On May 18, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported the release of an abstract on its drug candidate PB272 (neratinib) that will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which will be held June 3–7, 2016, in Chicago (Press release, Puma Biotechnology, MAY 18, 2016, View Source [SID:1234512548]). Abstracts are available to the public online on the ASCO (Free ASCO Whitepaper) website: www.abstract.asco.org.

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Abstract #516: Phase II Trial of Neratinib for HER2 Mutated, Non-Amplified Metastatic Breast Cancer (HER2mut MBC)

Poster Session: Breast Cancer-HER2/ER; Sunday, June 5, 8:00–11:30 a.m. CDT, Hall A, Poster Board #4

The abstract will be included in the Poster Discussion Session: Breast Cancer—HER2/ER; Sunday, June 5, 11:30 a.m.–12:45 p.m. CDT, June 5, Hall D2

On May 18, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported that clinical data on brigatinib, its investigational anaplastic lymphoma kinase (ALK) inhibitor, and Iclusig (ponatinib) will be presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held in Chicago, June 3 to 7, 2016 (Press release, Ariad, MAY 18, 2016, View Source;p=irol-newsArticle&ID=2169511 [SID:1234512549]).

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"The first early results are now available from the pivotal Phase 2 ALTA trial of brigatinib in patients with ALK+ non-small cell lung cancer whose disease had progressed on crizotinib therapy, and show encouraging early response rates and progression-free survival. We look forward to the oral presentation at ASCO (Free ASCO Whitepaper), which will reflect approximately three months of additional follow-up, including the opportunity for all responses to be confirmed," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "The presentation at ASCO (Free ASCO Whitepaper) will also include details on CNS activity."

The ALTA trial

The primary endpoint of the ALTA (ALK in Lung Cancer Trial of AP26113) trial is investigator-assessed confirmed objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Key secondary endpoints include progression free survival (PFS), confirmed ORR assessed by an independent review committee (IRC), CNS response and PFS, duration of response, safety and tolerability. Brigatinib received both Breakthrough Therapy and Orphan Drug designations from the U.S. Food and Drug Administration for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) whose tumors are resistant to crizotinib.

The 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.

Abstract Highlights on ALTA Trial

Data as of December 7, 2015

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 7-day lead-in at 90 mg and 112 patients in Arm A at the 90 mg dose level). The last patient enrolled in the study in September 2015.
The median time on treatment was 23 weeks in Arm B and 25 weeks in Arm A.
Investigator-assessed ORR in Arm B was 54% (49 confirmed responses plus 10 single responses awaiting confirmation), including 5 confirmed complete responses. ORR in Arm A was 46% (39 confirmed responses plus 12 single responses awaiting confirmation), including one confirmed complete response.
In the earlier Phase 1/2 trial, of ALK+ NSCLC patients treated with prior crizotinib, 10 responded at the 90 mg dose level and 19 responded at the 180 mg dose level (with a 90 mg lead-in). Of these initial responses, 7 of 10 (70%) and 18 of 19 (95%) respectively were confirmed.
Median PFS was 11.1 months and 8.8 months in Arm B and Arm A, respectively.
The most common treatment-emergent AEs, grade 3 or higher, (Arm B/A) were: increased creatine phosphokinase (CPK) (8%/3%), hypertension (5%/4%), pneumonia (5%/3%), rash (4%/1%), increased lipase (2%/3%) and pneumonitis (3%/2%).
A subset of pulmonary adverse events with early onset occurred in 6% of all patients (in 3% of patients, events were grade 3 or higher); no such events occurred after dose escalation to 180 mg QD in Arm B.
Discontinuations and dose reductions due to AEs (Arm B/A) were 6%/3% and 18%/7%, respectively.
In Arm B 67% of patients had brain metastases and in Arm A 71% of patients had brain metastases. CNS efficacy data will be included in the full ASCO (Free ASCO Whitepaper) presentation.
The schedule and meeting location for the sessions at ASCO (Free ASCO Whitepaper), together with the abstract information and ARIAD’s investor event, are listed below:

