On June 04, 2016 Celldex Therapeutics, Inc. (Nasdaq:CLDX) reported results from a Phase 2 clinical study evaluating CDX‑1401 and CDX‑301 in patients with malignant melanoma, which was conducted by the Cancer Immunotherapy Trials Network (CITN) under a Cooperative Research and Development Agreement (CRADA) between Celldex and the Cancer Therapy Evaluation Program of the National Cancer Institute (Press release, Celldex Therapeutics, JUN 4, 2016, View Source [SID:1234512995]). CDX‑1401 is an NY‑ESO‑1-antibody fusion protein for immunotherapy, and CDX‑301 (recombinant human Flt3 ligand) is a potent hematopoietic cytokine that uniquely expands dendritic cells and hematopoietic stem cells. Results from the study were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago in a poster titled "A Phase 2, Open-label, Multicenter, Randomized Study of CDX‑1401, a Dendritic Cell Targeting NY‑ESO‑1 Vaccine, in Patients with Malignant Melanoma Pre-Treated with CDX‑301, a Recombinant Human Flt3 Ligand."

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The study randomized 60 patients with resected stage IIb through IV melanoma into two cohorts (n=30 each) to assess whether the immune response to NY-ESO-1 elicited by CDX-1401 could be substantially increased by pre-treatment with CDX-301 to expand the number of dendritic cells, which are key cells in initiating immune responses. As this study was intended primarily for safety and immune endpoints, patients were not selected for NY‑ESO‑1 expression. Both treatment cohorts received four monthly cycles of CDX‑1401 and poly-ICLC (Hiltonol). Cohort 1 received pre-treatment with CDX‑301 for the first two cycles, whereas Cohort 2 did not receive CDX‑301. Both combination regimens were well tolerated, and no drug-related adverse events required discontinuation from treatment.

NY-ESO-1 specific T cell responses were significantly greater and developed earlier in Cohort 1 compared to Cohort 2. In addition, all patients in Cohort 1 (n=30) achieved a specific NY-ESO-1-specific T cell response compared to 22 out of 30 patients in Cohort 2. Substantial increases in innate immune cells (dendritic cells, natural killer cells and monocytes) and greater increases in antibody titer were observed in the CDX‑301 pre-treated Cohort 1.

"The Cancer Immunotherapy Trials Network has prioritized CDX-301 as a dendritic cell growth factor. The current study validates that Flt3 ligand can greatly expand peripheral blood dendritic cells and is highly effective at immunizing cancer antigen specific T cells when combined with CDX-1401, the immunotherapy that delivers NY‑ESO‑1 to dendritic cells," said Martin "Mac" Cheever, M.D., a member of the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Research Center, Professor of Medicine at the University of Washington and Director of the Fred Hutch-based Cancer Immunotherapy Trials Network. "These results, which show rapid cellular immune responses in a majority of patients, should stimulate significant interest in what appears to be a highly applicable, effective immunologic approach."

"This study confirms that CDX-1401 is effective at driving NY-ESO-1 immunity and further shows the value of CDX-301 as a combination agent for enhancing tumor-specific immune responses," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "With these results, we are initiating a targeted study in patients with NY‑ESO‑1 positive disease to determine if these enhanced immune responses can translate to improved clinical outcomes. This also provides exciting new opportunities for use of CDX-301 in other combination immunotherapy regimens."

The poster is available on the "Publications" page of the "Science" section of the Celldex website.

About CDX‑301
CDX‑301 (Flt3L) is a potent hematopoietic cytokine that has demonstrated a unique capacity to increase the number of circulating dendritic cells in both laboratory and clinical studies. In addition, CDX‑301 has shown impressive results in models of cancer, infectious diseases and inflammatory/autoimmune diseases. Celldex believes this ligand may hold significant opportunity for synergistic development in combination with other proprietary molecules in the Company’s portfolio.

