Increase In Median Overall Survival Research Articles

Abstract CT201: Final results of Phase II STELLAR trial: TTFields with chemotherapy in unresectable malignant pleural mesothelioma

Abstract Background Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable device. In-vitro, human mesothelioma cells were highly susceptible to TTFields. TTFields plus chemotherapy have significantly extended survival in glioblastoma. Method Patients (n= 80) with unresectable, previously untreated mesothelioma were treated with continuous 150 kHz TTFields (>18h/day) in combination with pemetrexed and cisplatin or carboplatin. Inclusion criteria: ECOG PS 0-1, pathologically proven mesothelioma and at least one measurable lesion per modified RECIST criteria. The primary endpoint was overall survival (OS) and secondary endpoints were response rate, progression free survival (PFS) and toxicity. EOCG status and cancer-related pain were assessed until disease progression using a visual analog scale. This prospective, single arm study assumed an historical control with a median survival of 12.1 months (Vogelzang, JCO. 2003). The sample size provides 80% power with a two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months. Result All 80 patients had a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology, similar to the Vogelzang study. Median OS was 18.2 months (95% CI 12.1-25.8) versus 12.1 months in the historical control. The 1-year survival rate was 62.2% (95% CI 50.3-72.0). Median OS for epithelioid patients was 21.2 months (95% CI 13.2-25.8). Clinical benefit (PR+SD) was seen in 97.2% of patients. ECOG score was stable during the first year of follow up. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. 63% (50 patients) received carboplatin. Median time to deterioration in performance status was 13.1 months. Average pain score was lower compared to baseline during the first 7 months of treatment and higher later with a median time to a clinical significant 33% increase in pain of 8.4 months. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Four patients (5%) had grade 3 dermatitis. Grade 3-4 systemic AEs were reported in >3% of patients: hematological AEs (15%) and fatigue (4%). Conclusion The study met its primary endpoint of significant extension of survival in previously untreated mesothelioma patients. Secondary efficacy endpoints were also improved compared to historical control. The study demonstrated no safety concerns for TTFields plus standard chemotherapy to the thorax. The use of the TTFields was not associated with a decrease in performance status or an increase in pain. TTFields in combination with chemotherapy are efficacious in malignant pleural mesothelioma vs chemotherapy alone in historical data. Citation Format: Giovanni Luca Ceresoli, Joachim Aerts, Jaroslaw Madrzak, Rafal Dziadziuszko, Rodryg Ramlau, Susana Cedres, Birgitta Hiddinga, Jan VanMeerbeeck, Manlio Mencoboni, David Planchard, Antonio Chella, Lucio Crino, Maciej Krzakowski, Federica Grosso. Final results of Phase II STELLAR trial: TTFields with chemotherapy in unresectable malignant pleural mesothelioma [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 CT201.

Tumor-associated macrophage expression of interferon regulatory Factor-8 (IRF8) is a predictor of progression and patient survival in renal cell carcinoma

Tumor-associated macrophages have been well-characterized in solid malignancies, including renal cell carcinoma and generally correlate with poor prognosis. However, the molecular mechanisms which govern intratumoral macrophage behavior and patient outcome are unclear. Here, we investigated whether alterations in macrophage expression of the transcriptional regulator for myeloid commitment and function, interferon regulatory factor-8 (IRF8), could predict survival of clear cell renal cell carcinoma patients. Transcriptional analysis of publicly available data revealed elevated IRF8 expression was associated with prolonged disease-free survival. Evaluation of protein expression within histologic sections of primary clear cell renal cell carcinoma patient samples showed intensity of IRF8 by CD68+ macrophages correlated inversely with stage. Survival outcomes of patients with primary or metastatic disease could be stratified on the basis of IRF8 levels by macrophages. Patients with high levels of IRF8 expression within metastatic sites had prolonged overall survival (log-rank P < 0.01, HR = 0.44, 95% C.I.: 0.23–0.84) compared to patients with low levels of IRF8 expression. When patient cohorts were further separated based on macrophage infiltration within metastatic lesions, patients with a macrophagelo IRF8hi profile had a more than 10 year increase in median overall survival compared to patients with a macrophagelo IRF8lo profile (log-rank, P < 0.001). In summary, we report that macrophage expression of IRF8 is inversely correlated with tumor mass and directly related to survival outcome. These findings support the utilization of IRF8 expression by macrophages to predict patient outcome, which may have important implications for guiding treatment decisions for renal cell carcinoma patients with metastatic disease.

