Year: 2016

ARIAD’s Investigational Medicine Brigatinib Demonstrated 15.6 Month Systemic Median Progression-Free Survival in ALTA Study

On December 7, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA), a rare cancer-focused innovative biotechnology company, reported clinical data on brigatinib, its investigational anaplastic lymphoma kinase (ALK) inhibitor, from the pivotal ALTA trial in ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients who had experienced disease progression on crizotinib therapy (Press release, Ariad, DEC 7, 2016, View Source;p=RssLanding&cat=news&id=2228143 [SID1234516982]). As of May 31, 2016, the data show that of patients on the 180-mg regimen with a median follow-up of 11 months, 55 percent achieved confirmed objective response as assessed by the investigator. In this arm, the median progression-free survival (PFS) was 15.6 months in this post-crizotinib setting, by both investigator and independent review committee (IRC) assessment. Additionally, in this arm, 67 percent of patients with measurable brain metastases achieved a confirmed intracranial objective response, and intracranial PFS was 18.4 months among patients with any brain metastases at baseline. These data will be presented today at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer (WCLC) being held in Vienna.

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"These updated ALTA trial data show that with additional follow-up, median progression-free survival from brigatinib given post-crizotinib is now 15.6 months, and that this is the same whether assessed by the investigators or an independent review committee," said D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the University of Colorado. "Whether this is a reflection of broader suppression of potential resistance mutations, or its effects on protecting the central nervous system, or both, requires further investigation but by itself these progression-free survival data should be very encouraging for physicians and patients alike. These data really support the idea to pursue brigatinib, not just post-crizotinib, but also in the ongoing ALTA 1L study, which aims to assess its potential in the ALK-treatment naive setting."

The ALTA Trial

The ALTA (ALK in Lung Cancer Trial of AP26113) trial enrolled 222 patients with ALK+ NSCLC who had been treated with and experienced disease progression on their most recent crizotinib therapy. Patients were randomized one-to-one to receive either 90 mg of brigatinib once per day (QD) (Arm A), or 180 mg QD, preceded by a lead-in dose of 90 mg QD for seven days (Arm B). In addition, patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib therapy.

The primary endpoint of the ALTA trial is investigator-assessed confirmed objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Key secondary endpoints include PFS, confirmed ORR assessed by an IRC, overall survival (OS), CNS response and PFS, duration of response, safety and tolerability.

Key Data from the ALTA Trial Update

Brigatinib Efficacy and Safety in ALK+ NSCLC Patients:
Clinical Data as of May 31, 2016 with IRC Data as of July 13, 2016

