New roles of Jak, PARP, and BTK inhibitors in cancer immunotherapies

FDA presentation focusing on trial designs to accelerate approval of promising new cancer drugs underscores the agency’s continued positive attitude towards industry. Deeper understanding of immune oncology approach. A number of abstracts will focus on correlating clinical responses for Merck & Co.’s PD-1 antibody MK-3475 with PD-L1 expression (melanoma, colorectal, lung). Additional focus includes: PD-L1 role in head/neck cancer, use of peptides to inhibit PD1 pathway, rationale for HDAC6 inhibition in combination with PDL1 blockade, novel TDO/IDO inhibitors, rationale for combining PD1/PD-L1 with IDO inhibitor.

New roles for Jak inhibitors in multiple tumor types. Presentations suggests a rationale for combining a Jak inhibitor with a BTK inhibitor in NHL specially in diffuse large B cell lymphoma (DLBCL), and using Jak2 inhibition in ovarian cancer; a loss of function Jak1 mutation study could provide a broad view of where Jak1 inhibitors may be useful in oncology.

Novel drugs targeting T790M EGFR mutant lung cancer. Multiple companies will have data for their novel inhibitor aimed at targeting lung cancer with the T790M EGFR mutation including: Clovis (CO-1686), AstraZeneca (AZD9291), Astellas (ASP8273), Innova Pharma (KL-ON113), Novartis (EEGF816), Roche/Genentech (series), and ImmunoGen (IMGN289-an ADC).

Role for PARP inhibitors beyond BRCA+ breast cancer. New data could broaden potential areas of interest for PARP inhibitors, including: a subset of lung cancer with overactive PARP, endometrial cancer, gastric cancer, Ewing’s sarcoma, in Herceptin resistant Her2+ breast cancer, head and neck cancer, and as combination therapy with a CDK inhibitor or radiation.

Novel early stage drugs of interest. New data for several products could be worth watching: Additional results for Sanofi’s anti-CD38 antibody SAR’984 in hematologic malignancies, Incyte’s selective delta PI3kinase inhibitor INC‘093, GlaxoSmithKline’s ADC ‘916 licensed from Seattle Genetics for myeloma, myeloma synergies for Celgene’s Revlimid and licensed HDAC6 inhibitor ACY-1215, Amgen’s Ang1/Ang2 antibody AMG-780 for renal cell carcinoma.

Novel roles for ibrutinib, second generation BTK inhibitor. There will be in vitro data for ibrutinib in Her2+ breast cancer cells.


Blinatumomab will change the future of relapsed/refractory Acute Lymphoblastic Leukemia patients?

During the ASCO 2014, Amgen had shown the latest data of a novel ALL treatment, Blinatumomab.

Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. Blinatumomab is currently investigated for acute lymphoblastic leukemia (ALL), specially in persistence or relapse/ refractory after chemotherapy indicates resistance to chemotherapy. As the current ALL treatment were knowing for the high toxicity and low medical response, Blinatumomab can offer a real medical alternative.  Blinatumomab, was designed as orphan drug by the FDA for ALL in 2008. Blinatumomab binds to CD19, a protein which is expressed solely by B cells and is overexpressed in ALL tumor cells. Blinatumomab also binds to cytotoxic T cells through an interaction with the protein CD3, redirecting T cells to lyse CD19-expressing B-precursor ALL cells. The Phase II study of blinatumomab, reflect the potential of this molecule as an first-in-class bispecific T cell antibody.

The results showed that 43% of the 189 blinatumomab-treated patients achieved complete remission (CR) or CR with partial hematological recovery (CRh) within the first two cycles of therapy, with 80% of responses occurring within the first cycle. The median relapse-free survival was 5.9 months, and OS was 6.1 months. In total, patients were treated with more than five cycles of blinatumomab.

In cycle 1, patients underwent a run-in phase of 9μg blinatumomab per day for the first week, with 28μg per day for the remaining three weeks.

In cycle 2, patients were treated with 28μg blinatumomab per day.

The primary endpoint assessment of CR/CRh was performed at the end of the second cycle, and patients who responded to blinatumomab therapy were eligible to receive three additional cycles of therapy.

