antibody OSE-127, a full IL7R antagonist which is not internalized by target cells and prevents IL7R heterodimerization and subsequent downstream signaling (Belarif et al., Nat. Commun. 2018, Belarif et al. JCI, 2019). Importantly, OSE-127 has recently been positively evaluated in a phase 1 study conducted in 63 healthy volunteers receiving either a single dose or two doses two weeks apart (EUDRACT 2018-001832-22). OSE-127 demonstrated an excellent safety and tolerability profile showing no signs of lymphopenia, cytokine release syndrome or T-cell compartment alterations. Based on these preclinical and clinical results, we investigated the anti-leukemic efficacy of OSE-127 immunotherapy in PDX models of BCP-ALL.First, to identify patients that may benefit from IL7R-immunotherapy, we measured IL7R surface expression in diagnostic BCP-ALL patient samples of different cytogenetic subgroups via flow cytometry.We detected IL7R-positivity (defined as ≥10% IL7R + BCP-ALL cells) in 52% (49/94) of patient samples including BCR-ABL + (25%; 5/20), TEL-AML1 + (41%; 7/17) and B-other (40%, 8/20) samples. Particularly high numbers of IL7R + patients were found in the E2A-PBX1 + and MLL-rearranged (MLLr) BCP-ALL subgroups (79%; 19/24 and 85%; 11/13 IL7R + patient samples, respectively).Next, we tested the efficacy of OSE-127 in NSG mice injected with PDX cells from two different E2A-PBX1 + patients (63.0% and 89.6% IL7R-positive blasts, respectively) modelling an MRD-situation by starting treatment one day after injection of PDX cells. While 100% of control animals developed overt leukemia, 0% of the OSE-127-treated animals developed the disease, with 10/10 and 7/10 mice per PDX-group being MRD-negative by the time of sacrifice. Of note, OSE-127-therapy was also effective in corresponding PDX models when therapy was initiated upon detection of 1% BCP-ALL cells in the peripheral blood, modelling an overt leukemia situation (P<0.0001 in both cases).To investigate the efficacy of OSE-127 in a variety of BCP-ALL samples, we conducted a preclinical phase II-like study using PDX from different cytogenetic patient subgroups (8E2A-PBX1 +, including 1 matched diagnostic/relapse sample, 1 BCR-ABL, 1 MLLr and 1 ETV6-NTRK3). Two mice per PDX were injected, randomly assigned to control or OSE-127 treatment groups and therapy was initiated when >1% blasts were detected in the peripheral blood. Response to OSE-127 was detected in 9/11 (82%) PDX samples in vivo, including BCR-ABL +, MLLr and E2A-PBX1 +-relapse samples. Accordingly, OSE-127 immunotherapy led to a significant increase in median overall survival (85 days versus 55 days; P=0.0122). Of note, OSE-127 therapy response associated with IL7R expression levels on BCP-ALL cells and no significant downregulation of the IL7R antigen was observed upon OSE-127 treatment.Taken together, our data demonstrate that IL7R-targeting using OSE-127, which has already demonstrated a good safety profile in healthy volunteers, is an efficient approach for BCP-ALL immunotherapy and may be particularly beneficial for patients with high IL7R-expression and/or relapsed/refractory disease after CD19-directed therapy. DisclosuresLenk: OSE Immunotherapeutics: Research Funding. Baccelli: OSE Immunotherapeutics: Current Employment, Other: Author of patents related to anti-IL7R antibodies. Corallo: OSE Immunotherapeutics: Current Employment. Schrappe: SHIRE: Other: research support; JazzPharma: Honoraria, Other: research support; Servier: Honoraria, Other: research support; Novartis: Honoraria, Other: research support; SigmaTau: Other: research support; Amgen: Other: research support; Servier: Honoraria; Novartis: Honoraria; JazzPharma: Honoraria. Cario: Novartis: Other: Lecture Fee. Brüggemann: Incyte: Other: Advisory Board; Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Poirier: OSE Immunotherapeutics: Current Employment, Other: Author of patents related to anti-IL7R antibodies. Schewe: OSE Immunotherapeutics: Research Funding; Bayer: Other: Advisory Board; SOBI: Other: Advisory Board; Jazz Pharmaceuticals: Other: Advisory Board.