Brigatinib Oral Presentation

Title:
Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)- refractory ALK+ non–small cell lung cancer (NSCLC): first report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA)
Abstract No: 9007
Presenter: Dong-Wan Kim, M.D., Ph.D., (Seoul National University Hospital)
Oral Session: Lung Cancer – Non-Small Cell Metastatic
Session Date & Time: Monday, June 6, 2016, 9:45 a.m. to 12:45 p.m. (CT)
Presentation Time: 11:57 a.m. to 12:09 p.m.
Location: Arie Crown Theater

Brigatinib Posters

Title:
Activity of brigatinib (BRG) in crizotinib (CRZ) resistant patients (pts) according to ALK mutation status
Abstract No: 9060
Presenter: Scott Gettinger, M.D., (Yale Cancer Center)
Poster Session: Lung Cancer – Non-Small Cell Metastatic
Date & Time: Saturday, June 4, 2016, 8:00 a.m. to 11:30 a.m. (CT)
Location: Hall A; poster #383

Title:
Activity and safety of brigatinib (BRG) in patients (pts) with ALK+ non–small cell lung cancer (NSCLC): Phase (ph) 1/2 trial results.
Abstract No: 9057
Presenter: Corey J. Langer, M.D., (University of Pennsylvania Abramson Cancer Center)
Poster Session: Lung Cancer – Non-Small Cell Metastatic
Date & Time: Saturday, June 4, 2016, 8:00 a.m. to 11:30 a.m. (CT)
Location: Hall A; poster #380

Ponatinib Posters

Title:
4-year results of the ponatinib phase 2 PACE trial in patients (pts) with heavily pretreated leukemia
Abstract No: 7013
Presenter: Jorge E. Cortes, M.D., (The University of Texas MD Anderson Cancer Center)
Poster Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Date & Time: Monday, June 6, 2016, 11:30 a.m. to 12:30 p.m. (CT)
Location: Hall A; poster #5
Discussion: Monday, June 6, 2016, 11:30 a.m. – 12:45 p.m. in room E354b

Title:
Impact of landmark responses on 3 year (yr) outcomes with ponatinib in heavily pretreated CPCML patients (pts)
Abstract No: 7053
Presenter: Martin C. Müller, M.D. (Universitatsmedizin Mannheim, Mannheim)
Poster Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Date & Time: Monday, June 6, 2016, 11:30 a.m. to 12:30 p.m. (CT)
Location: Hall A; poster #45

Investor and Analyst Briefing and Webcast

A breakfast meeting featuring D. Ross Camidge, M.D., Ph.D., director of thoracic oncology at the University of Colorado to review the updated brigatinib clinical data from the ALTA trial will be webcast live along with slides and can be accessed by visiting the investor relations section of ARIAD’s website at View Source

Date: Monday, June 6, 2016
Time: 7:00 a.m. to 8:00 a.m. (CT)
Location: Hyatt McCormick Place, Prairie Room-B
Space is limited. To request attendance at the meeting, please RSVP to [email protected] by Tuesday, May 31, 2016.

A replay of the investor event will be available on the ARIAD website approximately three hours after the presentation and will be archived on the site for four weeks. To ensure a timely connection to the live webcast, participants should log onto the webcast at least 15 minutes prior to the scheduled start time.

About Iclusig (ponatinib) tablets

Iclusig is approved in the U.S., EU, Switzerland, Canada, Australia and Israel.

Iclusig is a kinase inhibitor indicated in the U.S. for the:

• Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

•Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.
Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning, for additional important safety information.

On May 18, 2016 Cerulean Pharma Inc. (NASDAQ:CERU), a clinical-stage company developing nanoparticle-drug conjugates (NDCs), reported a scheduled poster presentation on CRLX301 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 3-7, 2016, at McCormick Place in Chicago (Press release, Cerulean Pharma, MAY 18, 2016, View Source [SID:1234512550]).