Current acute lymphoblastic leukemia chemotherapies were mainly composed by four-drug combination of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase, or a five-drug combination including vincristine, prednisone, anthracycline, cyclophosphamide, and L-asparaginase. Although, the treatment related high mortality rate around 20 to 30%. Otherwise, there is an important unmet need for innovative therapies, more safe and efficient for the patient.

If Blinatumomab will demonstrate efficacy and safety in ALL treatment, the new compound will have the chance to reach a high pricing regarding the FDA orphan drug accreditation. Blinatumomab is currently investigated in the Phase III TOWER trial versus the investigator’s choice of standard of care chemotherapy in adult subjects with R/R precursor B-cell ALL.

Regarding the blinatumomab’s result shown in ASCO convincing results in adult patients with R/R ALL, and the important medical need, blinatumomab seems to be a possible multi-indication revolution for ALL, and non-Hodgkin’s lymphoma patients.

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Gustave Roussy Announces Oncology Joint Strategic Research Alliance With AstraZeneca

Villejuif, France, 5 June 2014 – Gustave Roussy Comprehensive Cancer Center and AstraZeneca have entered into a joint strategic alliance focussed on early oncology drug development. Gustave Roussy and AstraZeneca will develop a joint Strategic Collaboration Plan that will be overseen by a Joint Steering Committee.

As part of this strategic alliance, AstraZeneca will make its entire portfolio of innovative oncology molecules for pre-clinical, translational and early clinical studies available to Gustave Roussy, with the goal of targeting molecular aberrations that drive individual cancers via the modulation of critical cellular signalling pathways and deepening our understanding of how the patient’s immune system interacts with cancer

The Alliance will involve several parallel and inter-connected projects that will span preclinical, translational and clinical phases of drug development.

“Over the last 5 years, AstraZeneca has entrusted Gustave Roussy with a growing number of phase I trials. Through this alliance we hope to strengthen such an interaction and accelerate access to innovative therapies for all our patients“ – say Pr Alexander Eggermont (General Director of Gustave Roussy, Comprehensive Cancer Center) and Pr Jean-Charles Soria (Chairman Drug Development Department, DITEP, at Gustave Roussy).

Susan Galbraith, Head of the Oncology Innovative Medicines Unit at AstraZeneca, commented: “I am delighted to formalise and expand our longstanding relationship with Gustave Roussy.  AstraZeneca has over 40 years’ experience in developing cancer drugs, pushing the boundaries of science to improve survival rates for patients around the world.  Gustave Roussy’s integrated, innovative approach to cancer research is renowned.  I hope very much that we will continue to build on this alliance to accelerate drug discovery and   ultimately get drugs to the patients who need them.”

Antoine Yver, Head of Oncology, AstraZeneca’s global medicines development unit added, “We have a number of pre-clinical and clinical projects already underway with Gustave Roussy. The signing of this alliance allows us to continue our endeavours led by three new steering groups which will determine strategy and drive individual projects within the pre-clinical and clinical arena.”

Françoise Bartoli, AstraZeneca France Company President said:  “With this Alliance, AstraZeneca reinforces its partnership in France with oncology academia and public research and its collaboration with Gustave Roussy’s highly experienced and talented teams.” 


Source: IGR

Eli Lilly’s CYRAMZA (Ramucirumab) first FDA approval for Advanced Gastric Cancer

 Eli Lilly and Company (NYSE: LLY) announced today that the U.S. Food and Drug Administration (FDA) has approved CYRAMZA™ (ramucirumab) as a single-agent treatment for patients with advanced or metastatic gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. With this approval, CYRAMZA becomes the first FDA-approved treatment for patients in this setting.

