On December 8, 2016 The Cancer Research Technology (CRT) Pioneer Fund reported an investment to develop a promising new class of drugs for blood cancer (Press release, Cancer Research Technology, AUG 8, 2016, View Source [SID1234523175]).

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The funding will support Cancer Research UK-funded scientists at The Institute of Cancer Research, London, who are designing the drugs, to treat patients with Diffuse Large B-Cell Lymphoma – a sub-type of Non-Hodgkin Lymphoma.

The CRT Pioneer Fund was launched in 2012 by CRT, the commercialisation arm of Cancer Research UK, and the European Investment Fund (EIF) in 2012 to bridge the funding gap between cancer drug discovery and early drug development. It is managed by Sixth Element Capital LLP and has received additional investment from investment company BACIT Limited.

The drugs will target a protein called B-Cell Lymphoma 6 (BCL6). It plays an important role in maintaining levels of antibody-secreting B-cells in the blood, and is an essential part of the body’s immune defences. Research shows that BCL6 is overactive in patients with Diffuse Large B-Cell Lymphoma and that this helps drive cancer growth. This suggests that drugs designed to inhibit BCL6 could help to treat the disease.

Ian Miscampbell, managing partner of Sixth Element Capital LLP, said: "We’re delighted to announce the CRT Pioneer Fund’s investment in the BCL6 project and to be collaborating with the Institute of Cancer Research and their world class team once again. This investment will pave the way for potential new cancer drugs to be developed and taken into phase I clinical trials."

Non-Hodgkin Lymphoma affects around 13,400 people in the UK each year and around 4,800 people die from it. Diffuse Large B-Cell Lymphoma is the most common type of Non-Hodgkin Lymphoma, accounting for about 40 per cent of cases.

Professor Paul Workman, chief executive of The Institute of Cancer Research, London, said: "Diffuse Large B-Cell Lymphoma is a fast-growing and all-too-often deadly cancer. Current therapies for the disease have serious side effects and many patients relapse. We need innovative new ways of treating the disease to give patients their best chance of overcoming it.

"The support from the CRT Pioneer Fund will help us to make progress with this challenging project, with the aim of designing a whole new class of potential cancer drugs that target BCL6 – a protein that is crucial for the cancer’s rapid progression."

Dr Phil L’Huillier, Cancer Research Technology’s director of business development, said: "We’re delighted that the CRT Pioneer Fund is providing key investment exactly where it’s needed, to help accelerate this potential new treatment through to early clinical trials, so it can start to benefit patients as quickly as possible. This announcement marks the ninth investment made by the CPF, providing potential new options for patients that might otherwise never have made it beyond the lab."

On December 8, 2016 GTx, Inc. (Nasdaq: GTXI) reported positive initial data from its ongoing open-label enobosarm Phase 2 clinical trial in women with advanced, estrogen receptor positive (ER+), androgen receptor positive (AR+) breast cancer (Press release, GTx, DEC 8, 2016, View Source;p=RssLanding&cat=news&id=2228459 [SID1234517002]). The pre-specified threshold for success of the trial was met early in the 9 mg cohort with 9 patients achieving a clinical benefit response at 24 weeks among the first 22 evaluable patients in that cohort, as reported by the Company on November 28, 2016. Clinical Benefit Response (CBR) is defined as a complete response (CR), partial response (PR) or stable disease (SD), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) at 24 weeks of treatment.

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For the 9 patients achieving CBR in the 9 mg cohort, the results are as follows:

2 patients demonstrated a PR with a mean reduction in tumor size of 44.4% from baseline;
7 patients exhibited SD; and of these patients:
3 patients had measurable disease with an average reduction in tumor size from baseline of approximately 13%. One of these 3 patients, whose tumor size was reduced by 25% from baseline at 24 weeks, had demonstrated a PR (≥ 30% reduction) at 12 weeks.
4 patients with SD had bone-only disease, which made them unevaluable for PR.
The mean duration of response at the time of the Company’s November 28, 2016 announcement for the 9 responders was 31 weeks, with 7 of the 9 patients still on study drug.
Based on a current CBR of 41%, the Company estimates the 95% confidence interval for the CBR rate in the 9 mg cohort to be 22% to 62% at study completion.
In addition to the CBR, the trial is evaluating the Best Overall Response (BOR) rate of the patients, defined as a CBR at any time point during treatment with enobosarm. Of the 22 evaluable patients:

