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VARGATEF® plus docetaxel significantly reduced tumour burden in lung cancer patients with advanced adenocarcinoma compared to docetaxel alone

On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, further data to support the efficacy of VARGATEF (nintedanib*) in combination with docetaxel for the treatment of advanced non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507557]). Further analysis of the data from the pivotal LUME-Lung 1 trial showed that after first-line chemotherapy adenocarcinoma patients receiving VARGATEF plus docetaxel had a significantly reduced rate of tumour growth over time, compared to patients receiving docetaxel alone.1 At the time of treatment initiation, the average tumour size of the 658 adenocarcinoma patients who took part in the trial was 82.5mm (diameter). After six months of treatment, the adenocarcinoma patients receiving VARGATEF plus docetaxel experienced about 10% less tumour growth over time (9.7mm), compared to those receiving placebo plus docetaxel (tumour size at 6 months: 98.4mm placebo plus docetaxel vs 88.7mm nintedanib plus docetaxel).1

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Advanced adenocarcinoma patients with the poorest prognosis received an even more pronounced benefit from VARGATEF plus docetaxel, compared to docetaxel alone, after first-line chemotherapy:

Adenocarcinoma patients whose disease progressed within nine months of starting first-line chemotherapy (T<9) received a 16.8mm reduction in tumour size over time after six months (tumour size at baseline 88.3mm; tumour size at 6 months: 114.6mm placebo plus docetaxel vs 97.8mm nintedanib plus docetaxel; difference in growth over time of 13%)
Adenocarcinoma patients who had continuously progressed during first-line therapy (PD-FLT) experienced a 19.7mm reduction in tumour size over time after six months (tumour size at baseline 98.1mm; tumour size at 6 months: 124.7mm placebo plus docetaxel vs 105mm nintedanib plus docetaxel; a difference in growth over time of 15%)

Professor Martin Reck, lead investigator of the LUME-Lung 1 trial said, "The reduction in tumour burden seen in adenocarcinoma patients receiving nintedanib plus docetaxel is very encouraging and it is particularly positive to see the additional benefit for those patients who progress quickly when receiving first-line therapy as they often have the poorest prognosis. Tumour burden is commonly associated with clinical outcomes and as such is a relevant and valuable measurement. These latest data add to our wealth of knowledge and reiterate the efficacy of nintedanib which has previously been shown to extend overall survival to over one year for this difficult to treat cancer."

The Phase III LUME-Lung 1 trial randomised 1,314 patients with stage IIIB/IV recurrent NSCLC to receive either VARGATEF plus docetaxel or placebo plus docetaxel (1:1).2 Tumour growth was evaluated in a planned post-hoc analysis using all available tumour measurements. Mixed-effects models were employed to measure the relationship between time from treatment initiation and tumour size (measured as the sum of longest diameter of target lesions [SLD]).1

Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented, "The announcement of the latest data from the LUME-Lung 1 trial further illustrates how VARGATEF in combination with docetaxel can potentially improve the lives of lung cancer sufferers following its EU approval in 2014. We have a long-term commitment to discovering novel and innovative treatments to better the lives of patients with different types of cancer and look forward to bringing further advances in the future."

VARGATEF in combination with docetaxel was approved in the EU in 2014 for use by adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. The LUME-Lung 1 study demonstrated the efficacy and safety of the treatment:2

VARGATEF plus docetaxel significantly prolonged progression-free survival compared to docetaxel alone for patients with adenocarcinoma (PFS: primary endpoint; 4.0 vs 2.8 months)
VARGATEF plus docetaxel significantly extended overall survival to beyond one year for patients with adenocarcinoma, compared to docetaxel alone (OS: key secondary endpoint; 12.6 vs 10.3 months)
VARGATEF plus docetaxel enabled one in four patients with adenocarcinoma to live for at least two years after first-line chemotherapy

VARGATEF in combination with docetaxel demonstrated a familiar and generally manageable side-effect profile without further compromising patients’ overall, health-related, quality of life compared to docetaxel alone. The most common adverse events for patients taking docetaxel vs VARGATEF plus docetaxel included: nausea 18% vs 24%; vomiting 9% vs 17%; diarrhoea 22% vs 42% and elevated liver enzymes 8% vs 29%.