A total of 222 patients with ALK+ NSCLC treated with prior crizotinib therapy were randomized in the study (110 patients in Arm B at the 180-mg dose level with a seven-day lead-in at 90 mg and 112 patients in Arm A at the 90-mg dose level). The last patient was enrolled in the study in September 2015.
The median follow-up was 11 months in Arm B and 10.2 months in Arm A. ALTA trial data presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting, as of February 29, 2016, had median follow-up of 8.3 months in Arm B and 7.8 months in Arm A.
Investigator-assessed confirmed ORR in Arm B was 55 percent. IRC-assessed confirmed ORR in Arm B was 54 percent. Investigator-assessed confirmed ORR in Arm A was 45 percent. IRC-assessed confirmed ORR in Arm A was 49 percent.
In a subgroup analysis of confirmed ORR by baseline characteristics, there was no difference in confirmed ORR based on prior chemotherapy versus no prior chemotherapy.
The subgroup analysis by best response to prior crizotinib (partial or complete response versus other) suggests that patients who had achieved partial or complete responses on prior crizotinib treatment had a significantly higher confirmed ORR, compared with patients who did not achieve these responses.
Responses in Arm B included a confirmed partial response in a patient with the ALK kinase domain G1202R mutation at baseline, which is associated with resistance to all approved tyrosine kinase inhibitors (TKIs).
Median PFS was 15.6 months by both investigator assessment and IRC assessment in Arm B. Median PFS was 8.8 months by investigator assessment and 9.2 months by IRC assessment in Arm A.
Probability of OS at one year was 82 percent and 71 percent in Arm B and Arm A, respectively. The median OS had not been reached in either arm.
Of the 44 patients with measurable intracranial brain metastases at baseline, the IRC-assessed intracranial ORR was 67 percent (12/18) in Arm B and 46 percent (12/26) in Arm A.
The median IRC-assessed intracranial PFS was 18.4 months in Arm B and 15.6 months in Arm A.
The most common treatment-emergent adverse events (TEAEs; ≥ 30% of all patients, [Arm B/A]), regardless of relationship to treatment, were nausea (43%/36%), diarrhea (39%/21%), cough (36%/23%), headache (30%/28%) and increased blood creatine phosphokinase (CPK) (33%/11%).
TEAEs, grade ≥3, occurring in ≥4 percent of all patients (excluding neoplasm progression; Arm B/A), were increased CPK (10%/3%), hypertension (6%/6%), pneumonia (5%/3%) and increased lipase (3%/5%).
A subset of pulmonary adverse events (AEs) with early onset (median: Day 2; range: Day 1-9) occurred in six percent of all patients (grade ≥3 in 3% of patients); no such events with early onset occurred after dose escalation to 180 mg QD in Arm B.
Discontinuations and dose reductions due to AEs (Arm B/A) were 10 percent/three percent and 23 percent/eight percent, respectively. Discontinuations due to documented progressive disease (Arm B/A) were 23 percent and 30 percent.
"We are encouraged by the maturing efficacy and safety profile of brigatinib in this later data cut, which adds three months of follow up compared to the data presented at ASCO (Free ASCO Whitepaper)," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "These data are intended to be submitted to the European Medicines Agency in early 2017 for marketing approval. Pending regulatory review, we expect that brigatinib may become an important therapeutic option for the crizotinib-resistant population."

The poster presentation, "Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial," (Abstract #4046, Poster ID P3.02a-013) will be presented today, Wednesday, December 7, 2016 from 14:30 – 15:45 GMT.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK+ NSCLC. The FDA has accepted brigatinib’s New Drug Application and has granted ARIAD’s request for Priority Review and set an action date of April 29, 2017 under the Prescription Drug User Fee Act (PDUFA). ARIAD intends to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.

KEYTRUDA® (pembrolizumab) Demonstrated Improved Health-Related Quality of Life Compared to Chemotherapy in First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC)

On December 7, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported positive health-related quality of life (HRQoL) findings from an exploratory analysis from the phase 3 KEYNOTE-024 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, compared to standard of care (SOC) platinum-containing chemotherapy for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express high levels of PD-L1 (tumor proportion score [TPS] of 50 percent or more) (Press release, Merck & Co, DEC 7, 2016, View Source [SID1234516980]). Specifically, patient-reported outcomes showed clinically meaningful improvement with KEYTRUDA compared to chemotherapy. Findings will be presented today at the 17th World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.

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"The patient-reported quality of life outcomes we are seeing in the KEYNOTE-024 study are very encouraging and, coupled with previously reported clinical data from this study, including a survival benefit, are important in understanding the robust clinical profile for KEYTRUDA compared to chemotherapy," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories.

Dr. Julie Brahmer of the Johns Hopkins Kimmel Cancer Center will present these findings as part of a plenary session at WCLC in Vienna, Austria at 8:45 a.m. CET (Abstract #PL04a.01).

"For people living with lung cancer, who often face serious health challenges brought on by the disease, quality of life is a major concern when determining treatment and the data presented today help us further understand the potential clinical benefit for KEYTRUDA in these patients," said Dr. Martin Reck, head of the thoracic oncology department, LungenClinic Grosshansdorf, Germany.

The KEYTRUDA (pembrolizumab) clinical development program includes more than 30 tumor types in nearly 400 clinical trials, including more than 200 trials that combine KEYTRUDA with other cancer treatments. Merck has an expansive research program in NSCLC and is currently advancing multiple registration-enabling studies with KEYTRUDA as monotherapy and in combination with other treatments.