7 patients who did not show CBR at 24 weeks had stable disease earlier at 12 weeks, corresponding to an approximately 73% (16/22) BOR;
3 patients discontinued early due to reasons other than progression, and therefore did not have post treatment scans; and
When the analysis is performed with those patients who had post treatment follow-up scans, the CBR is 47% (9/19), with a BOR of 84% (16/19).
The baseline demographics for the 22 evaluable patients are consistent with advanced breast cancer patients who typically undergo multiple treatments. The majority of the 22 patients in the 9 mg dose cohort were heavily pretreated prior to study entry. On average, these patients had 4 prior hormonal therapies for the treatment of their breast cancer and 91% also received prior chemotherapy. Eight of the 22 evaluable patients (36%) had bone-only disease, while the remaining patients had measurable disease per RECIST.

Enobosarm 9 mg appears to be safe and generally well tolerated. The majority of adverse events are grade 1 and 2. The most common adverse events (occurring in ≥10% of patients) reported include nausea (31%), fatigue (18%), and arthralgias (13%). Elevations in transaminases (ALT and AST) during enobosarm treatment were mild with the majority being grade 1 or 2. The independent Safety Monitoring Committee met on December 1, 2016, and recommended that the clinical trial continue as planned.

The trial will continue as planned with a daily dose of either enobosarm 9 mg or 18 mg until 44 evaluable patients in each cohort have been enrolled to better characterize the CBR, evaluate secondary endpoints and describe the safety profile of the dose levels. The Company plans to report top-line clinical results following completion of the clinical trial, which is anticipated to occur in mid-2017.

"From my perspective as a clinician, the results with enobosarm in treating advanced breast cancer are encouraging. The goal for treating advanced breast cancer patients who have exhausted other hormonal therapies for metastatic disease and whose only treatment alternative is chemotherapy, is to achieve stabilization of their disease," said Dr. Beth Overmoyer, from the Dana Farber Cancer Institute and the Harvard Medical School, who is the lead investigator for the clinical trial. "Stabilization of disease and delaying subsequent chemotherapy treatment while maintaining quality of life benefits a large population of patients with hormone-receptor positive metastatic breast cancer."

"We are pleased that the study has demonstrated an acceptable clinical benefit rate sooner than initially anticipated in the 9 mg cohort, which we believe warrants further development of the drug candidate for the treatment of advanced metastatic breast cancer," said Robert J. Wills, Ph.D., Executive Chairman of GTx.

About the Phase 2 Clinical Trial in ER+/AR+ Breast Cancer

The open-label, multi-center, multinational Phase 2 clinical trial (NCT02463032) will assess the efficacy and safety of orally administered enobosarm in up to 88 evaluable patients with metastatic or locally advanced, ER+/AR+ breast cancer. Patients will receive orally-administered enobosarm (9 mg or 18 mg) daily for up to 24 months. The two dose cohorts in the trial will be treated independently for the purpose of assessing efficacy. The first stage of evaluation will be assessed among the first 18 evaluable patients for each cohort. If at least 3 of 18 patients achieve CBR at week 24, then the trial will proceed to the second stage of enrollment for that cohort to assess CBR in a total of 44 evaluable patients per arm. As reported in September and November, 2016, respectively, patients in both the 9 mg and 18 mg cohorts demonstrated sufficient CBR among the first 18 evaluable patients in each such cohort to advance to the second and final stage of the clinical trial.

About Enobosarm

Enobosarm, a selective androgen receptor modulator (SARM) has been evaluated in 24 completed or ongoing clinical trials enrolling over 1,500 subjects, of which approximately 1,000 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg. At all evaluated dose levels, enobosarm was observed to be generally safe and well tolerated. Previously, enobosarm 9 mg has been tested in a Phase 2, proof of concept clinical trial of 22 postmenopausal women with ER+ metastatic breast cancer who have previously responded to endocrine therapy. 17 of the 22 patients were confirmed to be AR+, and 6 of those 17 patients demonstrated CBR at six months. In total, 7 patients (one patient with indeterminate AR status) achieved CBR at six months. The results also demonstrated that, after a median duration on study of 81 days, 41 percent of all patients (9/22) achieved CBR as best response . Enobosarm was well tolerated. The most common adverse events reported were pain, fatigue, nausea, hot flash/night sweats, and arthralgia.