Adenocarcinoma is the most common type of lung cancer and the majority of patients are diagnosed in an advanced stage.3 Most patients will experience disease progression during or after first-line chemotherapy and there is a significant need for new, effective second-line treatments.2,3

ECC 2015: GIOTRIF® (afatinib) demonstrates superior survival compared to Tarceva® (erlotinib) for patients with previously treated advanced squamous cell carcinoma of the lung, independent of EGFR mutation status

On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, new data from the Phase III LUX-Lung 8 trial which further highlights the benefits of afatinib* compared to erlotinib for the treatment of patients with previously treated advanced SCC of the lung (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507556]).2 Data from the trial showed that treatment with afatinib resulted in superior progression-free survival (PFS) and superior overall survival (OS) compared to erlotinib in this patient population.2 These improved survival outcomes observed with afatinib were not driven by the presence of EGFR mutations, according to a new analysis presented at ECC.2 Furthermore, a higher number patients treated with afatinib in the LUX-Lung 8 trial reported improvements in overall health and quality of life, as well as improvements in some lung cancer-related symptoms, compared to those treated with erlotinib.3

LUX-Lung 8 clinical trial investigator Glen D. Goss, M.D., Director of Clinical and Translational Research, The Ottawa Hospital Cancer Center, University of Ottawa, Canada, commented: "These latest data not only demonstrate benefits of afatinib compared to erlotinib for patients with SCC of the lung, but also suggest that afatinib is an effective treatment option for a broad group of patients and not just those whose tumours harbour EGFR mutations. We know that dysregulation of ErbB receptors plays a role in the underlying mechanisms of SCC of the lung and the fact that afatinib targets this family of receptors rather than only EGFR, may explain why it offered additional benefits for this patient population."

Afatinib is an oral, once daily targeted treatment which works by irreversibly blocking the ErbB family of receptors. Unlike other targeted treatments such as erlotinib which are reversible and specifically target EGFR (ErbB1), afatinib aims to provide a sustained, selective and complete ErbB Family Blockade. The Phase III LUX-Lung 8 trial compared afatinib to erlotinib in patients with advanced SCC of the lung progressing after treatment with first-line platinum-based chemotherapy. Data from the trial showed that treatment with afatinib resulted in superior PFS, reducing the risk of cancer progression by 19%, and superior OS, reducing the risk of death by 19% compared to erlotinib in this patient population.1,2 The PFS and OS advantages observed with afatinib compared to erlotinib were independent of the EGFR mutation status of the tumours analysed from this trial.2

Further data presented at ECC confirm the efficacy of afatinib observed in the LUX-Lung 8 trial was associated with improvements in patient reported outcomes.3 More patients had improved overall health-related quality-of-life (36% vs 28%, p=0•041), cough (43% vs 35%, p=0•029) and dyspnoea (51% vs 44%, p=0•061) with afatinib than with erlotinib.3 The rate of severe adverse events in the LUX-Lung 8 trial was similar between the two treatment arms with differences observed in the incidence of certain side effects.1 A higher incidence of severe diarrhoea and stomatitis (mouth sores) was observed with afatinib compared to erlotinib (grade 3 diarrhoea: 10% vs 2%; grade 3 stomatitis: 4% vs 0%), while a higher incidence of severe rash/acne was reported with erlotinib compared to afatinib (grade 3 rash/acne: 10% vs 6%).1 Diarrhoea occurring in patients treated with afatinib was manageable.3

Dr. Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "We are pleased to present these data at ECC 2015 which confirm that the advantages of afatinib, compared to erlotinib, are not limited to patients with squamous cell lung cancer whose tumours expressed EGFR mutations, which are rare in this disease. The LUX-Lung 8 trial shows that treatment with afatinib versus erlotinib not only leads to improved survival outcomes but also offered patients an improved quality of life. Afatinib is under review by both the FDA and EMA for the treatment of SCC of the lung and we look forward to working with regulatory authorities in the hope of making this much needed new treatment option available to patients."

Afatinib is currently approved in more than 60 countries for the first-line treatment of specific types of EGFR mutation-positive non-small cell lung cancer (NSCLC) (under brand names: GIOTRIF / GILOTRIF). Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently accepted filing applications for afatinib for the treatment of patients with advanced SCC of the lung progressing after treatment with first-line chemotherapy, based on the positive PFS and OS data from the LUX-Lung 8 trial. Afatinib has also been granted orphan drug designation by the FDA – a status given to a product intended for the treatment of a rare disease or condition.