High-dose interleukin-2 and interferon as first-line immunotherapy for metastatic melanoma: long-term follow-up in a large unselected Danish patient cohort

Background and patientsBetween January 2007 and April 2014, 464 Danish patients received high-dose (HD) interleukin-2 (IL-2) and interferon (IFN) as first-line treatment for metastatic melanoma. Our data represent the largest cohort of patients with metastatic melanoma worldwide, with relevant data on all patients and no patients lost to follow-up. Data have been gathered in a national database on the treatment of metastatic melanoma established since 2011. ResultsOne hundred eighteen patients (25%) obtained an objective response rate (ORR) to treatment with a median progression-free survival (PFS) of 3.4 months and a median overall survival (OS) of 14.2 months. Furthermore, 2-, 3- and 5-year survival was 32.0%, 23.2% and 16.6%, respectively. Ipilimumab as second-line therapy has been used since July 2010. We divided patients in two subgroups before and after this date to evaluate the effects of new treatment strategies. Patient characteristics, ORR and PFS were comparable in the two subgroups. Survival was significantly improved after 2010, with an increase in median OS from 12.2 to 16.0 months and in 5-year OS from 12.5% to 20.7%. ConclusionsOur data confirm that HD IL-2/IFN as first-line therapy in metastatic melanoma leads to long-term survival in a subset of treated patients. Potentially, IL-2/IFN might represent a treatment option in patients with active melanoma after established initial treatment with checkpoint inhibitors and BRAF/MEK-targeted therapies.

Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis.

The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90–1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26–1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.

Therapeutic Manipulation of Cancer Cell Metabolism with the Mitochondrial Metabolism Inhibitor Cpi-613 in Addition to Chemotherapy Abrogates the Adverse Prognostic Effect of Age in Relapsed and Refractory AML

Background: Acute myeloid leukemia is an aggressive malignancy with poor outcomes especially in patients 60 years of age or older. This thought to be in part from increased resistance to chemotherapy in AML cells arising in an older host. One of the nine recognized biological hallmarks of aging is a decline in mitochondrial quality. The effect of exploiting this age-related metabolic vulnerability in relapsed AML has not been previously established. CPI-613 is a first-in-class agent that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, effectively impairing the TCA cycle. We have combined CPI-613 with high dose cytarabine and mitoxantrone in phase I and II clinical trials in over 100 patients with relapsed or refractory AML.Methods: To determine the effect of the addition of CPI-613 in older patients, the phase I and II datasets were combined and outcomes by age were analyzed and compared to age related outcomes in a historical dataset of patients treated with a high dose cytarabine, mitoxantrone and L-asparaginase but without CPI-613. In both trials, patients were given CPI-613 as a 2-hour infusion on days 1 through 5. Cytarabine was dosed at 3,000 mg/m² (if younger than 60) or at 1,500 mg/m² (if 60 years of age or older), given every 12 hours for 5 doses, starting on day 3 following the CPI-613 infusion. The mitoxantrone was dosed at 6 mg/m² and is given once daily following the first, third and fifth cytarabine doses. At day 14, nadir marrow was evaluated, and patients with residual disease could be re-treated as above or with an abbreviated 3-day cycle. Responding patients were eligible to receive up to 2 abbreviated 3-day consolidation cycles. The historical cohort was treated identically without CPI-613, except L-Asparaginase was given at a dose of 6,000 units/m2 following the last dose of cytarabine.Results: Patient characteristics are summarized in Table 1. In the historical dataset younger patients had a highly significant increase in median overall survival when compared to patients ≥60 years of age (figure 1A). In contrast, older and younger patients treated with CPI-613 in addition to the chemotherapy had no significant difference in median survival (figure 1B). Additionally, when outcome by dose of CPI-613 was analyzed, older but not younger patients had a significant improvement in survival when given a dose of 2,000 mg/m2 compared to those given 1,500 mg/m2 (figure 1C+D). Patients 60 years of age or older had a response rate of 55% and a median overall survival of 12.4 months when treated with a dose of CPI-613 of 2,000 mg/m2.Conclusions: Targeting mitochondrial metabolism exploits an age-related metabolic vulnerability in AML arising in older patients. These results have led to a randomized phase III trial of CPI-613 at 2,000 mg/m2 in combination with high dose cytarabine and mitoxantrone compared to high dose cytarabine and mitoxantrone alone in relapsed or refractory AML patients 60 years of age or older. [Display omitted] DisclosuresPardee:Amgen: Speakers Bureau; Karyopharm: Research Funding; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment; Novartis: Speakers Bureau. Ellis:Alexion: Speakers Bureau. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1: Expanded analysis of a global phase 3 trial

BackgroundIn the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. Materials and methodsThe PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. ResultsFor PP patients, median OS was 8.9 (95% confidence interval: 6.4–10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0–7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3–5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7–3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). ConclusionA statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population.