About ER+/AR+ Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women, and one in eight women will develop invasive breast cancer in their lifetime. In 2012, 1.7 million women world-wide were diagnosed with breast cancer, and there were 6.3 million women alive who had been diagnosed with breast cancer in the previous five years. Clinical assessment of breast cancer provides for routine characterization of receptor status, including the presence or absence of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in the tumor tissue. Receptor status is used to assess metastatic potential as well as to guide treatment decisions. The majority of breast cancers are considered hormone receptor positive (expressing ER or progesterone receptor). Approximately 70 percent of women in the U.S. with breast cancer have ER+ tumors, and 75 to 90 percent of these cancers are also AR+.

Estrogen promotes the growth of breast cancers that are hormone receptor positive. Therefore, treatment is directed at blocking the effects of estrogen on the breast cancer either through blocking the estrogen receptor or minimizing the production of estrogen. This endocrine therapy is the cornerstone of treatment for the majority of women with hormone receptor positive advanced breast cancer and is the preferred initial treatment over alternative approaches such as chemotherapy, due to its efficacy and favorable safety profile. Patients who respond to one endocrine therapy are likely to respond to subsequent hormonal therapies. Therefore, the standard of care for women with hormone receptor positive breast cancer typically involves the sequencing of endocrine agents until intolerance or development of resistance occurs, or metastatic progression necessitates a transition to chemotherapy. Enobosarm may offer an alternate hormonal approach for the treatment of endocrine sensitive advanced breast cancer prior to the introduction of chemotherapy.

On December 8, 2016 Provectus Biopharmaceuticals, Inc. (OTCQB:PVCT, www.provectusbio.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "The Company"), and POETIC, The Pediatric Oncology Experimental Therapeutics Investigators Consortium, a group of 10 top-tier academic medical centers developing new pediatric cancer therapies, reported a joint research agreement focused on pediatric applications of PV-10, an investigational ablative immunotherapy, as a potential treatment for childhood cancers (Press release, Provectus Pharmaceuticals, DEC 8, 2016, View Source [SID1234517003]).

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Peter Culpepper, Interim CEO of Provectus, and Tanya Trippett, M.D., Co-Founder and Executive Director of POETIC, announced the signing of the agreement to establish a framework for collaborative pre-clinical research projects the Company may conduct with members of POETIC within the field of pediatric oncology.

The program will involve collaboration with a number of NCI Cancer Centers that are part of the POETIC group including Memorial Sloan Kettering Cancer Center (MSK), Alberta Children’s Hospital, and other top-tier cancer centers of excellence.

"We are pleased to collaborate with Provectus on this shared vision to advance promising new approaches for cancer that ultimately could lead to new treatments for pediatric patients, leveraging PV-10’s novel characteristics and mechanism of action," said Dr. Trippett.

PV-10 is an injectable formulation of Rose Bengal that is under investigation as an ablative immunotherapy for solid tumor cancers. Provectus has received orphan drug designations of PV-10 from the FDA for melanoma and hepatocellular carcinoma indications. The company is conducting a Phase 3 clinical trial of PV-10 for locally advanced cutaneous melanoma.

"Like many companies in our industry, our development efforts have historically focused on adult cancers," observed Dr. Eric Wachter, Ph.D., Chief Technology Officer of Provectus. "While we remain firmly committed to that core program, this collaboration allows us to team up with top researchers in pediatric oncology to comprehensively assess whether PV-10 has additional potential for pediatric cancers. If this proves successful, we look forward to working with POETIC to move promising indications from the lab to the clinic as quickly as possible, building upon our experience with adult cancers to make this happen."

For more information on this partnership, visit View Source

About POETIC

The Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) was founded in February 2003 by Dr. Lia Gore at the University of Colorado Cancer Center and Dr. Tanya Trippett at Memorial Sloan Kettering Cancer Center. POETIC is composed of ten large academic medical centers in North America with a major emphasis on comprehensive cancer care and research that provide the collaborative and research strength needed to complete intensive phase I and II studies. Each of the institutions is uniquely suited to complete early studies in the pediatric and adolescent populations. POETIC’s assets include membership in NCI-designated Comprehensive Cancer Centers, on-site NIH- funded pediatric and/or general clinical translational research centers (CTRCs/CTSAs), and active collaborations with developmental therapeutics programs for adults at a majority of its member institutions. The availability of strong basic science and translational research programs at the institutions allows focus on the development and evaluation of new therapeutic strategies for patients with cancer and related disorders. POETIC’s pediatric oncology studies focus on the biologic basis for anti-cancer therapy, and in particular, attempt to explore and evaluate new agents and novel combinations of therapies early in clinical development.

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.

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.