Findings from KEYNOTE-024

KEYNOTE-024 is a randomized, open-label, phase 3 study investigating KEYTRUDA monotherapy compared to SOC platinum-containing chemotherapy for the first-line treatment of patients with metastatic NSCLC. The study enrolled 305 patients who had not received prior systemic chemotherapy for their metastatic disease and whose tumors had high PD-L1 expression (TPS of 50 percent or more) with no EGFR or ALK aberrations. Patients were randomized to receive a 200 mg fixed dose of KEYTRUDA every three weeks (n=154) or four to six cycles of investigator’s choice platinum-based chemotherapy (n=151). The primary outcome measure was progression-free survival. Key secondary outcomes were overall survival, overall response rate and safety; exploratory outcomes were duration of response and patient-reported outcomes.

The HRQoL data presented at WCLC were based on change from baseline to week 15 as assessed by two European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaires measuring global health status (such as physical, emotional, cognitive, and social functioning as well as fatigue and pain) (QLQ-C30) and time to deterioration (measuring symptoms such as cough, chest pain, alopecia, and dyspnea) (QLQ-LC13). Across treatment arms, patient-reported outcome compliance was greater than 90 percent at baseline and approximately 80 percent at week 15.

The findings showed that HRQoL and symptoms were improved or maintained to a greater degree with KEYTRUDA compared to chemotherapy (based on 299 patients who completed at least one questionnaire). Specifically, the improvement in global health status from baseline to week 15 (difference in least squares) for KEYTRUDA was 6.9 (95% CI, 3.3-10.6) compared to -0.9 (95% CI, -4.8-3.0) in the chemotherapy arm. Analysis based on specific functioning and symptoms showed more patients treated with KEYTRUDA (pembrolizumab) reporting an improvement in global health status and/or quality of life, fatigue, and pain compared to patients treated with chemotherapy. Fewer patients in the KEYTRUDA arm experienced deterioration compared to chemotherapy (30.5% and 39.2%, respectively), with a prolonged time to deterioration also observed in the KEYTRUDA arm (hazard ratio: 0.66 [95% CI, 0.44-0.97; p=0.029]).

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA (pembrolizumab) for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes nearly 400 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

Compugen Discloses its Cancer Immunotherapy Program Targeting TIGIT Immune Checkpoint

On December 7, 2016 Compugen Ltd. (NASDAQ: CGEN), a leading predictive drug discovery company, reported CGEN-15137, its cancer immunotherapy program for TIGIT (Filing, 6-K, Compugen, DEC 7, 2016, View Source [SID1234516996]). TIGIT is an immune checkpoint in the B7/CD28 family which has recently gained broad industry interest in the field of immuno-oncology.

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At the recent Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), the Company disclosed data demonstrating that the CGEN-15029/PVRIG immune checkpoint, discovered by Compugen represents a new inhibitory component of the known TIGIT axis. Data was also presented that strongly support combining the Company’s COM701 anti-PVRIG antibody, which is now in preclinical studies, with an anti-TIGIT antibody. Compugen hypothesized that dual blockade of the two negative costimulatory arms of the axis – TIGIT and PVRIG – should result in a more robust T cell response, and therefore possibly a better anti-tumor immune response. To support this, in vitro studies were conducted which show that dual blockade of both TIGIT and PVRIG increases the activity of tumor infiltrating T cells (TILs) beyond the level achieved by blocking each alone. Leveraging its knowledge, Compugen initiated a therapeutic antibody program targeting TIGIT to complement its CGEN-15029 program.

Anat Cohen-Dayag, Ph.D., CEO and President of Compugen, stated, "We are excited to disclose our therapeutic program for TIGIT, an immuno-oncology target of high industry interest. Our efforts to date have demonstrated the potential enhanced efficacy of a combination treatment of a TIGIT antibody together with COM701. TIGIT and PVRIG represent two distinct arms of the same biological pathway. Based on this and our experimental data demonstrating synergistic activation of T cells, we believe there is a significant added value to developing both arms of this potential combination therapy. Currently we are in the process of developing a therapeutic antibody for CGEN-15137/TIGIT, and expect to select the lead antibody for this target by end of the first quarter of 2017."