1807P - STELLAR: Final results of a phase II trial of TTFields with chemotherapy for first-line treatment of pleural mesothelioma

Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, using low intensity alternating electric fields delivered non-invasively to the tumor using a portable, medical device. In vitro, human mesothelioma cells were highly susceptible to TTFields. TTFields have been shown to extend survival of patients with glioblastoma when added to chemotherapy. Methods: The trial accrued 80 patients with unresectable, untreated mesothelioma. Patients were treated with continuous 150 kHz TTFields in combination with pemetrexed and platinum. Inclusion criteria included ECOG 0-1 and at least one measurable lesion according to modified RECIST. Patients were followed q3w (CT scan q6w) until disease progression. The primary endpoint was overall survival (OS). This single arm study assumed historical control with a median survival of 12.1 months (Vogelzang et al. 2003). The sample size provided 80% power with a two-sided alpha of 0.05 to detect an increase in median OS of 5.5 months. Results: All patients had a minimum follow up of 12 months. Median age was 67 (range 27-78), 84% were male and 56% smokers. 16% (13 patients) had metastatic disease and 44% (35 patients) had an ECOG PS of 1. 66% (53 patients) had epithelioid histology. Compliance with TTFields was 68% (16.3 hours/day) during the first 3 months of therapy. Median OS was 18.2 months (95% CI 12.1-25.8) compared to 12.1 months in historical controls. Median PFS was 7.6 months (95% CI 6.7-8.6) compared to 5.7 months in historical controls. Partial responses were seen in 40.3% of patients and clinical benefit (PR+SD) was seen in 97.2% of patients. No device-related serious adverse events (AEs) were reported. Expected TTFields-related dermatitis was reported in 46% (37 patients). Only 4 patients (5%) had grade 3 dermatitis. Conclusions: The study met its primary endpoint of significant extension of survival for previously untreated mesothelioma patients. Secondary efficacy endpoints were also improved compared to historical control. The study demonstrated no safety concerns for the combination of TTFields to the thorax with chemotherapy. These results support the addition of TTFields to chemotherapy in the first-line treatment of malignant pleural mesothelioma. Clinical trial identification: NCT02397928. Legal entity responsible for the study: Novocure. Funding: Novocure. Disclosure: J.G. Aerts: Advisory boards: BMS, MSD, Roche, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Amphera; Stock owner: Amphera. R. Ramlau: Consultant: Novocure. All other authors have declared no conflicts of interest.

Intra-Arterial TheraSphere Yttrium-90 Glass Microspheres in the Treatment of Patients With Unresectable Hepatocellular Carcinoma: Protocol for the STOP-HCC Phase 3 Randomized Controlled Trial.

BackgroundGlobally, hepatocellular carcinoma is the second most common cause of cancer deaths. It remains challenging to intensify cancer treatment without impairing liver function.ObjectiveThe objective of the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study is to examine the hypothesis that transarterial radioembolization (TheraSphere yttrium-90 glass microspheres) combined with standard first-line treatment with sorafenib will improve outcomes over treatment with sorafenib alone in unresectable hepatocellular carcinoma. The STOP-HCC study is the largest international, multicenter, prospective study of intra-arterial treatment in combination with sorafenib in unresectable hepatocellular carcinoma. Here we report the study design.MethodsSTOP-HCC is a prospective, phase 3, open-label, randomized controlled study conducted across up to 105 sites in North America, Europe, and Asia. Eligible adults have unresectable hepatocellular carcinoma and a life expectancy of at least 12 weeks, 1 or more unidimensional measurable lesions, Child-Pugh score 7 points or less, and Eastern Cooperative Oncology Group Performance Status score 1 or lower, and are candidates for treatment with sorafenib. Presence of branch portal vein tumor thrombosis is permitted. Patients were randomly assigned in a 1:1 ratio to receive either sorafenib alone or transarterial radioembolization followed by sorafenib within 2 to 6 weeks. The primary outcome is overall survival. Secondary outcomes are time to progression, time to untreatable progression, time to symptomatic progression, tumor response, quality of life, and adverse event occurrence. The study is an adaptive trial, comprising a group-sequential design with 2 interim analyses with 520 patients, and an option to increase the sample size to 700 patients at the second interim analysis. The sample size of 520 patients allows for 417 deaths to give 80% power to detect an increase in median overall survival from 10.7 months for the sorafenib group (based on the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP] trial) to 14.2 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.754) with 2-sided alpha of .05. The increased sample size of 700 patients allows for 564 deaths to give 80% power to detect a smaller difference in median overall survival from 10.7 months for the sorafenib group to 13.7 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.781).ResultsEnrollment for the study completed in September 2017. Results of the first and second interim analyses were reviewed by the Independent Data Monitoring Committee. The recommendation of the committee, at both interim analyses, was to continue the study without any changes.ConclusionsThe STOP-HCC study will contribute toward the establishment of the role of combination therapy with transarterial radioembolization and sorafenib in the treatment of unresectable hepatocellular carcinoma with and without branch portal vein tumor thrombosis.Trial RegistrationClinicalTrials.gov NCT01556490; https://clinicaltrials.gov/ct2/show/NCT01556490 (Archived by WebCite at http://www.webcitation.org/7188iygKs).Registered Report IdentifierRR1-10.2196/11234

Overall Survival of Patients with Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma Treated with Nimotuzumab in the Real World.

