Joyson Joseph Karakunnel

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

BACKGROUND PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). METHODS We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. FINDINGS Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11-33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9-44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3-60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8-58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12-74] of ten patients). INTERPRETATION Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing. FUNDING MedImmune.

Phase Ib/II study to evaluate the safety and antitumor activity of durvalumab (MEDI4736) and tremelimumab as monotherapy or in combination, in patients with recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma

Meeting abstracts Despite improvements in diagnosis, surgical techniques, and multidisciplinary approaches to patient care, the median survival of patients with metastatic gastroesophageal adenocarcinoma is less than one year. Chemotherapy is the mainstay of treatment in patients with metastatic

Tumor response from durvalumab (MEDI4736) + tremelimumab treatment in patients with advanced non-small cell lung cancer (NSCLC) is observed regardless of PD-L1 status

Meeting abstracts As single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective

Development of MEDI4736, an anti-programmed cell death ligand 1 (PD-L1) antibody, as monotherapy or in combination with other therapies in the treatment of non-small cell lung cancer (NSCLC)

Meeting abstracts MEDI4736 is an engineered human IgG1 that blocks PD-L1 binding to PD-1 and allows T-cells to recognize and kill tumor. MEDI4736 has single-agent activity and potential for further increased activity in combination. A comprehensive development programme is underway in NSCLC, as

Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors

Introduction The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs. Methods Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry. Results PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p<0.01), and was associated with longer overall survival (p = 0.02). TIM-3 and GITR were expressed in all TETs, including 18/23 and 12/23 with at least moderate/high expression, respectively. Moderate/high CD137 expression correlated with CD8+ (p = 0.01) and moderate/high GITR expression co-associated with PD-1 (p = 0.043). Conclusions TETs are characterized by frequent PD-L1 expression and PD-L1 is associated with improved survival, suggesting PD-L1 signaling may be biologically important in TETs. Robust expression of markers of immune activation and immunotherapeutic target molecules in TETs emphasizes the potential for development of anti-PD-1/PD-L1 therapies.

A Phase I study to evaluate the safety and antitumor activity of durvalumab (MEDI4736) in combination with tremelimumab in patients with advanced solid tumors

Meeting abstracts The immune system is able to control the growth of many types of cancers. Most tumors show infiltration by tumor infiltrating lymphocytes, but tumors modulate the local microenvironment by expressing immune-inhibitory molecules. Blockade of immune checkpoints such as cytotoxic T-

Abstract 5045: Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD1 monoclonal antibody, in patients with advanced malignancies

Background: MEDI0680 (AMP-514) is a humanized immunoglobulin gamma 4, kappa (IgG4κ) monoclonal antibody (mAb) specific for human programmed cell death-1 (PD-1), developed for the treatment of cancer. The primary objectives of this analysis were to (a) describe the pharmacokinetics (PK) of MEDI0680 and quantitate the impact of patient/disease characteristics on PK variability (b) to compare body weight (WT)-based and fixed dosing regimens of MEDI0680 and (c) to characterize PK-pharmacodynamic (receptor occupancy) relationship. Methods: A total of 905 serum concentration records from 58 patients in Phase 1 study (D6020C00002) designed to evaluate safety, tolerability and PK following 0.1, 0.5, 2.5, 10, and 20 mg/kg every 3 weeks (Q3W), every 2 weeks (Q2W) or weekly doses (QW) as intravenous (IV) infusion of MEDI0680 were included in this analysis. The population PK analysis was performed using a non-linear mixed effects modeling approach in NONMEM (version 7.2) software. Impact of patient demographics, clinical indices and biomarkers on PK parameters were explored. The appropriateness of the final model was tested using visual predictive check (VPC). A sequential PK-PD analysis was performed using receptor occupancy (RO) data from 35 subjects. Results: MEDI0680 PK profiles were best described using a 2-compartment model with linear clearance. The clearance (CL), volume of distribution (Vc) were 0.27 L/day, 5.07 L with a modest between-subject variability of 30% and 19%, respectively. None of the evaluated covariates showed any impact on PK parameters except a minor (not clinically relevant) impact of body weight on volume of distribution. VPC results demonstrated good predictability of the final population PK model. A direct Emax model described the PK-PD relationship of MEDI0680. The estimate of EC50 was approximately 9.3 µg/mL. PK/PD simulations indicate that following 20 mg/kg Q2W dose, >90% receptor occupancy can be maintained in all subjects. Based on preclinical/clinical PK, PD, and safety data, a dose of 20 mg/kg Q2W was selected for phase 2 studies. Conclusions: A population PK model of MEDI0680 was developed and validated. Modeling results indicate no need for dose adjustment based on patient/disease characteristics. Similar PK is expected following both WT-based and fixed dosing regimens. PK/PD findings support the dose of 20 mg/kg Q2W. Clinical studies are ongoing in various tumor types. Citation Format: Xuyang Song, Xizhe Gao, Bo Zheng, Chelsea Black, Matthew Gribbin, Joyson Karakunnel, Lorin Roskos, Rajesh Narwal. Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD1 monoclonal antibody, in patients with advanced malignancies [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 5045. doi:10.1158/1538-7445.AM2017-5045

Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)

Background: Programmed cell death ligand-1 (PD-L1) is widely expressed on antigen presenting cells (APC) and other immune cells. PD-L1 binds two important regulatory receptors on T-cells: programmed cell death-1 (PD-1) and CD80/B7. Targeting Programmed Death-1 (PD-1) and its ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid tumors and growing data implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma (GBM). PD-1 is expressed by many GBM infiltrating lymphocytes while PD-L1 is expressed by 61-100% of GBM tumors. Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in GBM. These findings indicate that PD-L1 is an attractive and important therapeutic target in GBM. MEDI4736 (M), a human IgG1κ blocking monoclonal antibody against PD-L1, represents a compelling immune-mediated anti-tumor treatment for GBM. Methods: Phase 2, multicenter, open-label study (NCT02336165) is evaluating the clinical efficacy and safety of M in GBM patients. Eligible patients include those who are newly diagnosed with unmethylated MGMT GBM scheduled for standard radiotherapy (Cohort A); Bevacizumab-naive patients with recurrent GBM (Cohort B); and Bevacizumab-refractory patients with recurrent GBM (Cohort C). Cohort A patients will receive M at 10 mg/kg i.v. Q2W for up to 12 months beginning with standard radiotherapy. Cohort B will receive M at 10 mg/kg i.v. Q2W for up to 12 months as monotherapy. Cohort C will receive M at 10 mg/kg i.v. Q2W for up to 12 months in combination with continued bevacizumab at 10 mg/kg Q2W. Primary endpoints include overall survival (OS) at 12 months (cohort A), progression free survival rate at 6 months (PFS-6) (cohort B) and OS-6 (cohort C). Secondary endpoints are safety/tolerability, PFS, median OS, radiographic response, and quality of life (QoL) by EORTC QLQ-C30/BN20. Exploratory endpoints are patient neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale, as well as immuno-correlative biomarkers and pharmacokinetics. Cohort A represents the first time MEDI4736 is being given in combination with radiation, so a 3+3 subject safety run-in is required by protocol. Subjects must clear a 10 week DLT observation period before enrollment opens to the remainder of the cohort. If 2 or more DLTs are noted within the first 6 patients, then the MEDI4736 dose will be de-escalated. Cohort C represents the first time MEDI4736 is being given in combination with bevacizumab, so a 3+3 subject safety run-in period similar to that for Cohort A is also required, but with a 6 week DLT observation period. Study Status: All cohorts opened to enrollment in March 2015 with Cohorts A and C currently limited by the subject safety run-in period. As of 10 June 2015, the numbers of subjects enrolled by cohort are: Cohort A = 2, Cohort B = 26, Cohort C = 3. No DLTs have been reported, and clinical efficacy and safety data collection are ongoing. Citation Format: David A. Reardon, Jorg Dietrich, Thomas Kaley, Hui Gan, Gavin P. Dunn, Timothy Cloughesy, Michael Lim, Jennifer Clarke, Andrew Park, Linda Pan, Domenic W. Lai, Joyson Karakunnel, Paul Robbins, Rajesh Narwal, Ralph Venhaus. Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A046.