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Details of the poster presentation are as follows:

Title: A Phase 1 Study of CRLX301, a Novel Nanoparticle-Drug Conjugate (NDC) Containing Docetaxel (DOC), in Patients with Refractory Solid Tumors
Poster Session: Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Date and Time: June 5, 2016 8:00-11:30 am CDT
Abstract Number: 2526
Poster Board Number: 226
Location: Hall A
Summary: CRLX301 is generally well tolerated with hints of antitumor activity, and with differentiated pharmacokinetics compared to DOC.

An electronic copy of the poster will be available upon request following ASCO (Free ASCO Whitepaper) by emailing [email protected].

About CRLX301

CRLX301 is a dynamically tumor-targeted NDC designed to concentrate in tumors and slowly release its anti-cancer payload, docetaxel, inside tumor cells. In preclinical studies, CRLX301 delivers up to 10 times more docetaxel into tumors, compared to an equivalent milligram dose of commercially available docetaxel and was similar to or better than docetaxel in seven of seven animal models, with a statistically significant survival benefit seen in five of those seven models. In addition, preclinical data show that CRLX301 had lower toxicity than has been reported with docetaxel in similar preclinical studies. CRLX301 is in Phase 1/2a clinical development.

About Cerulean’s Dynamic Tumor Targeting Platform

Cerulean’s Dynamic Tumor Targeting Platform creates NDCs that are designed to provide safer and more effective cancer treatments. We believe our NDCs concentrate their anti-cancer payloads inside tumors while sparing normal tissue because they are small enough to pass through the "leaky" vasculature present in tumors but are too large to pass through the wall of healthy blood vessels. Once inside tumors, our NDCs enter tumor cells where they slowly release anti-cancer payloads from within the tumor cells.

On May 19, 2016 CTI BioPharma Corp. (CTI) (NASDAQ and MTA:CTIC) reported that data highlighting pacritinib, including additional safety and long-term follow up data from the Phase 3 PERSIST-1 clinical trial, will be presented at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting to be held June 3-7 in Chicago, IL (Press release, CTI BioPharma, MAY 18, 2016, View Source;p=RssLanding&cat=news&id=2169602 [SID:1234512572]). The abstracts are available on the ASCO (Free ASCO Whitepaper) website at www.asco.org. Details regarding the poster presentations, which will include additional data not available in the abstracts, follow.

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Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): Outcomes in patients (pts) with baseline (BL) thrombocytopenia
First Author: Claire Harrison, M.D., Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom
Date/Time: Monday, June 6 at 8:00 a.m.-11:30 a.m. CT
Poster Discussion Session: Monday, June 6, 11:30 a.m.-12:45 p.m. CT in Room E354b
Location: Hall A
Poster Session: Hematologic Malignancies- Leukemia, Myelodysplastic Syndromes, and Allotransplant
Abstract #7011 / Poster Board #3

Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): 60 week follow-up of the phase III PERSIST-1 trial
First Author: Ruben Mesa, M.D., Mayo Clinic Cancer Center, Chair of the Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ
Date/Time: Monday, June 6 at 8:00 a.m.-11:30 a.m. CT
Location: Hall A
Poster Session: Hematologic Malignancies- Leukemia, Myelodysplastic Syndromes, and Allotransplant
Abstract #7065 / Poster Board #57

Outcomes in patients with myelofibrosis and RBC-transfusion dependence in the phase III PERSIST-1 study of pacritinib vs. best available therapy
First Author: Claire Harrison, M.D., Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom
Date/Time: Monday, June 6 at 8:00 a.m.-11:30 a.m. CT
Location: Hall A
Poster Session: Hematologic Malignancies- Leukemia, Myelodysplastic Syndromes, and Allotransplant
Abstract #7066 / Poster Board #58

Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): Long-term follow-up of patient-reported outcomes (PROs) in the phase III PERSIST-1 trial
First Author: Ruben Mesa, M.D., Mayo Clinic Cancer Center, Chair of the Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ
Date/Time: Monday, June 6 at 8:00 a.m.-11:30 a.m. CT
Location: Hall A
Poster Session: Hematologic Malignancies- Leukemia, Myelodysplastic Syndromes, and Allotransplant
Abstract #7067 / Poster Board #59

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy. Clinical studies for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016.