Despite improvements in surgical techniques and treatments introduced into clinical practice, the overall survival of patients with esophageal squamous cell carcinoma remains low. Several epidermal growth factor receptor inhibitors are being evaluated in the context of clinical trials, but there is little evidence of effectiveness in real-world conditions. This study aimed at assessing the effectiveness of nimotuzumab combined with onco-specific treatment in Cuban real-life patients with locally advanced or metastatic esophageal squamous cell carcinoma. A comparative and retrospective effectiveness study was performed. The 93 patients treated with nimotuzumab were matched, with use of propensity score matching, with patients who received a diagnosis of locally advanced or metastatic squamous cell carcinoma of the esophagus in three Cuban provinces reported between 2011 and 2015 to the National Cancer Registry. The Kaplan-Meier method was used to estimate event-time distributions. Log-rank statistics were used for comparisons of overall survival between groups. A two-component mixture model assuming a Weibull distribution was fitted to assess the effect of nimotuzumab on short-term and long-term survival populations. There was an increase in median overall survival in patients treated with nimotuzumab (11.9months versus 6.5months without treatment) and an increase in the 1-year survival rate (54.0% versus 21.9% without treatment). The 2-year survival rates were 21.1% for patients treated with nimotuzumab and 0% in the untreated cohort. There were statistically significant differences in survival between groups treated and not treated with nimotuzumab, both in the short-term survival population (6.0months vs 4.0months, p=0.009) and in the long-term survival population (18.0months vs 11.0months, p=0.001). Our study shows that nimotuzumab treatment concurrent with chemoradiotherapy increases the survival of real-world patients with locally advanced or metastatic esophageal squamous cell carcinoma. Further prospective studies are required to confirm the therapeutic effectiveness of nimotuzumab in esophageal cancer.

EPID-02. SURVIVAL BENEFIT OF GLIOBLASTOMA PATIENTS AFTER FDA APPROVAL OF BEVACIZUMAB, A POPULATION-BASED STUDY USING SEER, TCR, AND NCDB DATABASES

The nationwide studies on survival change in GBM patients treated with bevacizumab (BEV) after Food and Drug Administration (FDA) approval in May 2009 were limited. We investigated the impacts of BEV on survival in general GBM patient population by conducting a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER), Texas Cancer Registry Limited-Use datasets (TCR), and National Cancer Database (NCDB). The adult patients diagnosed with GBM between 2005 and 2013 were included from SEER (N=14827), TCR (N=2709), and NCDB (N=32731). Patients were categorized into two calendar periods based on date of GBM diagnosis: pre-BEV (2005–2008, P1), and post-BEV (2010–2013, P2). The association between calendar periods and GBM survival was analyzed in SEER, TCR, and NCDB separately, by applying the Kaplan-Meier method and Cox proportional hazards model. A significant increase in median overall survival (OS) was observed from P1 to P2 in SEER (P1: 10, P2: 11, months; P<0.001), TCR (P1: 9.97, P2: 12.00, months; P<0.001), and NCDB (P1: 10.71, P2: 12.25, months; P<0.001). One-year survival rate was remarkably increased during P2 in SEER (P1: 41.9%, P2: 45.4%; P<0.001) and NCDB (P1: 45.1%, P2: 50.8%; P<0.001). In NCDB, 2-year survival rate was improved by 23.1% after BEV approval (P1: 18.6%, P2: 22.9%, P<0.001). No significant change of 1-year and 2-year survival rate was detected between P1 and P2 in TCR. After controlling different sets of covariates, including demographics, clinical characteristics, and treatments in multivariate analysis, the risk of death was significantly reduced by 9%, 28%, and 11% in SEER, TCR, and NCDB, respectively. Comparison and validation analysis were performed in the combined dataset (SEER+TCR), and consistent results were observed. Therefore, the administrations of BEV for recurrent GBM after FDA approval may contribute to the improvement of OS, 1-year and 2-year survival rate in GBM patients.

Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma

BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up. Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140mg/day) or placebo. Final OS and updated safety data are reported. ResultsMinimum follow-up was 42months. Kaplan–Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64–1.12; P=0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3months for cabozantinib versus 18.9months for placebo [HR, 0.60; 95% CI, 0.38–0.94; P=0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5months (HR, 1.12; 95% CI, 0.70–1.82; P=0.63) in the RET M918T–negative subgroup. Median treatment duration was 10.8months with cabozantinib and 3.4months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis. ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib. Trial Registration NumberNCT00704730

Impact of exon 19 versus exon 21 EGFR-activating mutation on outcomes with upfront pemetrexed-carboplatin chemotherapy.