MA16.03 CRISPR Screen Reveals XPO1 as a Therapeutic Target Strongly Sensitizing to First and Second Line Therapy in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an exceptionally aggressive disease comprising 13% of all lung cancer cases. With limited treatment options that typically result in transient responses, SCLC is responsible for approximately 250,000 deaths globally per year. The recent addition of immunotherapy to first-line platinum-based doublet chemotherapy appears to benefit only a small subset of patients, resulting in a 2-month increase in median overall survival. Major hurdles to improving SCLC treatment include development of rapid chemoresistance and ineffective second line therapies. The identification of more durably effective therapeutic strategies is a major unmet clinical need. We performed an in vitro CRISPR screen in seven SCLC cell lines, including commercially available and short term-cultured cell lines derived from patient-derived-xenografts (PDXs), representing all major SCLC subtypes. We used an in-house druggable genome library including targets for which active inhibitors, either FDA-approved or in clinical development, are available. The screen was performed with two conditions per cell line, untreated and cisplatin-treated, to identify targets whose disruption would specifically sensitize to cisplatin. Candidate targets of interest were validated genetically with independent sgRNAs in Cas9-expressing in vitro and in vivo models (pSpCTRE-PDXs) and pharmacologically, with in vitro synergy assays and PDX treatments. Signaling pathways were studied by western blot, and toxicity studies were performed in vivo, to assess the safety of the agents at pharmacologically effective doses. We performed immunohistochemistry (IHC) to assess expression of candidate targets in SCLC tissue microarrays (TMAs). Our CRISPR screen approach revealed XPO1 (Exportin 1) as a candidate that may contribute to cisplatin resistance across all SCLC subtypes. Combination of Exportin 1 inhibitors with cisplatin demonstrated synergy in vitro, and use of cisplatin with the Exportin 1 inhibitor selinexor showed combinatorial efficacy in vivo in chemonäive SCLC PDXs representing all SCLC subtypes. This efficacy was associated with increased DNA damage and apoptosis. The combination was well tolerated in mice at the drug concentrations tested. Exportin 1 inhibition also exhibited combinatorial synergy with irinotecan, a standard agent use for recurrent SCLC, and combination of selinexor with irinotecan demonstrated substantial efficacy in SCLC PDXs derived from chemorelapsed tumors including models for all SCLC subtypes, again with manageable toxicity profiles. We found SCLC to have the highest XPO1 mRNA expression among a diverse array of tumor histologies. High XPO1 expression was confirmed at the protein level in a SCLC tissue microarray, independent of SCLC subtype. Exportin 1 is highly expressed in SCLC tumors, independent of their subtype, and its inhibition enhances sensitivity to the chemotherapeutic drugs used in first line and second line treatment of SCLC tumors. Our results provide preclinical rationale for the combination of selinexor with cisplatin or with irinotecan as first or second line treatment, respectively, of SCLC.

Modern possibilities of immunotherapy in the treatment of extensive-stage small cell lung cancer: experience of durvalumab application. Case report

Extensive-stage small cell lung cancer (ES-SCLC) is characterized by an aggressive course, a high recurrence rate and fast progression. For a long time, the survival prognosis for the most patients suffering from this disease remained unfavorable. The situation changed with the appearance of chemoimmunotherapy in clinical practice. Chemotherapy based on durvalumab in comparison with the standard chemotherapy demonstrated the statistically and clinically significant increase in median overall survival in patients with previously untreated ES-SCLC in the CASPIAN international trial. This article deals with the case of the application of standard chemotherapy in combination with durvalumab as a first-line ES-SCLC therapy. The patient started receiving durvalumab therapy in June 2017 as a part of the CASPIAN international trial. In March 2021 the duration of therapy was 45 months, the patient had a complete regression of the disease.

A critical appraisal of Japan's new drug approval process: a case study of FLT3-ITD inhibitor quizartinib.