About CDX‑1401
CDX‑1401 is an NY‑ESO‑1-antibody fusion protein for immunotherapy, which is designed to activate the patient’s immune system against cancers that express the tumor marker, NY‑ESO‑1. CDX‑1401 consists of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC‑205 genetically linked to the NY‑ESO‑1 tumor antigen. Celldex has accessed NY‑ESO‑1 through a licensing agreement with the Ludwig Institute for Cancer Research. By selectively delivering the NY‑ESO‑1 antigen to dendritic cells in the body, CDX‑1401 is intended to induce robust immune responses against the antigen-expressing cancer cells.

On June 4, 2016 Celgene Corporation (NASDAQ:CELG) reported that results from multiple sponsored and independent studies presented during the 52nd ASCO (Free ASCO Whitepaper) Annual Meeting evaluated the use of ABRAXANE (paclitaxel protein-bound particles for injectable suspension)(albumin-bound) in combination with gemcitabine in first-line metastatic pancreatic cancer (Press release, Celgene, JUN 4, 2016, View Source [SID:1234512994]).

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"This year’s ASCO (Free ASCO Whitepaper) meeting continues to evaluate sequential therapy with ABRAXANE plus gemcitabine in the first-line and as a combination partner for investigational agents to treat metastatic pancreatic cancer," said Michael Pehl, President, Hematology and Oncology for Celgene. "The ABRAXANE plus gemcitabine combination is playing a key part in research designed to advance care for patients in this historically challenging disease."

Evaluating a Treatment Plan in Metastatic Pancreatic Cancer

For patients with metastatic pancreatic cancer, important considerations in defining a treatment plan include sequence, patient characteristics, comparative effectiveness and cost. At ASCO (Free ASCO Whitepaper) 2016 health outcomes analyses evaluating the treatment sequence with ABRAXANE plus gemcitabine as the first-line option are being presented.

An Italian multi-center real-life retrospective analysis highlighted outcomes of 122 patients who received first-line ABRAXANE plus gemcitabine followed by second-line treatment. (Abstract #4124 – Giordano). Second line treatments included FOLFOX/XELOX (45%). FOLFIRI (22%), FOLFIRINOX (18%), and other single agent therapies (15%). Median overall survival for patients receiving a second-line therapy following ABRAXANE plus gemcitabine was 13.5 months (95% CI 12.659-14.341), compared with 6.8 months for patients (99 patients) receiving BSC (95% CI 5.567-8.033), p < 0.0001. Also of note in the research presented at ASCO (Free ASCO Whitepaper) were two studies evaluating ABRAXANE plus gemcitabine in patients who exhibited elevated bilirubin levels, a common disease effect in metastatic pancreatic cancer. These studies provide insight into this patient population, which was excluded from the Phase III study of ABRAXANE plus gemcitabine.

In one observational interim analysis (Abstract #e15739 – zur Hausen), 20 (of 219) patients with a mean bilirubin level of 4.4 mg/dl (1.5-12.9) at baseline were followed for up to 4 cycles of ABRAXANE plus gemcitabine and methods of hyperbilirubinaemia were assessed. The mean bilirubin level of these patients dropped to 1.8 mg/dl (0.35-14.1; p=0.031) by the 2nd cycle. There were 14 (70%) patients that started treatment with a standard dosage and 6 (30%) that started with a reduced dose. Grade 3 or 4 toxicities were seen in 70 percent of patients with the most common being leukopenia, anemia and fever (each 20%).

An additional analysis of 29 patients (Abstract #e15717 – Pelzer) examined safety and survival with ABRAXANE/Gemcitabine in patients with elevated total bilirubin levels (≥ 1.2 to > 5 x ULN).

Administration of ABRAXANE in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression. According to the prescribing information, ABRAXANE is not recommended in patients who have total bilirubin > 5 x ULN or AST > 10 x ULN.

Multiple studies evaluated real-world comparative effectiveness and economic evaluations of first-line metastatic pancreatic treatments.