« Lilly Oncology is committed to delivering innovative medicines that extend the lives of people with cancer, » said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. « Until now, there were no FDA-approved options for patients in this indication. We are pleased that the FDA has approved CYRAMZA for these patients. This is an aggressive disease that is difficult to treat, and the prognosis has typically been very poor. »

The CYRAMZA (ramucirumab injection 10 mg/mL solution) approval is based on results of REGARD, a multicenter, randomized, placebo-controlled, double-blind trial of patients with locally advanced or metastatic gastric cancer including GEJ adenocarcinoma previously treated with fluoropyrimidine- or platinum-containing chemotherapy. It is the first Phase III trial to show improved overall survival and progression-free survival with a biologic agent in advanced gastric cancer after prior chemotherapy. Results demonstrated that CYRAMZA (8 mg/kg by infusion every two weeks) plus best supportive care (BSC), as compared to placebo plus BSC, increased the median overall survival of patients with advanced gastric cancer by 37 percent (median overall survival of 5.2 months [95% confidence interval (CI) 4.4, 5.7] vs. 3.8 months [95% CI 2.8, 4.7] for placebo, P=0.047, hazard ratio 0.78 [95% CI 0.60, 0.998]). Additionally, CYRAMZA significantly improved progression-free survival, demonstrating a 62 percent increase in median progression-free survival (2.1 months [95% CI 1.5, 2.7] vs. 1.3 months [95% CI 1.3, 1.4] for placebo, P < 0.001, hazard ratio 0.48 [95% CI 0.38, 0.62]).

The labeling for CYRAMZA contains a Boxed Warning regarding increased risk of hemorrhage, including severe and sometimes fatal events. CYRAMZA should be discontinued in patients who experience severe bleeding. The most commonly reported adverse reactions (all grades) in REGARD, occurring in at least 5 percent of patients receiving CYRAMZA and at a rate at least 2 percent higher than those receiving placebo, were hypertension (16% vs. 8%), diarrhea (14% vs. 9%), headache (9% vs. 3%), and hyponatremia (6% vs. 2%). The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs. 8.7% of patients who received placebo. Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade greater than or equal to 3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in the REGARD trial was 0.8% and the rate of infusion-related reactions was 0.4%. This is not a complete list of adverse reactions. For full safety information, see the Important Safety Information at the end of this press release and the full Prescribing Information.

« There is a high unmet medical need in patients with this disease, » said Charles Fuchs, M.D., M.P.H., principal investigator of the REGARD trial and director, Gastrointestinal Malignancy Program,Dana-Farber Cancer Institute. « This approval represents a meaningful advance for patients and gives those of us who treat them an important new second-line treatment option. »

« As someone who has experienced firsthand the limited options available to treat this devastating disease, I consider this approval to be much needed. This is a significant moment for many patients and their families, » said Debbie Zelman, president and founder of a leading international patient advocacy organization, Debbie’s Dream Foundation, which is dedicated to raising awareness about gastric cancer, advancing funding for research, and providing education and support to those affected by the disease. Zelman founded the organization following her own gastric cancer diagnosis. Lilly Oncology and Debbie’s Dream Foundation have established a partnership to improve patient and caregiver awareness of and access to gastric cancer resources.

CYRAMZA is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. VEGF Receptor 2 is an important mediator in the VEGF pathwayi,ii. In an in vivo animal model, ramucirumab inhibited angiogenesis. Angiogenesis is a process by which new blood vessels form to supply blood to normal healthy tissues as well as tumors, enabling the cancer to grow.

FDA approval of CYRAMZA marks a pivotal regulatory milestone in Lilly’s research and development program for the molecule, which it acquired when it purchased ImClone Systems in 2008. CYRAMZA has been granted Orphan Drug Designation by the FDA for this indication. Orphan drug status is given in the U.S. by the FDA’s Office of Orphan Products Development (OOPD) to medicines that show promise for the treatment of rare diseases. Lilly expects to make CYRAMZA available in the coming weeks and is committed to offering patient assistance programs for eligible patients receiving CYRAMZA treatment.

Source Eli Lilly

Roche provides update on phase III study of onartuzumab in people with specific type of lung cancer

Roche  announced  that an independent data monitoring committee has recommended that the phase III METLung study be stopped due to a lack of clinically meaningful efficacy.