BackgroundEGFR mutation subtype is a recognised factor impacting outcomes of patients receiving oral tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Evidence for the effect of this factor on outcomes in patients receiving pemetrexed is limited.MethodsWe completed a study comparing pemetrexed–platinum combination versus oral TKI in EGFR mutation-positive patients in lung cancer. We analysed the impact of EGFR mutation subtype, specifically, exon 19 and 21 on the PFS and OS of patients treated with pemetrexed (500 mg/m2 on day 1) and carboplatin (AUC 5 on day 1) as first-line therapy. Patients underwent axial imaging for response assessment on D42, D84, D126 and subsequently every two months till progression. Patients post-progression were treated with gefitinib.ResultsFifty-one patients (36%) had exon 21 mutation, while 92 patients (64%) had exon 19 mutation. Response rates in evaluable patients was 47.7% in exon 19 patients (41 patients, n = 86) and 42.9 % in exon 21 patients (18 patients, n = 42). There was a significant increase in median overall survival for patients with exon 19 mutations (24.5 months, 95% CI: 21.3–27.7 months ) over the exon 21-mutated patients (18.1 months, 95% Cl: 13.5–22.6 months, p = 0.002). This differential impact was due to second-line gefitinib having a differential outcome on these mutations.ConclusionPemetrexed-based chemotherapy does not have a differential impact on exon 19- or exon 21-mutated patients. However, second-line treatment with gefitinib has a favourable response and outcome in exon 19-mutated patients.

The Role of Chemotherapy in the Treatment of Low-grade Gliomas

The standard postsurgical options for low-grade gliomas include watchful waiting or radiotherapy depending on the risk factors for recurrence. The use of chemotherapy for the treatment of this disease is generally controversial, although the recently published results of the first of two large randomized phase III clinical trials (RTOG 9802 a EORTC 22033-26033), focusing on the evaluation of chemotherapy for the upfront treatment of newly diagnosed low-grade gliomas, are reassuring in this respect. The long-term results of a RTOG 9802 comparing radiotherapy alone with radiotherapy and six cycles of adjuvant PCV chemotherapy (procarbazine, lomustine, vincristine) in patients with high-risk low-grade gliomas will probably have an impact on daily clinical practice. The increase in median overall survival from 7.8 years to 13.3 years, mainly for patients with oligodendrogliomas, is unprecedented, but the toxicity of PCV is too high and molecular marker analysis remains inadequate. It is still unclear whether less toxic temozolomide can replace PCV and whether temozolomide can be used upfront alone instead of with radiotherapy. This question is addressed by the ongoing EORTC 22033-26033 study. The preliminary results show no significant difference in progression-free survival between patients receiving radiotherapy and those receiving temozolomide alone. Treatment with temozolomide was not associated with an improvement in cognitive function compared with treatment with radiotherapy. Despite limited follow-up, the study clearly confirmed the importance of molecular characterization of low-grade gliomas, as currently defined in the new 2016 WHO Classification of Tumors of the Central Nervous System. The aim of the review is to summarize available information from listed key clinical trials of chemotherapy for low-grade gliomas and draw attention to unresolved issues concerning the use of chemotherapy for the treatment of this disease.Key words: glioma - astrocytoma - chemotherapy - PCV - temozolomide - RTOG 9802 This work was supported by MH CZ - RVO (MMCI, 00209805) and by project of the Ministry of Education, Youths and Sports of the Czech Republic CEITEC 2020 (LQ1601). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 21. 2. 2017Accepted: 20. 3. 2017.

Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Patients with Relapsed or Refractory Multiple Myeloma

In a previous study, the quantitative relationship between progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM) was assessed. However, that analysis combined studies of newly-diagnosed MM and relapsed/refractory MM (rrMM) and, since that analysis, there have been several randomized controlled trials (RCTs) of novel treatments for rrMM. The aim of this study is to provide an update of that analysis using randomized controlled trials (RCTs) only conducted in rrMM. Two bibliographic databases (PubMed and Embase) were systematically searched for RCTs published between 1970 to 2017. Firstly, the association between median PFS and median OS was assessed using the non-parametric Spearman’s rank correlation coefficient. Secondly, the quantitative relationship between PFS and OS was assessed using the Two Stage Least Square (2SLS) estimator. This approach was justified by relevant statistical tests in favor of the instrumental variable approach. 22 RCTs (42 treatment arms, 7,884 rrMM patients) were included. The average median PFS and median OS were 8.26 months (SD= 4.85), and 24.34 months (SD= 9.80), respectively. The correlation coefficient of median PFS and median OS was 0.712 (P < 0.00001). After adjustment for median age, sex and publication year, a 3.10 month (95%CI: 2.20 to 4.00) increase in median OS is estimated for each additional month increase in median PFS. Based on newer evidence from RCTs, PFS can be used to predict OS in rrMM and this analysis suggests that novel treatments may be providing additional months of OS gained for each month of PFS.

Metastatic prostate cancer : Update: position paper for the use of chemotherapy

Taxen-based chemotherapy has been established as an effective treatment option in castration-resistant metastatic prostate cancer (mCRPC). Randomized phaseIII studies, however, have shown that even in the hormone-naïve metastatic state, the early use of chemotherapy in addition to the classical androgen deprivation therapy (ADT) approach leads to asignificant increase in median overall survival. This position paper aims to provide current data and orientation in the evidence-based treatment of mPC patients in daily clinical practice. AGerman group of clinical experts analyzed the current data and developed criteria for the treatment of mPC patients in daily clinical practice. In the current treatment of hormone-naïve mPC, abeneficial effect of chemotherapy in addition to ADT has become evident. Provided patients are in an appropriate condition, those with ahigh metastatic load should receive chemotherapy in addition to ADT. Especially in high-risk mCRPC patients (PSA >114 ng/ml, visceral metastasis, ADT response <12months, tumor-associated complaints), first-line chemotherapy is indicated. After docetaxel failure, continuous treatment with cabazitaxel shows superior overall survival compared to sustained antihormonal therapy. Chemotherapy is firmly established in treating patients with mCRPC. Long-term, it will be important to identify molecular predictors. The authors suggest the early use of chemotherapy in hormone-naïve mPC, but note that the approval in this indication is currently nonexistent. After disease progression, patients should be treated analogous to mCRPC.