Aduro Biotech Announces Phase 1b Mesothelioma Trial Featured in Spotlight Poster at ESMO/ECC

On September 26, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO) reported the presentation of updated, interim safety and efficacy data from an ongoing Phase 1b clinical trial of its novel immunotherapy, CRS-207, in combination with standard of care chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM) (Press release, Aduro BioTech, SEP 26, 2015, View Source;p=RssLanding&cat=news&id=2090581 [SID:1234507554]). Of the 34 evaluable patients, disease control was observed in 94% (32/34), including 59% (20/34) with partial responses and 35% (12/34) experiencing stable disease following treatment with CRS-207 and chemotherapy. Of note, in three patients who had tumor biopsies completed, biomarker analysis data available at the time of the presentation showed in all three patients a consistent and marked recruitment of immune cells, including CD8+ T-cells, dendritic cells and natural killer cells, following treatment with CRS-207.

The results were presented by Raffit Hassan, M.D., co-chief of the Thoracic and GI Oncology Branch at the National Cancer Institute, in a spotlight poster presentation (abstract #515/P249) at the 40TH European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper)/18TH European Cancer Congress (ECC) being held September 25-29, 2015 in Vienna, Austria.

"The data in this trial continue to be impressive in the front-line treatment of mesothelioma," said Dr. Hassan. "We are encouraged by the high disease control rate in patients treated with this combination and will continue to evaluate and track the durability of the responses, which are ongoing."

Dirk G. Brockstedt, Ph.D., senior vice president of Research and Development at Aduro added, "Our new immunohistochemistry biomarker data is interesting as it is supports our hypothesis that the tumor microenvironment is altered by our immunotherapy. These data show an increase of tumor-attacking immune cells recruited and deployed where they are needed most. We look forward to presenting final results from this trial with additional biomarker data in 2016. As previously announced, based on the compelling data thus far, we plan to advance the combination regimen with CRS-207 and chemotherapy into a pivotal Phase 3 clinical trial in the front-line setting."

At the time of the ESMO (Free ESMO Whitepaper) presentation, the multi-center Phase 1b study had completed enrollment with 38 patients who were chemotherapy-naïve, with unresectable MPM, good performance status (ECOG 0 or 1) and adequate organ function. Under the trial design, eligible patients received two treatments with CRS-207 two weeks apart, followed by up to six cycles of standard of care pemetrexed and cisplatin chemotherapy three weeks apart and two CRS-207 treatments three weeks apart. Clinically stable patients receive CRS-207 maintenance courses every eight weeks and are followed until disease progression. Objectives of the study are safety, immunogenicity, objective tumor responses and tumor marker kinetics.

Median duration of response was 5.3 months (95% CI: 4.7 – 16.7 months) and median progression free survival was 8.5 months (95% CI: 6.9 – 10.8 months). No treatment-related serious adverse events or unexpected toxicities were observed. Treatment, follow-up and immune response evaluations are ongoing.

About Malignant Pleural Mesothelioma

Mesothelioma is a form of cancer that affects the smooth layer of mesothelial cells that surround the chest, lungs, heart and abdomen. Malignant pleural mesothelioma (MPM), which affects the thin balloon-shaped lining of the lungs, is the most common form of this disease and accounts for approximately 3,000 cases a year in the United States. MPM is an aggressive disease with a poor prognosis. Most MPM patients are not candidates for surgical resection. Based on prior studies, expected median time to progression is 5.7 months and median overall survival is 12.1 months with combination pemetrexed and cisplatin chemotherapy. The tumor-associated antigen mesothelin is overexpressed on the majority of mesothelioma tumors.

About CRS-207

CRS-207 is one of a family of product candidates based on Aduro’s live-attenuated, double-deleted (LADD) Listeria monocytogenes immunotherapy platform that induces a potent innate and T cell-mediated adaptive immune response. CRS-207 has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.

MedImmune and 3m drug delivery systems partner to develop novel TLR agonist cancer therapies

On September 25, 2015 MedImmune, the global biologics research and development arm of AstraZeneca, and 3M Drug Delivery Systems, reported a research collaboration focused on developing next generation toll-like receptor (TLR) agonists – promising agents that activate innate immune cells and enhance the visibility of cancer tumors (Press release, MedImmune, SEP 25, 2015, View Source [SID:1234509410]).

As part of the agreement, MedImmune has in-licensed from 3M MEDI9197 (formerly 3M-052), a novel TLR 7/8 dual agonist. The U.S. Food and Drug Administration recently accepted an investigational new drug application (IND) for a Phase I study to explore the safety and tolerability of MEDI9197 as a potential treatment for patients with solid tumors.