CTI BioPharma and Baxalta Incorporated are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S.

On May 18, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported final overall survival (OS) data from KEYNOTE-006 and new findings from KEYNOTE-001, including updated response rates, duration of response data and three-year OS data with KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with unresectable or metastatic melanoma (Press release, Merck & Co, MAY 18, 2016, View Source [SID:1234512551]). Findings from the final OS analysis from KEYNOTE-006, a phase 3 study evaluating KEYTRUDA as monotherapy compared to ipilimumab, continue to show a significant survival benefit compared to ipilimumab in the first-line setting for advanced melanoma. These data will be presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, June 3 – 7, 2016.

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Long-term OS data from KEYNOTE-006 to be presented at ASCO (Free ASCO Whitepaper) showed that with KEYTRUDA, 55.1 percent and 55.3 percent of patients were alive two years after starting treatment (10 mg/kg every two weeks and three weeks, respectively), compared to 43 percent of patients receiving ipilimumab (hazard ratio: 0.68 [95% CI, 0.53-0.87; p=0.0008] and hazard ratio: 0.68 [95% CI, 0.53-0.86; p=0.0008], respectively). These data will be presented by Dr. Jacob Schachter, Ella Institute for Research and Treatment of Melanoma, Sheba Medical Center, in an oral session on Monday, June 6, from 2:27 to 2:39 p.m. CDT (Location: Arie Crown Theater) (Abstract #9504).

Additionally, data from KEYNOTE-001, including the long-term, three-year OS analysis, were featured in the official ASCO (Free ASCO Whitepaper) Press Program today and will be presented at ASCO (Free ASCO Whitepaper) in Chicago. The primary efficacy measure in KEYNOTE-001 was overall response rate (ORR), and secondary outcome measures included duration of response, progression-free survival (PFS) and OS. The data from KEYNOTE-001 discussed today will be presented along with additional findings in an oral session by Dr. Caroline Robert, Institut Gustave-Roussy, on Monday, June 6, from 2:15 to 2:27 p.m. CDT (Location: Arie Crown Theater) (Abstract #9503).

"With longer-term follow-up from two studies, including a head-to-head trial demonstrating superior survival compared to another immunotherapy, we are continuing to see durability of response with KEYTRUDA as monotherapy," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "These results add to the growing body of data supporting the use of KEYTRUDA as first-line treatment in advanced melanoma, and serve as an important reminder for what we are aiming to achieve through our immuno-oncology development program – enhanced survival for people with cancer."

Findings from the melanoma cohorts of the phase 1b KEYNOTE-001 trial, which included 655 patients, showed an ORR of 33 percent (per RECIST v1.1). At the time of the analysis, a response duration of two years or more was observed in 73 percent of patients. Long-term OS data showed an estimated 40 percent of patients were alive three years after starting treatment with

KEYTRUDA (pembrolizumab), with a median survival of 24.4 months (95% CI, 20.2-29.0). Median duration of response has not yet been reached (range, 1.3+ to 38.8+).

Data from KEYNOTE-001 served as the basis for the U.S. Food and Drug Administration’s accelerated approval of KEYTRUDA in September 2014. The label was subsequently updated to reflect data from the KEYNOTE-006 (phase 3) and KEYNOTE-002 (phase 2) trials, expanding the indication to include treatment of first-line advanced melanoma regardless of BRAF status. Today, KEYTRUDA is approved for the treatment of advanced melanoma in more than 50 countries, including the United States and throughout Europe.