Abstract CT160: Modeling long-term survival outcomes in glioblastoma patients treated with TTFields plus temozolomide and temolozomide monotherapy

Abstract Background: Glioblastoma is the most common and aggressive primary brain tumor. Survival times for GBM have improved significantly since 2005. Researchers in 2005 demonstrated that adding TMZ, an oral alkylating agent, to surgery and radiation extended median overall survival from 12 to 15 months, and 2-year survival rates from 11% to 27%. More recently the addition of Tumor Treating Fields (TTFields), a loco-regionally delivered anti-mitotic treatment, to TMZ demonstrated an increase in median overall survival of 5 months, and survival rates of 43% and 17% at 2-years and 4-years respectively. Trial data for TMZ and TTFields both demonstrated increasing conditional probabilities of survival as patients survived longer from diagnosis. Increasing conditional probability of surviving GBM has also been reported in epidemiological literature. Accordingly, standard parametric survival models based on regression analysis will not provide reliable estimates of lifetime survival benefits and an alternative modelling method is provided here. Clinicians and policy makers need to understand the lifetime survival estimates for GBM patients, as the rate of GBM patients surviving to 4-years and 5-years is now significant. Methods: Lifetime patient survival was simulated using a synthesis of parametric survival curves fit to the recently completed EF-14 Trial’s 4-year follow-up data and conditional survival probabilities from a SEER state cancer registries database analysis. The 4-year parametric curves were extrapolated to estimate 5-year survival. We then used GBM-specific conditional survival estimates to model patient survival at 10 and 15 years given survival to year 5, and assumed patients surviving beyond 15 years had survival equivalent to population averages. We performed one-way and probabilistic sensitivity analyses to assess result uncertainty due to parameter variability. Results: Our modeled analysis showed that TTFields plus TMZ resulted in 3.63 (95% credible range [CR], 3.32 to 3.93) life-years versus 2.53 (95% CR, 2.36 to 2.69) life-years for TMZ monotherapy, a difference of 1.10 years (95% CR, 0.96 to 1.23) discounted; the difference was 1.56 years (95% CR, 1.33 to 1.80) undiscounted. The results were most sensitive to uncertainty in the 10- and 15- year survival estimates conditional on survival to years 5 and 10, respectively. Conclusions. This analysis presents a new approach to model lifetime survival benefits of adding TTFields to TMZ for GBM by combining long-term clinical trial data and epidemiological data. The model demonstrates that adding TTFields to TMZ for GBM increases lifetime survival substantially. Citation Format: Greg Guzauskas, Bruce Wang, Marc Salzberg. Modeling long-term survival outcomes in glioblastoma patients treated with TTFields plus temozolomide and temolozomide monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT160. doi:10.1158/1538-7445.AM2017-CT160

Abstract 4295: AZ’5576, a selective CDK9 inhibitor, demonstrates in vitro and in vivo activity in diverse preclinical models of non-Hodgkin lymphoma