In the last two decades, simultaneous global development of novel drugs become more common by conducting multiregional clinical trials. However, regulatory authorities of different regions often make different decisions on the approvals of the same new drugs. We would like to discuss the appropriateness of Japanese regulatory approach through a case study of quizartinib, a novel anti-leukemia drug developed in Japan. The pivotal clinical trial "QuANTUM-R" conducted in 19 countries showed a modest increase in median overall survival with quizartinib than the conventional chemotherapy. However, because several critical defects in this trial were pointed out by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA), quizartinib has not been approved in the US and Europe to date. On the contrary, the regulatory authority of Japan gave a notice of approval to quizartinib as a "standard of care", and the country becomes the sole country that granted market authorization. In our paper, we provide more detailed discussion about the methodology for scientific evaluation of the new drug.

Outcomes and applicability of a deep learning virtual tumor board (DLVTB) in community-dwelling colorectal cancer (CRC) patients.

e18635 Background: With almost 85% of patients treated outside NCI-designated cancer centers, providing comprehensive, state-of-the-art cancer care to millions of patients in the U.S. remains a significant challenge. We aimed to combine cutting edge AI based technology of DLVTB with high value-added services to provide evidence-based care management recommendations and implementation support to the patients and physicians in the community. To further demonstrate the feasibility, reproducibility, scalability, and benefits of DLVTB, we evaluated key outcomes from incorporating DLVTB in a cohort of 35 patients with advanced colorectal adenocarcinoma (CRC). Methods: Our core-enabling technology is a deep learning based Natural Language Understanding Engine that employs (1) natural language processing for medical text digestion and structuring, (2) decision trees and multilayer perception models to produce evidence-based treatment protocols, and (3) natural language based report generation. The technology platform is combined with human support from oncology sub-specialists to deliver a comprehensive Interpretive Report with a prioritized list of recommendations for each patient. These recommendations are operationalized by a case management team to ensure care implementation and monitoring of outcomes. Results: Thirty-five patients with CRC were referred for incorporation of DLVTB into clinical practice. Median age of patients was 57 years with 68.6% males. About 88.6% of the patients were Stage IV and 82.9% were treated by community practice oncologists. Median time since diagnosis was 17 months (1-73 months). Overall, DLVTB-cohort demonstrated an increase in median Overall Survival of 12 months per patient in comparison with historical cohorts. More specifically, DLVTB recommended initial and/or additional biomarker testing for 71% of the patients with further precision oncology-guided treatment recommendation (e.g. an EGFR inhibitor) for 80% of the patients. 63% of the patients were eligible for at least one clinical trial. 58% of the trials identified were within proximity (≤50 miles) of the patient’s primary residence. Thus, DLVTB was able to identify a trial that did not require extensive travel, provided eligibility and actionability closer to the point-of-care. 14% of the DLVTB evaluated patients subsequently enrolled in the recommended clinical trial, far surpassing the national average (3%). Moreover, DLVTB recommended treatments achieved on average savings of $39,194 per patient which is 35% of the average drug cost per patient. Conclusions: Our results demonstrate the feasibility and benefits of incorporating DLVTB into clinical practice. The utilization of DLVTB as a clinical trial enrollment tool and an engine for development of pathways resulting in improved clinical outcomes, in a cost-effective, and innovative care delivery model.

Outcomes with definitive local treatment to the primary site in non-nasopharyngeal head and neck squamous cell carcinoma patients with synchronous distant metastasis.