The study evaluated if onartuzumab (MetMab) in combination with Tarceva (erlotinib) helped patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose tumours were identified as MET-positive live longer compared to Tarceva alone. Overall adverse event rates were generally similar between the two groups. Data will be submitted for presentation at a forthcoming medical meeting.

« These results are disappointing because new options are needed for patients with lung cancer, the most common and deadly cancer worldwide,” said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. « We remain committed to helping patients with lung cancer and are studying several investigational medicines in this disease.”

Roche is evaluating the implications of the METLung study results across the ongoing onartuzumab clinical programme.

About the METLung Study (NCT01456325)

  • METLung is a Phase III, randomised, double-blind study evaluating the efficacy and safety profile of onartuzumab in combination with Tarceva in patients with previously treated (second- or third-line) advanced NSCLC identified to be MET-positive. The METLung study included a companion diagnostic immunohistochemistry (IHC) test that was co-developed with Ventana Medical Systems, Inc., a member of the Roche Group.
  • Four hundred and ninety-nine patients were randomized to receive 150 mg of Tarceva taken daily plus either:
    • Intravenous 15 mg/kg of onartuzumab every three weeks
    • Intravenous placebo every three weeks
  • The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate and safety profile.
  • The results announced today are from a pre-specified interim analysis.

About Lung Cancer

According to the World Health Organization, it is estimated that nearly 1.6 million people worldwide died of lung cancer in 2012; NSCLC accounts for 85 percent of all lung cancers.

About the MET Pathway

MET is a protein found on the surface of cells and acts as a receptor that binds to another protein called Hepatocyte Growth Factor (HGF), also known as « Scatter Factor ». When HGF binds to MET, it causes MET proteins to form pairs (dimerise), which triggers a signalling cascade that tells cells to grow, divide, and spread to other parts of the body. Activation of the MET pathway has been proposed as a mechanism of tumour growth and spread (metastasis).

About Onartuzumab

Onartuzumab, an investigational monovalent (one-armed) monoclonal antibody designed to specifically target the MET receptor, is being studied in various cancers.


Source: Roche

CHMP recommends EU approval of a new formulation of MabThera

Roche announced that the EU Committee for Medicinal Products for Human Use (CHMP) recommended that the European Commission approve MabThera (rituximab) 1400mg solution for subcutaneous (SC) injection for the treatment of patients with common forms of non-Hodgkin lymphoma (NHL).

“We are excited the MabThera SC data confirm the efficacy and safety of a significantly shortened treatment time,“ said Sandra Horning, M.D., Chief Medical Officer and Head, Global Product Development. “We are confident that reducing treatment to approximately five minutes with MabThera SC will be an improvement for patients and healthcare professionals alike.”

Currently, MabThera is delivered by an intravenous infusion which takes approximately 2.5 hours. The new MabThera SC formulation can be delivered over approximately five minutes and comes as a ready-to-use, fixed dose, which reduces pharmacy preparation time and overall impact on hospital resources. The CHMP opinion is based primarily on data from the phase III SABRINA study. Roche expects a final decision from the European Commission in the coming months.

About MabThera

MabThera is a therapeutic monoclonal antibody that binds to a particular protein – the CD20 antigen – on the surface of normal and malignant B-cells. It then recruits the body’s natural defences to attack and kill the marked B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.

MabThera (Rituxan in the United States), discovered by Biogen Idec, first received FDA approval for the treatment of relapsed indolent NHL in 1997 and was the first targeted cancer medicine approved by the U.S. Food and Drug Administration (FDA). MabThera was approved in the EU in June 1998. For more than 15 years, the efficacy and safety of MabThera has been documented in more than 300 phase II/III clinical studies. MabThera has been approved for the treatment of several blood cancers, specifically, certain types of NHL and for chronic lymphocytic leukemia (CLL). In that time, MabThera has been used to treat more than 2.7 million people with specific blood cancers since its launch. It continues to be studied in other types of blood cancers and disease areas where CD20-positive cells are believed to play a role.

MabThera is known as Rituxan in the United States, Japan and Canada. Genentech, a member of the Roche Group, and Biogen Idec collaborate on Rituxan in the United States, and Roche markets MabThera in the rest of the world, except Japan, where MabThera is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd.