TLR agonists are promising agents that activate antigen presenting cells such as dendritic cells, enhancing the visibility of a tumor to the immune system. MEDI9197 has been designed to activate a broad range of innate immune cells through targeting of both TLR 7 and 8, leading to a more robust adaptive immune response. A TLR7 and 8 dual agonist can additionally convert immune suppressive cells in the tumor to those with anti-tumor properties, allowing the generation of an effective anti-tumor response. MEDI9197 will also be the first dual TLR7and 8 agonist administered directly into a tumor in a clinical setting.

Preclinical studies demonstrate that intratumoral dosing of MEDI9197 may inhibit tumor growth of both the injected and distant lesions in multiple types of cancer, including melanoma. MEDI9197 is uniquely designed for intratumoral injection, allowing the compound to be retained in the tumor and provide specific immune activation, enhancing its safety and tolerability profile.

Yong-Jun Liu, MD, PhD, Senior Vice President, R&D and Head of Research, MedImmune, said: "We’re pleased to collaborate with 3M Drug Delivery Systems to explore TLR agonists as monotherapy and in combination with our internal immuno-oncology portfolio. By targeting tumor antigen presentation, MEDI9197 adds a unique mechanism of immune activation to our growing portfolio and supports our strategy of maximizing anti-tumor immunity through scientifically rational combinations."

Cindy Kent, President and General Manager, 3M Drug Delivery Systems, said: "Everyone here at 3M’s Drug Delivery Systems is very excited to collaborate with MedImmune, a world leader in cancer immunotherapy. Our companies continue to work well together on this groundbreaking program and we’re very pleased with the progression of MEDI9197 into the clinic. The acceptance of the IND marks an important step in exploring this unique TLR 7/8 agonist intratumoral immunotherapy approach in patients with solid tumors."

Under the agreement, MedImmune is responsible for the clinical development and strategy for MEDI9197. 3M will continue to develop additional TLR agonists in oncology and other therapy areas, with MedImmune holding exclusive rights to conduct research on new molecules resulting from the collaboration and to determine which to progress to clinical development. The terms of the agreement include an upfront payment and development-related milestone payments for MEDI9197 in addition to research funding paid by MedImmune to 3M. 3M retains the rights to 3M-052 in certain topical applications and use in vaccine admixtures.

Immuno-oncology is a promising therapeutic approach that harnesses the patient’s own immune system to help fight cancer. The agreement with 3M supports AstraZeneca’s strategy of developing novel combinations that target multiple mechanisms in the immune system where cancer wages its battles – T-cell activation, antigen presentation and innate immunity, and the tumor microenvironment.

Presentation of IPH4102 rationale and phase I design at the cutaneous lymphoma task force meeting of the EORTC

On September 26, 2015 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that Professor Martine Bagot, Head of the Dermatology Department at the Saint-Louis Hospital in Paris and co-discoverer of the target KIR3DL2, today presented the rationale of IPH4102 for the treatment of CTCL as well as the protocol of the upcoming Phase I trial at the EORTC Cutaneous Lymphoma Task Force meeting in Turin, Italy (Press release, Innate Pharma, SEP 25, 2015, View Source [SID:1234507572]). IPH4102 is a first-in-class cytotoxic antibody against KIR3DL2, a tumor marker specifically expressed in most subtypes of CTCL.

Professor Martine Bagot, principal investigator of the Phase I trial, said: "The unmet need in CTCL, notably in Sézary syndrome and transformed mycosis fungoides, the most aggressive forms of CTCL, is very large. Thanks to its novel target specifically expressed by the tumor cells, IPH4102 has a unique potential for being both very effective and well tolerated". She added: "This Phase I trial includes cohort expansions aiming at an early detection of antitumor activity. We hope that this approach will accelerate the development of IPH4102".

The Phase I trial is an open label, multicenter study of IPH4102 in patients with relapsed/refractory cutaneous T-cell lymphomas which will be performed in Europe (France, the Netherlands, and the United Kingdom) and in the US. Participating institutions will include several hospitals with internationally recognized expertise: the Saint-Louis Hospital (Paris, France), the MD Anderson Cancer Center (Houston, Texas), the Stanford University Medical Center (Stanford, CA), the Ohio State University (Columbus, OH), the Leiden University Medical Center (Netherlands), and the Guy’s and St Thomas’ Hospital (United Kingdom). Approximately 60 patients with KIR3DL2-positive CTCL having failed at least two prior lines of treatment are expected to be enrolled in a dose-escalation / cohort expansion study. The cohort expansion is expected to be performed in 2 CTCL subtypes displaying the highest expression of KIR3DL2, transformed mycosis fungoides and Sézary syndrome, depending on the findings during the dose escalation part of the study.