e18014 Background: Data on the efficacy of including definitive local therapy to the primary head and neck disease (PHN) for non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) patients with synchronous distant metastasis are lacking. Methods: In this single institution retrospective study, we evaluated the outcomes of patients treated from 2000-2020 at UPMC for non-nasopharyngeal HNSCC with synchronous distant metastasis whose therapy included definitive therapy to the PHN. We evaluated overall survival (OS), calculated as date of diagnosis to date of death and progression free survival (PFS), calculated as date of diagnosis to date of death or progression. Based on an initial univariate analysis, the potential significant predictors were evaluated further in the multiple covariates Cox model via stepwise procedures. The relative mortality rates were summarized with hazard ratio (HR), with HR &gt; 1.0 corresponding to increased mortality. Results: A total of 40 patients met inclusion criteria. The median age was 61, primary sites included 52.5% oropharynx (48% HPV +), 40% larynx/hypopharynx, 7.5% oral cavity, and 85% had a solitary metastatic lesion, most commonly in the lung. Definitive treatment of the PHN was with surgery (55%) or chemoradiation (45%), and 45% also underwent local treatment for all distant disease. The median PFS was 8.6 months (95% CI, 6.4-11.6), and OS was 14.2 months (95% CI, 10.9-27.5). In the 28% of patients that received induction therapy, there was a two-fold increase in median OS to 27.5 vs. 13.7 months, p = 0.06. In the 33% of patients that received anti-PD-1 mAb immunotherapy (IO), the median OS was significantly increased to 41.7 months (95% CI, 8.7-NR) vs. 12.1 months (95% CI, 8.4-14.4), p = 0.01, with a numeric increase in PFS as well (11.3 vs. 8.2 months respectively, p = 0.07). Notably no difference in PFS or OS was seen with type of local therapy to the PHN, receipt of local treatment to all distant disease, by HPV status, or year of diagnosis. In multivariate analysis including induction and other variables significant in univariate analysis (age, number of metastatic sites), IO was independently associated with improved OS (HR 3.123 (No IO vs. IO) (95% CI, 1.198-8.137), p = 0.02), as was age and number of metastatic sites. In the patients that received IO started as part of induction the median PFS and OS were 19.5 and 45.5 months respectively. Conclusions: We observed impressive survival in select non-nasopharyngeal HNSCC patients with synchronous distant metastasis treated with definitive local therapy to the primary head and neck disease in addition to induction and/or IO, with IO independently associated with improved OS. To our knowledge this is the first evaluation of the efficacy of definitive local therapy and IO in this population. Prospective evaluation is warranted.

The role of social determinants on overall survival in advanced-stage non-small cell lung cancer patients.

e21117 Background: Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. Many studies have evaluated the association of social determinants with outcomes in early-stage NSCLC. These studies have shown statistically and clinically significant associations between overall survival (OS) and other social factors (e.g marital status, educational attainment). The aim of our study was to better understand the role of various social determinants of health (SDH) on OS in advanced-stage NSCLC patients in a community oncology practice in Florida. Methods: In this retrospective study, 125 patients with stage III and IV NSCLC were recruited between January 1st, 2014 until December 31st, 2018. We performed both categorical and continuous analyses (Pearson’s chi-square and Kruskal-Wallis test, respectively) to evaluate the association between median OS and several independent variables, including; gender, race, marital status, insurance status, living status, receiving financial assistance (FA), alcohol use, and smoking histories. OS is defined as the date of diagnosis up to the date of death. Other confounders that were analyzed included histology, treatment modality, comorbidities, and performance status of the patients. Results: Of the total study population (n = 125), 60% identified as male with a mean age of 73 years for the study population. The majority of patients (89%) identified as white; 56% were married, and 81% lived with someone. 66% of patients had an HMO insurance plan, and 51% of patients obtained FA to help with treatment care costs. 47% of patients identified as former smokers and 54% denied any alcohol use. The median OS for the patient population was 0.756 years. Chi-square analyses revealed that patients who received FA were more likely to live longer than median OS as opposed to patients that did not receive FA (OR = 2.41, 95% CI [1.18, 4.96], p = 0.050). Kruskal-Wallis analyses demonstrated that patients receiving FA had nearly a two-fold increase in median OS compared to patients without financial assistance (median OS = 1.01 years vs. 0.545 years, respectively; p = 0.013). However, other social determinants evaluated did not have a significant impact on relative OS in advanced-stage NSCLC. Conclusions: Ultimately, our study concludes that receiving FA has a significant association with increased OS in advanced-stage NSCLC patients. This study highlights the importance of reducing the financial burden of advanced-stage NSCLC patients and how FA impacts patient outcomes. Future prospective cohort studies with a larger sample size are warranted to identify other SDH, as well as the underlying mechanisms affecting median OS, in patients with advanced-stage NSCLC.