An independent, retrospective, Canadian comparative effectiveness analysis of ABRAXANE plus gemcitabine, FOLFIRINOX, and gemcitabine alone (Abstract #6561 – Wang) in five British Columbia cancer centers found the median overall survival of these treatments was 8.5 months for ABRAXANE plus gemcitabine (n=59), 7.8 months for FOLFIRINOX (n=59) and 3.1 months for gemcitabine alone. The analysis noted that patients receiving FOLFIRINOX were significantly younger (p < 0.001), had better performance status (p < 0.001) and had less disease burden at presentation (p=0.049), compared with ABRAXANE plus gemcitabine. Treatment discontinuation due to toxicities occurred in 36% of patients receiving FOLFIRINOX, 17% of patients receiving ABRAXANE plus gemcitabine and 23% of patients receiving gemcitabine alone.

A retrospective review of U.S. de-identified hospital data (Abstract #e15741 – Kim) evaluated the median time to treatment discontinuation and cost of ABRAXANE plus gemcitabine and FOLFIRINOX in the first-line setting. In this analysis, patients treated with FOLFIRINOX had higher median total monthly treatment costs compared to ABRAXANE plus gemcitabine ($18,743 vs. $12,192; p < 0.05).

ABRAXANE plus gemcitabine as a foundation for investigational combinations in metastatic pancreatic cancer

Multiple studies presented at ASCO (Free ASCO Whitepaper) also evaluated ABRAXANE in combination with potential new agents in first-line metastatic pancreatic cancer. Agents being evaluated in combination with ABRAXANE plus gemcitabine in the first line include PEGPH20 (Abstract #4104 – Bullock), necuparanib (Abstract # 4117 – O’Reilly), indoximod (Abstract #3020 – Bahary) and napabucasin (Abstract #4128 – El-Rayes).

About ABRAXANE

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment
Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

On June 4, 2016 AstraZeneca reported that it has entered into a definitive agreement with Foundation Medicine, Inc. (Foundation Medicine) to develop a novel companion diagnostic assay for Lynparza (olaparib) to support its global development programme (Press release, AstraZeneca, JUN 4, 2016, View Source [SID:1234512993]). The companion diagnostic will enable physicians to identify those patients most likely to benefit from AstraZeneca’s first-in-class poly ADP-ribose polymerase (PARP) inhibitor.

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Lynparza is an innovative, oral PARP inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives Lynparza the potential for activity in a range of tumour types with DNA repair deficiencies. It is approved in the US for the treatment of patients with germline BRCA-mutated advanced ovarian cancer and in the EU for patients with platinum-sensitive relapsed BRCA-mutated high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer.

Nina Mojas, Global Medicine Lead for Lynparza at AstraZeneca said: "This agreement supports the broad development programme for our first-in-class PARP inhibitor, Lynparza. Utilising Foundation Medicine’s leading capabilities in molecular information will help our work to assess the potential of the medicine to address unmet patient need across a number of cancers driven by DNA repair deficiencies, including and – significantly – beyond the BRCA mutations."

Under the terms of the agreement, Foundation Medicine will develop and make available a regulatory approved product utilising the Quality Systems Regulations (QSR) compliant version of its FoundationOne comprehensive genomic profiling platform. This assay will detect multiple classes of genomic alterations across a range of genes involved in Homologous Recombination Repair (HRR). The assay, based on a scientifically selected panel of genes known to be involved in driving the HRR process, will be developed alongside the clinical programme for Lynparza, as part of a coordinated drug-diagnostic regulatory strategy.

Steven J. Kafka, Ph.D., President and chief operating officer for Foundation Medicine said: "Following our new master collaboration agreement with AstraZeneca, we are pleased to launch this first strategic initiative to support and advance the development of Lynparza in a number of cancers. The work we’ve undertaken with AstraZeneca underscores the importance and potential of utilising our rigorously validated, comprehensive profiling approach to make available to physicians an FDA-approved universal companion diagnostic solution for use with targeted medicines."