Abstract Cyclin-dependent kinase 9 (Cdk9) is a serine/threonine kinase that regulates elongation of transcription through phosphorylation of RNA polymerase II at serine 2 (pSer2-RNAPII). Transient inhibition of Cdk9 results in modulation of genes with short-lived transcripts and labile proteins, thereby representing a potential therapeutic opportunity in tumors dependent upon oncogenes fitting these criteria. Mcl1, an anti-apoptotic protein that has been linked to increased survival and chemotherapy resistance in various cancers, and Myc, a proto-oncogenic transcription factor that coordinates diverse transcription programs and is over-expressed, amplified, or translocated in many cancers, are two such oncogenes. AZ’5576 is a potent, highly selective, and orally bioavailable inhibitor of Cdk9 that inhibits Cdk9 enzyme activity with an IC50 &amp;lt;5nM and decreases phosphorylation of Ser2-RNAPII in cells with an IC50 of 96nM. In sensitive cell lines, short-term treatment with AZ’5576 led to a rapid dose- and time-dependent decrease in pSer2-RNAPII with concomitant loss of Mcl1 and Myc mRNA and protein, resulting in the cleavage and activation of caspase 3 and loss of cell viability. Using cell potency and magnitute of caspase activation to define sensitivity, we previously reported that AZ’5576 demonstrates broad in vitro and in vivo activity across hematological malignancies. Initially focusing on acute myeloid leukemia (AML) and multiple myeloma (MM), we have now expanded our scope to encompass non-Hodgkin lymphoma (NHL), which includes diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma (BL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM). In vitro screening assays reveal about half (19/35) of NHL cell lines undergo cell death in response to AZ’5576, demonstrating a potency &amp;lt;520nM and a maximum caspase activation &amp;gt;55% after 6 hour treatment. Combining AZ’5576 with a BTK inhibitor further enhances cell death compared to that observed with either single agent alone in BTK inhibitor-sensitive ABC-DLBCL cell lines. Consistent with the in vitro data, significant anti-tumor activity was associated with short-term reduction of pSer2-RNAPII tumor levels after intermittent dosing of AZ’5576 in a mouse xenograft model of ABC-DLBCL cell line OCILY10. Similarly, combining AZ’5576 with a BTK inhibitor in vivo drove tumors into regression (combination=199% TGI) compared to the partial TGI from either single agent alone (AZ’5576=79% TGI, Acalabrutinib=58% TGI) in the OCILY10 xenograft model. Finally, in an agressive Eµ-Myc transgenic mouse model of B-cell lymphoma, AZ’5576 treatment results in potent induction of apoptosis in vitro and a greater than 50 day increase in median overall survival in vivo. Together, these results highlight the therapeutic potential for selective CDK9 inhibition in the treatment of patients with non-Hodgkin lymphoma. Citation Format: Justin Cidado, Theresa Proia, Gareth Gregory, Izabela Todorovski, Scott Boiko, Maryann San Martin, Ricky Johnstone, Lisa Drew. AZ’5576, a selective CDK9 inhibitor, demonstrates in vitro and in vivo activity in diverse preclinical models of non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4295. doi:10.1158/1538-7445.AM2017-4295

Abstract 4566: OncoVEXmGM-CSF (HSV-1 modified similarly to Talimogene Laherparepvec) in combination with CTLA-4 blockade leads to both local and systemic efficacy in a murine syngeneic model of metastatic melanoma

Abstract Talimogene laherparepvec is an oncolytic immunotherapy based on a modified herpes simplex virus type 1 (HSV-1) designed to kill cancer cells through two mechanisms: a) direct viral-mediated lysis and b) stimulation of a tumor antigen-specific adaptive immune response. We developed a mouse model of metastatic melanoma using the B16F10 cell line to study local and systemic responses following treatment with talimogene laherparepvec alone or in combination with CTLA-4 blockade. OncoVEXmGM-CSF, an HSV-1 modified similarly to talimogene laherparepvec (murine GM-CSF is expressed instead of human GM-CSF) was used in these studies. B16F10 cells have been reported to be resistant to HSV-1 infection due to a lack of requisite entry receptors. To overcome resistance, we transduced B16F10 cells with a lentiviral vector expressing mouse nectin1 (mNectin1) or eGFP as a control. Expression was confirmed by ddPCR and sensitivity to OncoVEXmGM-CSF evaluated in an in vitro viability assay. B16F10-mNectin1 cells were highly sensitive to OncoVEXmGM-CSF with a multiplicity of infection (MOI) IC50 of 0.001 (B16F10-eGFP were insensitive at MOI of 100). In vivo, B16F10-mNectin1 and B16F10-eGFP cells showed similar growth when injected subcutaneously. OncoVEXmGM-CSF treatment of B16F10-mNectin1 tumors (intratumoral, 5x106 PFU/dose, 3X) caused a significant (p&amp;lt;0.0001) inhibition of tumor growth and prolonged median overall survival compared to control animals. To assess the local and systemic effect of OncoVEXmGM-CSF in combination with CTLA-4 blockade, we developed a model of experimental metastatic melanoma by delivering the B16F10-eGFP cells intravenously (systemic, non-injectable tumors) on day 0 and implanting the B16F10-mNectin1 cells SC (local, injectable tumors) on day 2. Mice were dosed with OncoVEXmGM-CSF and anti-CTLA-4 antibody 9D9 (100ug/dose) every 3 days between days 12 and 19. Subcutaneous tumor growth inhibition was assessed and lung metastasis were quantified on day 28. Both OncoVEXmGM-CSF and CTLA-4 treatment significantly inhibited subcutaneous tumor growth and lung metastasis. The combination of both therapeutics resulted in significantly greater local and systemic efficacy than either agent alone. The strong local and systemic anti-tumor activity of the combination resulted in a significant increase in median overall survival (p&amp;lt;0.0001) compared to control mice that received intravenous B16F10-eGFP cells only. In conclusion, OncoVEXmGM-CSF in combination with CTLA-4 blockade significantly reduced systemic tumor burden and prolonged median overall survival in a B16F10 mouse model of metastatic melanoma. These data support the proposed MOA by which OncoVEXmGM-CSF treatment can cause direct tumor lysis along with potentiation of an adaptive, systemic anti-tumor immune response. Citation Format: Keegan Cooke, Juan Estrada, Jinghui Zhan, David Hill, Andrea Boden, Jon Werner, Pedro J. Beltran. OncoVEXmGM-CSF (HSV-1 modified similarly to Talimogene Laherparepvec) in combination with CTLA-4 blockade leads to both local and systemic efficacy in a murine syngeneic model of metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4566. doi:10.1158/1538-7445.AM2017-4566

Results of the randomized phase II portion of NRG Oncology/RTOG 0848 evaluating the addition of erlotinib to adjuvant gemcitabine for patients with resected pancreatic head adenocarcinoma.