SURG-05. IDEAL TREATMENT REGIMEN FOR PATIENTS WITH ≥1 BRAIN METASTASIS FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

Abstract BACKGROUND Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). The aim of this study was to assess the comparative effectiveness of treatments for BM from NSCLC. METHODS We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published until October 2018. We also searched the Chinese databases Wanfang Data, Wanfang Med Online, China National Knowledge Infrastructure, and Chongqing VIP Information for RCTs published until September 2019. Trials including &amp;gt; 10 patients were selected. The primary outcomes were overall survival (OS) and intracranial progression-free survival (PFS). We used a frequentist random-effects model for network meta-analysis and assessed the certainty of evidence using the GRADE approach. RESULTS Among 8798 abstracts, 106 RCTs (9452 patients) met inclusion criteria. Median sample size was 67 (range 25-554). All trials included adult patients with histologically proven NSCLC and &amp;gt;1 BM proven on CT/MRI. Of trials that reported performance status (e.g. ECOG or KPS, n=67), 63/67 excluded patients with non-favorable performance status. Interventions assessed included surgery, WBRT, SRS, targeted therapies (i.e. EGFR/ALK inhibitors), and chemotherapy. Compared to WBRT alone, several interventions demonstrated a statistically significant increase in median OS, including non-targeted chemotherapy + surgery (MD: 415.3 days, 95% CI: 31.3-799.4), WBRT + EGFRi (MD: 200.2 days, 95% CI:146.3-254.1), and EGFRi alone (MD: 169.7 days, 95% CI: 49.7-289.7). Among all interventions, only WBRT + EGFRi showed a significant improvement in median PFS (MD: 108.0 days, 95%CI: 48.5-167.5). CONCLUSIONS Our preliminary analyses indicate an OS and PFS benefit on the addition of EGFR inhibitors to WBRT for the treatment of BMs from NSCLC. Further analyses of hazard ratios for OS/PFS are underway, and subgroup analyses are planned. These data support the growing role of targeted therapies in the treatment of BMs, particularly in susceptible mutant tumours.

Abstract 2219: OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models

Abstract Inhibition of the immune-checkpoint axis that involves PD-L1/PD-1 has improved responses and outcomes for certain cancer patients, but there remains unmet need as only a fraction of patients respond to these therapies. Talimogene laherparepvec (T-VEC) is an FDA-approved, first-in-class oncolytic immunotherapy based on a modified herpes simplex virus type 1 (HSV-1) designed to selectively replicate in tumors and produce granulocyte-macrophage stimulating factor (GM-CSF) to enhance a tumor-antigen specific adaptive immune response. Intratumoral treatment with T-VEC has been shown to promote an inflammatory tumor microenvironment both preclinically and clinically. Combining T-VEC with immune checkpoint inhibitors is of high interest to potentially broaden and deepen the clinical responses in checkpoint-resistant tumors. In the current study, we evaluated the efficacy of OncoVEXmGM-CSF (an HSV modified like T-VEC, except that it produces murine GM-CSF) in combination with anti-PD-1/PD-L1 treatment in multiple syngeneic mouse tumor models. Bilateral tumor models were used, where only one tumor was treated with OncoVEXmGM-CSF (representing the local oncolytic effect), allowing the evaluation of systemic abscopal effect in the uninjected contralateral tumors. OncoVEXmGM-CSF in combination with anti-PD-L1/PD-1 enhanced tumor growth inhibition in both treated and contralateral tumors in the A20 and MC38 syngeneic models and overcame anti-PD-L1 resistance in the CT26 model. The combination treatment also led to a significant increase in median overall survival compared to either agent as a monotherapy. In addition, tumor antigen epitopes were identified by combining exome sequencing and MHC/HLA-binding prediction algorithms. Antigen-specific T cell response was measured in an IFN-γ ELISPOT assay using splenocytes from treated mice. OncoVEXmGM-CSF induced and /or enhanced systemic T cell responses directed against both tumor neoantigens and tumor-associated antigens. Together, these data reveal that OncoVEXmGM-CSF treatment can cause direct tumor lysis along with the potentiation of an adaptive, systemic T cell-mediated anti-tumor immune response that can be enhanced by the addition of PD-L1/PD-1. Our study provides a strong rationale for the ongoing clinical evaluation of the combination of T-VEC and PD1-/PD-L1-targeted therapy in cancer patients. Citation Format: Keegan Cooke, Juan Estrada, Petia Mitchell, Jinghiu Zhan, Pedro J. Beltran, Jing Qing, Jude Canon. OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models [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 2219.