Lynparza is the first approved medicine in a comprehensive pipeline of compounds AstraZeneca is developing targeted at the DNA Damage Repair (DDR) system. DDR is a term describing the network of cellular pathways that minimise the daily impact of DNA damage. Currently, many cancers are known to have defects in DDR pathways, which makes them dependent on and therefore highly sensitive to inhibition of the remaining DDR pathways. Targeting DDR deficiencies to preferentially kill cancer cells, while minimising the impact on normal cells, has potential for more selective, better tolerated therapies to improve survival in multiple cancers.

On June 4, 2016 Array BioPharma (Nasdaq: ARRY), Pierre Fabre and Merck KGaA, Darmstadt, Germany, reported that they have jointly initiated the BEACON CRC (Binimetinib, Encorafenib And Cetuximab Combined to treat BRAF-mutant Colorectal Cancer) trial, a randomized, global Phase 3 clinical trial designed to assess the safety and efficacy of binimetinib (MEK inhibitor), encorafenib (BRAF inhibitor) and Erbitux (monoclonal antibody) in comparison to Erbitux and irinotecan-based therapy in patients with BRAF-mutant colorectal cancer (BRAFm CRC) (Press release, Array BioPharma, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175101 [SID:1234512992]). The primary endpoint is overall survival (OS) and key secondary endpoints include progression-free survival (PFS) and objective response rate (ORR).

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Array BioPharma. (PRNewsFoto/Array BioPharma Inc.)
"We are pleased to announce the initiation of this innovative Phase 3 trial studying the effects of binimetinib, encorafenib and Erbitux for patients with BRAF-mutant colorectal cancer," said Victor Sandor, M.D., Chief Medical Officer of Array. "We believe the encouraging results shown in our Phase 2 study suggest that concurrent inhibition of EGFR and MAPK signaling pathways has the potential to improve outcomes for this high unmet need patient population."

Trial Design
BEACON CRC is a randomized, open-label, global study evaluating the efficacy and safety of binimetinib, encorafenib and Erbitux in patients with BRAFm metastatic CRC who have previously received first-line systemic therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet therapy (binimetinib, encorafenib and Erbitux), doublet therapy (encorafenib and Erbitux) or the control arm (irinotecan-based therapy and Erbitux).

The primary endpoint of the trial is overall survival (OS) of the triplet therapy compared to the control arm. The secondary endpoints address efficacy of the doublet therapy compared to the control arm, and the triplet therapy compared to the doublet therapy. Other key secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response, safety and tolerability. Health related quality of life data will also be assessed.

"Historical studies suggest that BRAF-mutant colorectal cancer patients who have progressed after first-line systemic treatment have an estimated median overall survival of less than 6 months," said Josep Tabernero, MD, PhD, Head of Medical Oncology and the Institute of Oncology at Vall d’Hebron University Hospital. "The BEACON CRC trial will explore innovative combinations which have the potential to offer new treatment options to these patients who currently have few good choices remaining."

The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.

About the Collaboration
Array BioPharma is the owner of binimetinib and encorafenib and will act as the global sponsor of the study. Pierre Fabre licensed commercial rights to binimetinib and encorafenib for Europe and other global markets from Array in December 2015. As part of their collaboration, Pierre Fabre has elected to co-fund 40% of the cost of the BEACON CRC trial. Merck KGaA, Darmstadt, Germany, is the owner of Erbitux outside the United States and Canada, and will supply Erbitux to all trial sites outside the United States and Canada as part of the collaboration. If successful, results would support regulatory submissions for all three parties.

About BRAF-mutant Colorectal Cancer
Colorectal cancer is the third most common cancer among men and women in the United States, with more than 134,000 new cases and nearly 50,000 deaths from the disease projected in 2016. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients. Historical published PFS and OS results after first-line treatment range from 1.8 to 2.5 months and 4 to 6 months, respectively, and published response rates from various studies for EGFR-based therapy in this population range from 6 percent to 8 percent.

About Binimetinib & Encorafenib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, non-small cell lung, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway.

Binimetinib and encorafenib are being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the recently initiated BEACON trial that will study encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant colorectal cancer.