About the SABRINA study (BO22334)

SABRINA is a two-stage international phase III trial designed to investigate the pharmacokinetics, efficacy and safety of SC versus IV administration of MabThera in FL patients receiving induction and maintenance therapy. In the first stage (dose-confirmation) with pharmacokinetics (Ctrough) as primary endpoint, treatment-naïve patients with follicular lymphoma, a common type of NHL, were randomised to receive 375 mg/m2 MabThera administered intravenously or a fixed dose of 1,400 mg of MabThera via subcutaneous delivery, both given in combination with either CHOP or CVP chemotherapy. Patients who achieved a complete or partial response after 8 treatment cycles continued MabThera maintenance therapy as per their initial randomisation with either SC or IV administration. The SABRINA study met its primary endpoint of demonstrating non-inferior MabThera serum concentration after SC injection compared with IV infusion. No new medically relevant safety signals were observed and administration related reactions were mostly of mild to moderate severity. Exploratory efficacy analysis from SABRINA was also performed to demonstrate that a switch from IV to SC administration can be achieved without compromising MabThera’s anti-lymphoma efficacy: Similar overall response rates (ORR) [84.4% IV and 90.5% SC] and complete response (CR) rates [29.7% IV and 46% SC] support the conclusion of comparable efficacy. In the second stage with efficacy as the primary endpoint, additional patients will be randomized to either SC or IV administration of MabThera.

Source: Roche

Ipsen announces at ASCO GI that ELECT® clinical trial of Somatuline® in the control of symptoms in GEP-NET1 patients with carcinoid syndrome met its primary endpoint

Results of ELECT® phase III study showed that treatment with  Somatuline® resulted in a statistically significant reduction in the
number of days of rescue medication use versus placebo during the 16-week double-blind phase of the study

Safety data generated are consistent with known safety profile of Somatuline®

Ipsen announced that the results of the ELECT® phase III clinical study with Somatuline® Autogel® / Somatuline® Depot®
(lanreotide) Injection (hereafter referred to as Somatuline®)
Results of the ELECT® phase III study (poster 268) showed that treatment with Somatuline® 120 mg versus placebo resulted in a statistically significant reduction in the number of days in which immediate release octreotide was used as rescue medication, representing a mean difference of -14.8% (95%CI: -26.8, -2.8; p = 0.017). Somatuline® significantly improved the rates of complete/partial treatment success versus placebo (odds ratio = 2.4; 95%CI: 1.1, 5.3; p = 0.036).

Safety data collected during ELECT® study was consistent with known safety profile of Somatuline®.  Somatuline® is approved for the treatment of symptoms associated with carcinoid syndrome in  patients with neuroendocrine tumors in many markets worldwide; it is marketed as Somatuline®  Autogel®, but not in the US, where it is marketed as Somatuline® Depot® for acromegaly only. As such, data arising from the ELECT® study can be considered as an investigational use of Somatuline®
Depot® in the United States.

Claude Bertrand, Executive Vice-President, Research & Development and Chief Scientific Officer of Ipsen stated: “The results observed in the multinational ELECT® study add to the body of evidence evaluating the efficacy and safety of Somatuline® in the control of symptoms in GEP-NET patients with carcinoid syndrome. Along with the recently reported CLARINET® results demonstrating the antiproliferative effect of Somatuline®, ELECT results represent new data to document the efficacy  and safety of Somatuline® in gastroenteropancreatic neuroendocrine tumors.”

Edward M. Wolin, MD, Co-Director, Carcinoid and Neuroendocrine Tumor Program Medical Oncology, Samuel Oschin Cancer Center, Cedars-Sinai (USA) stated: “In the ELECT® study, rescue medication with immediate release formulation of octreotide was allowed for all patients in the Somatuline® and placebo arms when needed to control their symptoms. This study demonstrated a decreased use of octreotide as rescue medication in patients treated with Somatuline® 120mg when compared to those receiving placebo (both naïve to treatment or previously treated with a somatostatin analogue).”

Source: Ipsen