60. IDEAL TREATMENT REGIMEN FOR PATIENTS WITH ≥1 BRAIN METASTASIS FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

BACKGROUNDBrain metastases (BM) are common in non-small cell lung cancer (NSCLC). The aim of this study was to assess the comparative effectiveness of treatments for BM from NSCLC.METHODSWe searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published until October 2018. We also searched the Chinese databases Wanfang Data, Wanfang Med Online, China National Knowledge Infrastructure, and Chongqing VIP Information for RCTs published until September 2019. Trials including > 10 patients were selected. The primary outcomes were overall survival (OS) and intracranial progression-free survival (PFS). We used a frequentist random-effects model for network meta-analysis and assessed the certainty of evidence using the GRADE approach.RESULTSAmong 8798 abstracts, 106 RCTs (9452 patients) met inclusion criteria. Median sample size was 67 (range 25–554). All trials included adult patients with histologically proven NSCLC and >1 BM proven on CT/MRI. Of trials that reported performance status (e.g. ECOG or KPS, n=67), 63/67 excluded patients with non-favorable performance status. Interventions assessed included surgery, WBRT, SRS, targeted therapies (i.e. EGFR/ALK inhibitors), and chemotherapy. Compared to WBRT alone, several interventions demonstrated a statistically significant increase in median OS, including non-targeted chemotherapy + surgery (MD: 415.3 days, 95% CI: 31.3–799.4), WBRT + EGFRi (MD: 200.2 days, 95% CI:146.3–254.1), and EGFRi alone (MD: 169.7 days, 95% CI: 49.7–289.7). Among all interventions, only WBRT + EGFRi showed a significant improvement in median PFS (MD: 108.0 days, 95%CI: 48.5–167.5).CONCLUSIONSOur preliminary analyses indicate an OS and PFS benefit on the addition of EGFR inhibitors to WBRT for the treatment of BMs from NSCLC. Further analyses of hazard ratios for OS/PFS are underway, and subgroup analyses are planned. These data support the growing role of targeted therapies in the treatment of BMs, particularly in susceptible mutant tumours.

P-57 Effectiveness and safety of trifluridine/tipiracil in patients with metastatic colorectal cancer in clinical practice in Poland

Trifluridine/tipiracil is indicated for adult patients with metastatic colorectal cancer (mCRC) previously treated (refractory), or not considered as candidates for available therapies. The randomized phase 3 RECOURSE trial showed a significant increase in median overall survival (OS) of 1.8 months compared to the placebo, significant benefit in progression-free survival (PFS), and prolonged time to ECOG PS worsening. We assessed the effectiveness and safety of trifluridine/tipiracil in daily clinical practice before public reimbursement in Poland.

Irinotecan, cetuximab, and bevacizumab (CBI) versus irinotecan, cetuximab, and placebo (CI) in irinotecan-refractory metastatic colorectal cancer (mCRC): Results from an ACCRU network randomized phase II trial.

102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.

HOUT-17. UTILITIES OF RARE CANCERS LIKE MALIGNANT PLEURAL MESOTHELIOMA AND GLIOBLASTOMA MULTIFORME - DO THEY COMPARE?

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary brain cancer in adults. Malignant pleural mesothelioma (MPM) is an invasive and generally fatal malignancy of the pleura mainly caused by exposure to asbestos fibers. TTFields treatment has been shown effective in both MPM and GBM with a comparable increase in median overall survival (OS). Differences in utility values however, could significantly influence assessment of cost-effectiveness for MPM and GBM, despite similar clinical efficacy. METHODS We reviewed the published literature adressing health state preference values or health utilities in both indications using a boolean search of the PubMed database. The results were compiled separately for both diseases and then compared to each other. RESULTS Estimates of health states preference values or utilities in GBM all refer to one single publication by the UK NICE. Healthy members of the NHS Value of Health Panel (VoHP) rated a total of nine descriptive health state scenarios using the standard gamble method for preference elicitation. Utilities for MPM were derived at individual patient level from the EQ-5 questionnaire collected during one trial. Other publications do not use specific mesothelioma heath state preference velues but assume applicability of utilities derived from a non small cell lung cancer (NSCLC) population. CONCLUSIONS GBM utilites use different health states for elicitation, while utilities used in MPM were elicited at patient level. GBM utilities can be used in a health state disease model but there are no similar published values for MPM. MPM utilities using the EQ-5 questionnaire however better describe individual utilities and their change during the course of disease. Despite similar costs and clinical efficacy of TTFields treatment for GBM and MPM, the difference in elicitation methods and sources of utilites may lead to significant disparities in cost effectiveness assessment and subsequent adoption of TTFields treatment in different indications.