Dr. Cohen-Dayag continued, "It is becoming clearer that more closely tailored combination therapies will be able to address, in the future, a higher percentage of cancer patients. We therefore have high expectations for our diversified portfolio of novel immune checkpoint candidates."


Internally designated as CGEN-15137, TIGIT was discovered by Compugen utilizing its in silico predictive discovery infrastructure and experimentally validated as an immune checkpoint. The findings were published by Compugen in the October 2009 issue of the Proceedings of National Academy of Sciences (PNAS) 1. In the same year, two other groups also published papers disclosing the same checkpoint. Antibodies targeting TIGIT being developed by others entered Phase I clinical testing during the past few months.

Additional information regarding the CGEN-15137/TIGIT program, as well as other programs, will be provided today at the Company’s R&D Day in New York City. A live webcast of the event will be available on the investors section of Compugen’s website beginning at 9:00 a.m. ET today. An archived replay of the webcast will be available on the website for 30 days following the event.

About TIGIT
TIGIT is an immune checkpoint that can inhibit both T cell and NK cell activation when bound to its ligand, PVR (also known as CD155). TIGIT expression is increased on tumor infiltrating lymphocytes (TILs), and inhibition of T cell activation by TIGIT has been reported to be mediated by its ability to disrupt DNAM-1 (also known as CD226) costimulatory signals. Recent preclinical studies have shown that antibody antagonists of TIGIT can potently inhibit tumor growth in mouse cancer models when combined with PD1 pathway blockade.

European Commission Grants Conditional Marketing Approval for AbbVie’s VENCLYXTO™ (venetoclax) Monotherapy for Appropriate Patients with Difficult-To-Treat Chronic Lymphocytic Leukaemia

On December 8, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported the European Commission (EC) has granted conditional marketing authorization for VENCLYXTO (venetoclax) monotherapy for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor (Press release, AbbVie, DEC 7, 2016, View Source [SID1234516994]).1 The EC approved VENCLYXTO as a first-in-class, oral, once-daily medicine that selectively inhibits the function of the BCL-2 protein.1 BCL-2 prevents the natural death of cells, including CLL cells.1 VENCLYXTO is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the U.S. and by AbbVie outside of the U.S.

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"The European approval of VENCLYXTO is an important step forward for patients with chronic lymphocytic leukaemia in Europe," said Richard Gonzalez, chairman of the board and chief executive officer of AbbVie. "AbbVie has led the way in researching ways to block BCL-2 activity, and, as the first approved BCL-2 inhibitor in Europe, VENCLYXTO delivers on AbbVie’s promise to develop cancer medicines where an unmet need exists."

CLL, a cancer of the bone marrow and blood, is typically a slow-progressing cancer.2 The 17p deletion, a genomic alteration in which a part of chromosome 17 is absent, is found in 3 to 10 percent of previously untreated CLL cases and up to 30 to 50 percent of relapsed or refractory CLL cases.3 A TP53 mutation occurs in 8 to 15 percent of patients at first-line treatment and up to 35 to 50 percent of cases in refractory CLL.3 Those with the 17p deletion or TP53 mutations often have a particularly poor prognosis3 and a median life expectancy of less than two to three years with current standard-of-care regimens.4

Conditional marketing authorization is granted to medicines that address an unmet medical need, where the benefit of its immediate availability to patients outweighs the risk of limited data availability, and where comprehensive data will be provided.5

"Results from the clinical trial program show that VENCLYXTO provides significant overall response among both patients with previously treated CLL with 17p deletion and patients with CLL who had been previously treated with and failed a B-cell receptor inhibitor," said Stephan Stilgenbauer, M.D., Ulm University, Germany, investigator in the VENCLYXTO clinical trial program. "While advances in treatment over the past few years have been meaningful for patients in Europe living with CLL, new options are still needed."