4007 Background: NRG/RTOG 0848 is a 2-step study designed to determine whether erlotinib (E) added to gemcitabine (G) (randomized Ph II) &amp;/or adjuvant radiation with concurrent 5-FU or capecitabine following 6 months of systemic chemotherapy (Ph III), improve survival in patients (pts) with resected pancreatic head adenocarcinoma. The erlotinib results are reported here. Methods: Eligible pts include those with resected pancreatic head adenocarcinoma, pathologic stage T1-T3, N0-1, M0; PS 0-1, &amp; CA19-9 ≤ 180 IU/L. Pts in Arms 1 &amp; 2 received G 1 gm/m2 weekly for 3 weeks in a 28-day cycle for 6 cycles. Pts in Arm 2 also received E 100 mg/day. The primary hypothesis for the E portion was that G+E would increase overall survival (OS) compared to G alone. With a 1-sided alpha of 0.15, 200 OS events provide 80%/90% power to detect a signal for an increase in median OS from 22 to 28.8/30.6 months (mos). OS was estimated by the Kaplan-Meier method &amp; arms compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 336 pts were randomized from 11/17/2009 to 2/28/2014, with 163 pts evaluable for G and 159 for G+E. Median age was 63 years (39-86). Most pts had pathologic T3 disease (78%) &amp; CA19-9 ≤ 90 (93%). There are 32 pts (20%) with grade 4 adverse events (AEs) &amp; 2 pts (1%) with grade 5 AEs on G and 27 (17%) &amp; 3 (2%) on G+E arm, respectively. There are fewer grade ≥ 3 GI AEs on the G arm (22%) as compared to the G+E arm (28%), and 110 (69.2%) &amp; 93 (59.6%) pts received at least 85% of planned G dose for the G &amp; G+E arms, respectively. 58% of E pts received at least 85% of planned E dose. The median follow-up for alive pts is 42.5 mos (min-max: &lt; 1-75). With 203 deaths, median &amp; 3-yr OS (95% CI) are 29.9 mos (21.7-33.4) &amp; 39% (30, 45) for G and 28.1 mos (20.7-30.9) &amp; 39% (31, 47) for G+E; log-rank p = 0.62. The hazard ratio (95% CI) comparing OS of G+E to G is 1.04 (0.79- 1.38). Conclusions: The addition of adjuvant E to G did not provide a signal for increased OS in pts with resected pancreatic head cancer compared to G alone. Accrual to the trial is continuing to answer the Ph III radiation question. Clinical trial information: NCT01013649.

Effect of adjuvant therapy on resected gallbladder adenocarcinoma: A propensity score matched analysis of national data.

e15669 Background: There is a paucity of data and no consensus regarding administration of adjuvant therapy after resection of gallbladder cancer. In the absence of a completed clinical trial, we retrospectively reviewed US cancer data. Methods: National Cancer Data Base was queried for patients diagnosed with gallbladder adenocarcinoma between 2004-2014 who underwent definitive resection for non-metastatic disease (pT1b, pT2, pT3, pN0, pN1, pNX) and had R0 and R1 resection margins. One-to-one propensity score matching was used to account for potential selection bias in patient and tumor characteristics. Kaplan-Meier method was used to compare overall survival. Results: Of 4830 patients identified, 1489 (30.8%) received adjuvant chemotherapy. Patients who received adjuvant chemotherapy were more likely to be younger, have private insurance or Medicare, have no comorbidities, higher T stage, and moderately to poorly differentiated tumors (all p-values &lt; 0.0001). The majority of patients who received adjuvant chemotherapy also received adjuvant radiation (58.0%). On unadjusted analysis, patients who received adjuvant chemotherapy had no difference in median overall survival compared to those who did not (25.8 vs 29.0 mo; p = 0.3060). After matching for sex, age, race, insurance, comorbidity, facility type, pT stage, lymph node status, resection margins (R0 vs R1), adjuvant radiation, and tumor grade no difference in median overall survival remained between patients who did (21.8 mo) and did not (22.6 mo) receive adjuvant chemo (p = 0.6843). However, after matching on the propensity to receive adjuvant radiation in addition to the above covariates, receipt of adjuvant radiation resulted in a persistently significant increase in median overall survival (27.8 vs 22.2 mo; p = 0.0005). Conclusions: After matching for potential confounders, there is no difference in overall survival for patients who did and did not receive adjuvant chemotherapy after R0/R1 resection for pT1b, pT2, and pT3 gallbladder adenocarcinoma; however, adjuvant radiation does appear to confer a survival advantage. These results support the current treatment guidelines until evidence from RCTs becomes available.