Effectiveness of BRAF inhibitors in patients with BRAF V600 mutation positive glioma: a systematic review

Abstract Background BRAF inhibitor treatment with vemurafenib and dabrafenib have produced significant increases in median overall survival for BRAF V600 mutation-positive melanoma patients and are in wide clinical use. BRAF inhibitors have also been used in an ad hoc fashion in BRAF V600 mutation-positive glioma in a number of glioma subtypes with varying prognoses. Methods An electronic search was performed on MEDLINE and Embase on February 1, 2019 to identify studies of any design that reported the outcome of patients with BRAF V600 mutation-positive glioma treated with BRAF inhibitors. Data was collected for demographic information, tumour information (type and grading), BRAF mutation type, prior treatment regimens, type of BRAF inhibitor, dose and duration of treatment, best objective response, progression free survival (PFS), overall survival (OS), glioma specific symptomatic relief and adverse events. Preliminary Results Seventy-nine case reports, case series and single arm cohort studies with a total of 286 patients were included. Duration of treatment was available for 197 patients and varied from 0.1 to 54 months, with 104 patients still undergoing treatment at the time of publication. Progression occurred in 158 patients (including both low-grade and high-grade glioma) at between 0.805 and 36 months following the start of treatment. 34 people died, at between 0.329 and 40.1 months following the start of treatment. Conclusions Our systematic review shows varying clinical effectiveness of BRAF inhibitors in BRAF V600 mutation-positive glioma depending on low-grade or high-grade glioma. This evidence may inform future trials of BRAF inhibitors for glioma patients.

1059TiP - Tumour treating fields (200 kHz) concomitant with weekly paclitaxel for platinum-resistant ovarian cancer: Phase III INNOVATE-3/ENGOT-ov50 study

BackgroundTumour Treating Fields (TTFields) are a non-invasive, regional antimitotic therapy. In preclinical models of ovarian cancer, TTFields (200kHz) reduced cell viability and showed synergistic effects with taxanes in vitro and in vivo. The Phase 2 INNOVATE study [NCT02244502] demonstrated safety of TTFields plus weekly paclitaxel in 31 PROC (platinum-resistant ovarian cancer) patients (Vergote et al Gyn Onc 2018;150:471). No increase in grade 3–4 TTFields were reported; 26 patients (84%) had TTFields-related dermatitis; one patient permanently discontinued TTFields due to dermatitis. Patients received median of 4 prior therapies; 100% prior platinum and 97% prior taxanes. Median PFS was 8.9 months, 25% had partial response and clinical benefit rate was 71%. The median overall survival was not reached: the one-year survival rate was 61%. This phase 3 INNOVATE-3/ENGOT-ov50 study [NCT03940196] investigates TTFields combined with weekly paclitaxel in PROC patients. Trial designPatients (N=540) will have disease progression (PROC per RECIST V1.1) within 6 months of last platinum therapy with a maximum of 2-5 prior lines of systemic therapy, ECOG score of 0-1 and no peripheral neuropathy above grade1. Patients with primary refractory disease (progression during first line therapy) will be excluded. Patients will be randomized 1:1 to either weekly paclitaxel alone or weekly paclitaxel plus TTFields (200kHz). Weekly paclitaxel will be administered at standard starting of dose 80mg/m2 weekly for 8 weeks, and then on Days 1, 8, and 15 for subsequent 28-day cycle. TTFields will be delivered for 18hours/day and continued if no progression in the abdominal or pelvic regions (“in-field region”) per RECIST V1.1. Clinical follow up will be performed q4w, with radiological follow up (CT or MRI scans of the abdomen and chest) q8w. The primary endpoint is overall survival. Main secondary endpoints: progression-free survival, objective response rate, severity and frequency of AEs, and quality of life (EORTC QLQ-C30 with QLQ-OV28). Sample size (n=540) will detect an increase in median overall survival from 12 to 16 months (Hazard ratio 0.75). Clinical trial identificationENGOT/ov50; NCT03940196. Legal entity responsible for the studyNovocure. FundingNovocure. DisclosureI.B. Vergote: Advisory / Consultancy: Roche NV, Genmab A/S, Advaxis Inc., Morphotek Inc., F. Hoffmann-La Roche Ltd.; Research grant / Funding (institution): Amgen and Roche; Advisory / Consultancy: Cerculean Pharma Inc., Novocure GmBh, AstraZeneca,; Advisory / Consultancy: Mateon Therapeutics Inc., Immunogen; Advisory / Consultancy: Eli Lilly Benelux NV, Amgen Inc., Theradex Europe; Advisory / Consultancy: Pfizer Inc., Debiopharma International SA, Vifor Pharma België; Advisory / Consultancy: Novartis Pharma AG, MSD Belgium BVBA, Janssen-Cilag; Advisory / Consultancy: Bayer Pharma AG, Clovis Oncology, Takeda, Pharma Mar, Oncoinvent; Travel / Accommodation / Expenses: Tesaro, Clovis Oncology, Takeda,; Travel / Accommodation / Expenses: Pharma Mar, Roche, Genmab and Oncoinvent. D. Cibula: Advisory / Consultancy: Roche, AstraZeneca, Sotio. V. Salutari: Honoraria (self) / Advisory role / Speaker Bureau: Roche, AstraZeneca, Tesaro, PharmaMar, MSD, Clovis. All other authors have declared no conflicts of interest.