"The approval of VENCLYXTO represents an innovation in treatment options for people living with CLL who may harbor the 17p deletion or TP53 mutation and typically have a poor prognosis," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "With this approval, we are pleased to be able to bring a new treatment option to patients in more countries around the world with this difficult-to-treat cancer."

In October 2016, AbbVie announced the European Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion for the conditional marketing authorization of VENCLYXTO.6 Additionally, the European Medicines Agency (EMA) granted Orphan Drug Designation to VENCLYXTO for the treatment of multiple myeloma,7 a type of cancer that forms in plasma cells in bone marrow,8 and for diffuse large B-cell lymphoma (DLBCL),9 an aggressive type of lymphoma and the most common form of non-Hodgkin lymphoma (NHL).10 Previously, the EMA granted Orphan Drug Designation to VENCLYXTO for the treatment of CLL6 and for the treatment of acute myeloid leukaemia (AML),11 the most common type of acute leukaemia in adults.12 Orphan Drug Designation is granted to therapies aimed at the treatment, prevention or diagnosis of life-threatening diseases that affect no more than five in 10,000 persons in the EU and for which no satisfactory therapy is available. The medicine must also provide significant benefit to those affected by the condition.13

VENCLYXTO Clinical Trial Program
Study 1: Previously treated patients with CLL harboring 17p deletion
The safety and efficacy of VENCLYXTO was evaluated in a Phase 2, single arm, open-label, multi-center study in 107 patients (main cohort) with previously treated CLL with 17p deletion, with an additional 51 patients in a safety expansion cohort. Patients followed a 4- to 5-week dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally 400 mg once-daily. Patients continued to receive VENCLYXTO 400 mg once daily until disease progression or unacceptable toxicity was observed. The median time on treatment at the time of evaluation was 12 months (range: 0 to 22 months) for the main cohort. The median time on treatment for the combined cohort (main cohort plus safety expansion cohort, N=158) was 25 months (range: 0.5 to 50 months). The main cohort was assessed by an independent review committee, while the combined cohort was assessed by the investigators. Results showed:1

The primary efficacy endpoint, overall response rate (ORR), was 79 percent (95% Confidence Interval [CI]: 70.5, 86.6) in the main cohort and 77 percent (95% CI: 69.9, 83.5) in the combined cohort.
Median duration of response (DOR) was not reached in the main cohort and was 27.5 months (95% CI: 26.5, NR) for the combined cohort.
Median progression-free survival (PFS) was not reached in the main cohort and was 27.2 months (95% CI: 21.9, NR) for the combined cohort.
Complete remission (CR) plus complete remission with incomplete marrow recovery (CRi) was achieved in 7 percent of patients in the main cohort and 18 percent of patients in the combined cohort.
Partial remission (PR) was reached in 69 percent of patients in the main cohort and 53 percent of patients in the combined cohort.
Nodular partial remission (nPR) was reached in 3 percent of patients in the main cohort and 6 percent of patients in the combined cohort.
Minimal residual disease (MRD) was evaluated in 93 of 158 patients who achieved CR, CRi or nPR with VENCLYXTO. MRD negativity in peripheral blood was achieved in 27 percent (41/158) of patients, including 15 patients who were MRD negative in the bone marrow. MRD negativity is an exploratory endpoint.
Study 2: Patients with CLL who have failed a B-cell receptor inhibitor
The safety and efficacy of VENCLYXTO was evaluated in a Phase 2 open-label, multi-center, non-randomized study in patients with CLL who had been previously treated with and failed ibrutinib (median number of prior oncology treatments was 4 [range: 1 to 12]) or idelalisib (median number of prior oncology treatments was 3 [range: 1 to 11]) therapy. Patients received VENCLYXTO via a recommended dose-titration schedule. Patients continued to receive VENCLYXTO 400 mg once daily until disease progression or unacceptable toxicity was observed. At the time of data cut-off, 64 patients were enrolled and treated with VENCLYXTO. Of these, 43 patients had received prior ibrutinib therapy (Arm A) and 21 had received prior idelalisib therapy (Arm B). Of the patients, 91 percent (39/42) in Arm A and 67 percent (14/21) in Arm B had relapsed on or were refractory to ibrutinib and idelalisib, respectively. Chromosomal aberrations were 11q deletion (30%, 19/62), 17p deletion (36%, 23/61), TP53 mutation (26%, 16/61) and unmutated IgVH (86%, 36/42). At the time of evaluation, median duration of treatment with VENCLYXTO was 11.7 months (range: 0.1 to 17.9 months). Results showed:1