About Erbitux
Erbitux, marketed by Merck KGaA, Darmstadt, Germany, globally except North America, is a highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth.

The most commonly reported side effect with Erbitux is an acne-like skin rash that seems to be correlated with a good response to therapy. In approximately 5% of patients, hypersensitivity reactions may occur during treatment with Erbitux; about half of these reactions are severe.

Erbitux has already obtained market authorization in over 90 countries world-wide for the treatment of colorectal cancer and for the treatment of squamous cell carcinoma of the head and neck (SCCHN). Merck KGaA, Darmstadt, Germany, licensed the right to market Erbitux outside the US and Canada from ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, in 1998. Merck KGaA, Darmstadt, Germany, has an ongoing commitment to the advancement of oncology treatment and is currently investigating novel therapies in highly targeted areas.

On June 04, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO) reported the presentation of updated data from an ongoing Phase 1b clinical trial of its immunotherapy product candidate CRS-207 in combination with pemetrexed and cisplatin (standard of care chemotherapy) as front-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) (Press release, Aduro BioTech, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175099 [SID:1234512991]). The results from the first of two cohorts were presented today in a poster presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting (ASCO) (Free ASCO Whitepaper) held in Chicago. Of the 36 evaluable patients, disease control was observed in 94% (34/36), including 3% (1/36) with a complete response, 56% (20/36) with partial responses and 36% (13/36) experiencing stable disease following treatment with CRS-207 and chemotherapy. Prior to receiving chemotherapy, 31% (11/36) of patients experienced some tumor shrinkage (range: -1% to -43%) after receiving CRS-207 alone. The estimated median overall survival was 16.4 months (95% CI: 11.0 – 20.6 months). CRS-207 was generally well-tolerated with no treatment-related serious adverse events or cumulative toxicities when administered with chemotherapy.

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"The observed responses with the combination of CRS-207 and standard chemotherapy are unprecedented in mesothelioma," said Dean Fennell, Ph.D., F.R.C.P., professor of Thoracic Medical Oncology at the University of Leicester and president of the International Mesothelioma Interest Group (iMig). "Pleural mesothelioma is a devastating disease, and these data suggest that immunotherapy has the potential to advance treatment options for these patients."

Dirk G. Brockstedt, Ph.D., executive vice president of Research and Development at Aduro added, "These results demonstrate that CRS-207 induces anti-tumor activity in patients with malignant pleural mesothelioma. We are looking forward to the results from the study’s second cohort, which is evaluating the addition of immune modulating doses of cyclophosphamide to the CRS-207 chemotherapy combination. Preclinical data suggest that the simultaneous inhibition of regulatory T-cells through the addition of a checkpoint inhibitor may amplify the tumor response and overall survival seen with CRS-207. As such, the combination of CRS-207 with a checkpoint inhibitor could be the regimen we advance in our mesothelioma program going forward."

The multi-center Phase 1b study enrolled chemotherapy-naïve patients with unresectable MPM and good performance status (ECOG 0 or 1) to receive two doses of CRS-207, followed by up to six cycles of chemotherapy and two additional CRS-207 doses. Clinically stable patients receive CRS-207 maintenance every eight weeks and are followed every eight weeks until disease progression. Objectives of the study are safety, immunogenicity, objective tumor responses and tumor marker kinetics.

A second cohort of 22 patients is receiving an immunomodulatory dose of cyclophosphamide one day prior to each CRS-207 administration in the same treatment regimen utilized in the first cohort. This cohort is fully enrolled and patient follow-up is 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.I The tumor-associated antigen mesothelin is overexpressed on the majority of mesothelioma tumors.

About LADD and CRS-207
LADD is Aduro’s proprietary platform of live, attenuated double-deleted Listeria monocytogenes strains that have been engineered to generate a potent innate immune response and to express tumor-associated antigens to induce tumor-specific T cell-mediated immunity.

CRS-207 is one of a family of product candidates based on Aduro’s LADD immunotherapy platform that 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.