Abstract CT174: Phase III INNOVATE study of tumor treating fields (200 kHz) concomitant with weekly paclitaxel for platinum-resistant ovarian cancer (ENGOT-ov50/BGOG study groups)

Abstract Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality approved for glioblastoma by the FDA. TTFields act by disrupting mitotic spindle formation during metaphase. In multiple preclinical models of ovarian cancer, TTFields (200 kHz) reduced viability of cell lines through apoptosis. TTFields have demonstrated synergistic effects with taxanes in vitro and in vivo. The Phase II INNOVATE clinical study [NCT02244502] demonstrated the safety of TTFields combined with weekly paclitaxel in 31 PROC (platinum-resistant ovarian cancer) patients. No serious adverse events related to TTFields were reported. There was no increase in grade 3-4 adverse events compared to the frequency of such events reported in the literature with single agent weekly paclitaxel. Twenty-six patients (84%) had TTFields-related dermatitis but only one patient permanently discontinued TTFields due to dermatitis. The median PFS was 8.9 months, 7 patients (25%) had partial response and the clinical benefit rate was 71%. The median overall survival was not reached: the one-year survival rate was 61%. In this Phase III INNOVATE-3 [ENGOT-ov50], we study TTFields combined with weekly paclitaxel in PROC patients. Study Design: Patients (N=540) with PROC (progression per RECIST V1.1) within 6 months of last platinum therapy with a maximum of two to five prior lines of systemic therapy will be enrolled. Patients (ECOG score of 0-1) will have no peripheral neuropathy. Patients with primary refractory disease (progression during first line therapy) will be excluded. Patients will be randomized in a ratio of 1:1 to receive either weekly paclitaxel alone or weekly paclitaxel in combination with TTFields (200 kHz). Weekly paclitaxel will be administered at standard starting of dose 80 mg/m2 weekly for 8 weeks, and then on Days 1, 8, and 15 for each subsequent 28-day cycle. TTFields will be applied in the experimental arm for at least 18 hours/day on average, and maybe continued as long as there is no progression in the abdominal or pelvic regions (“in-field region”) per RECIST V1.1. Clinical follow up will be performed q4w, with radiological follow up (CT or MRI scans of the abdomen and chest) q8w. The primary endpoint will be overall survival. Main secondary endpoints will include progression-free survival, objective response rate, severity and frequency of adverse events and quality of life based on EORTC QLQ-C30 with the QLQ-OV28 questionnaire. A sample size of 540 patients is sufficient to detect an increase in median overall survival from 12 to 16 months (Hazard ratio 0.75). Citation Format: Ignace Vergote. Phase III INNOVATE study of tumor treating fields (200 kHz) concomitant with weekly paclitaxel for platinum-resistant ovarian cancer (ENGOT-ov50/BGOG study groups) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT174.