The primary efficacy endpoint, ORR, was 67 percent (95% CI: 51.5, 80.9) in Arm A, 57 percent (95% CI: 34, 78.2) in Arm B and 64 percent (95% CI: 51.1, 75.7) in the total study population based on investigator assessment. The efficacy data were further evaluated by an IRC demonstrating a combined ORR of 67 percent (Arm A: 70 percent, Arm B: 62 percent).
The ORR for patients with 17p deletion/TP53 mutation was 71 percent (15/21) (95% CI: 47.8, 88.7) in Arm A and 50 percent (1/2) (95% CI: 1.3, 98.7) in Arm B.
For patients without 17p deletion/TP53 mutation, the ORR was 68 percent (15/22) (95% CI: 45.1, 86.1) in Arm A and 63 percent (12/19) (95% CI: 38.4, 83.7) in Arm B.
Median PFS and DOR were not reached with median follow-up of approximately 12 months for Arm A and 9 months for Arm B.
CR plus CRi was achieved in 7 percent of patients in Arm A, 14 percent of patients in Arm B and 9 percent of patients in the total patient population, per investigator assessment.
PR was reached in 56 percent of patients in Arm A, 43 percent of patients in Arm B and 52 percent of patients in the total patient population, per investigator assessment.
nPR was reached in 5 percent of patients in Arm A, zero percent in Arm B and 3 percent in the total patient population, per investigator assessment.
The safety of VENCLYXTO is based on pooled data of 296 patients treated in two Phase 2 studies and one Phase 1 study. In all, the studies enrolled patients with previously treated CLL, including 188 patients with 17p deletion and 92 patients who had failed a B-cell receptor inhibitor. The most commonly occurring adverse reactions (?20 percent) of any grade in patients receiving VENCLYXTO were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation. The most frequently reported serious adverse reactions (?2 percent) were pneumonia, febrile neutropenia and tumour lysis syndrome (TLS). Discontinuations due to adverse reactions occurred in 9.1 percent of patients. Dosage adjustments due to adverse reactions occurred in 11.8 percent of patients.1

About VENCLYXTO (venetoclax)
VENCLYXTO (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.1 It is also being evaluated for the treatment of patients with various blood cancer types.1,14,15,16,17 The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.1 VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.1

VENCLYXTO is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in Phase 3 clinical trials for the treatment of relapsed/refractory CLL, along with studies in several other cancers.

In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval of VENCLEXTA (venetoclax) tablets for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.18 The FDA approved this indication under accelerated approval based on overall response rate, and continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.18 Venetoclax is also currently approved in Argentina, Puerto Rico and Canada. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Important EU Safety Information

Contraindications
Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced. Hypersensitivity to the active substance or to any of the excipients is contraindicated.

Special Warnings & Precautions for Use
Tumour lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumour burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS.

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations
VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

UC Davis to Conduct Phase 2 Trial of the Combination of TG4010 with Opdivo® (nivolumab) for 2nd Line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

On December 7, 2016 Transgene (Paris:TNG), a company focused on designing and developing targeted immunotherapies for the treatment of cancer and infectious diseases, reported the signature of a collaborative arrangement with UC Davis (USA, California) to support an investigator-initiated study led UC Davis Medical Center that will evaluate TG4010 in combination with Opdivo (nivolumab) for the treatment of 2nd line metastatic non-small cell lung cancer (NSCLC) (Press release, Transgene, DEC 7, 2016, View Source [SID1234516993]). This trial is supported by Transgene through financial support and supply of TG4010 and by Bristol-Myers Squibb through supply of nivolumab for use in the clinical study.

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Karen Kelly, MD, a world-renowned expert of lung cancer and Associate Director for Clinical Research at UC Davis Comprehensive Cancer Center, is the Principal Investigator of this Phase 2 study. The enrollment of the first patients is expected in the coming weeks.

TG4010 is an active immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2). TG4010, which is based on a modified vaccinia virus (MVA), induces an immune response against MUC1 expressing tumors, such as non-squamous NSCLC. Its mechanism of action and excellent safety profile make TG4010 a very suitable candidate for combinations with other therapies, such as Opdivo, a PD-1 immune checkpoint inhibitor that is designed to prevent the PD-1 pathway from suppressing the immune system’s response against tumors. Opdivo is approved in the USA for the 2nd line treatment of advanced non-small cell lung cancer.

This study is a Phase 2, multi-center, single arm, open-label trial. Its primary objective is to evaluate the efficacy (Overall Response Rate) of the combination of TG4010 plus Opdivo in patients with stage IV non-squamous NSCLC who have progressed after one line of platinum-based chemotherapy. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response and safety.

Immunotherapy, particularly the use of immune checkpoint blockers such as the anti-PD-1 Opdivo, is rapidly transforming cancer care, due to its demonstrated antitumor activity. There is increasing interest among the medical community in exploring whether combining different immunotherapy agents could provide additional benefit to patients. This study will evaluate the efficacy of this combination of immunotherapies that target distinct stages of the immune cycle.

Philippe Archinard, Chairman and CEO of Transgene, added: "We are delighted to start a collaboration with a highly respected clinical investigator, Dr. Karen Kelly of UC Davis. We are also glad that Bristol-Myers Squibb, a leader in cancer immunotherapy research, is supporting this trial. The interest from such a leading company in investigating the potential of TG4010 in combination with Opdivo supports confidence in researching whether our active immunotherapies are complementary to an immune checkpoint inhibitor."

About non-small cell lung cancer
Lung cancer is one of the most common malignancies worldwide with an estimated 1.8 million new cases annually. It is also a leading cause of cancer-related deaths, accounting for an estimated nearly 1.6 million deaths in 2012 (Source: GLOBOCAN 2012). NSCLC represents approximately 85% or more of all lung cancers of which about 75% are non-squamous. According to the American Cancer Society, deaths due to lung cancer were expected to account for about 27% of all U.S. cancer deaths in 2015, more than any other cancer type. It is estimated that there will be over 221,000 new cases of lung cancer in the U.S. in 2015 and over 158,000 deaths due to this disease. Recent statistics from GLOBOCAN 2012 estimate that there were over 448,000 cases of lung cancer in Europe in 2012, and over 388,000 people in Europe died from this disease. Advanced lung cancer remains one of the cancer types with the worst prognosis (five-year survival rate for advanced NSCLC of less than 5%), underlining the unmet need in this disease.

About TG4010
TG4010 is a novel MUC1 targeting immunotherapy. This therapeutic vaccine is in development for the treatment of metastatic NSCLC. TG4010 is a recombinant vaccinia virus of the Ankara strain (MVA) expressing the coding sequences of the MUC1 antigen and of the cytokine, Interleukin-2 (IL2). In healthy cells, the MUC1 protein is normally found on the surface of epithelial cells in many types of tissue and works to protect these cells. In tumor cells, several modifications of MUC1 can occur: over expression, hypo-glycosylation and changes in cellular localization. These changes transform the MUC1 protein into a highly immunogenic tumor associated antigen (TAA) and make it an attractive target for cancer immunotherapy. Thus, the strategy is to induce MUC1 antigen expression in a non-tumor environment, i.e., where the immune system is fully functional, in order to induce both innate and MUC1 specific adaptive immunity. In addition to NSCLC, the MUC1 TAA is expressed in many other solid tumor types, such as lung, breast, colorectal, kidney and prostate cancers. The results from the Phase 2b part of the Phase 2b/3 TIME trial with TG4010 immunotherapy in non-small cell lung cancer (NSCLC) have been published in the peer-reviewed medical journal, The Lancet Oncology in December 2015.