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

Key Findings from the KEYNOTE-006 Study

KEYNOTE-006 is a global, open-label, randomized, pivotal, phase 3 study evaluating KEYTRUDA (pembrolizumab) compared to ipilimumab in patients with unresectable stage III or IV advanced melanoma with no more than one prior systemic therapy. The study randomized 834 patients to receive KEYTRUDA 10 mg/kg every three weeks, KEYTRUDA 10 mg/kg every two weeks, or four cycles of ipilimumab 3 mg/kg every three weeks. The co-primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response and safety, with an exploratory analysis for health-related quality of life (QoL). Tumor response was assessed at week 12, then every 6 weeks thereafter per RECIST v1.1 by independent, central, blinded radiographic review and investigator-assessed, immune-related response criteria.

Based on data to be presented at ASCO (Free ASCO Whitepaper), KEYTRUDA (10 mg/kg every two or three weeks) continued to provide superior OS, PFS and ORR compared to ipilimumab. Specifically, long-term OS data showed 55.1 percent and 55.3 percent of patients were alive two years after starting treatment with KEYTRUDA (every two weeks and three weeks, respectively) compared to 43 percent of patients receiving ipilimumab (hazard ratio: 0.68 [95% CI, 0.53-0.87; p=0.0008] and hazard ratio: 0.68 [95% CI, 0.53-0.86; p=0.0008], respectively). Median OS was not reached for KEYTRUDA; for ipilimumab, median OS was 16 months.

Additionally, an estimated 31.2 percent and 27.8 percent of patients receiving KEYTRUDA (every two weeks and three weeks, respectively) were alive and were disease progression-free at two years compared to 13.5 percent of patients receiving ipilimumab (hazard ratio: 0.61 [95% CI, 0.50-0.75; p<0.0001] for both). For patients receiving KEYTRUDA, ORR was 36.9 percent and 36.1 percent (every two weeks and three weeks, respectively) compared to 13.3 percent for patients receiving ipilimumab (p<0.0001 for both groups).

With longer follow-up, adverse events have remained consistent with previously reported safety data. There was one treatment-related death (due to sepsis) in the KEYTRUDA every two week group.

Key Findings from the KEYNOTE-001 Study

KEYNOTE-001 is a phase 1b multicenter, open-label, multi-cohort trial evaluating KEYTRUDA in various advanced cancers, including advanced melanoma. Patients in the melanoma cohorts received 2 mg/kg or 10 mg/kg of KEYTRUDA every three weeks or 10 mg/kg of KEYTRUDA every two weeks until unacceptable toxicity or disease progression. The major efficacy outcome measure was confirmed ORR as assessed by blinded independent central review using RECIST v1.1. Tumor response was assessed every 12 weeks. The secondary outcome measures included PFS, OS and duration of response.

The findings to be presented at ASCO (Free ASCO Whitepaper) include updated response rates and duration of response data, as well as three-year OS data from the 655 patients with unresectable or metastatic melanoma and progression of disease. All patients were followed for at least two years, with some being followed for almost four years (with median follow-up duration of 32 months).

Of those patients who responded to treatment with KEYTRUDA (pembrolizumab), a complete response (CR) was observed in 10 percent of patients. Among the 61 patients who stopped treatment once a complete response had occurred, the response duration ranged from 17+ to 44+ months (median duration not reached). Only two patients who had a complete response experienced disease progression after stopping treatment. In addition, long-term survival data showed that 40 percent of patients survived three years after starting treatment with KEYTRUDA (n=655).

With longer follow-up, adverse events have remained consistent with previously reported safety data. Immune-mediated treatment-related adverse events observed in this trial were hypothyroidism (9.6%), pneumonitis (4.3%), hyperthyroidism (2.3%), colitis (2.3%), uveitis (1.5%), hepatitis (0.9%), and nephritis (0.5%).

About KEYTRUDA (pembrolizumab) Injection 100 mg

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 indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. 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.

Immune-mediated colitis occurred in 31 (2%) of 1567 patients, including Grade 2 (0.5%), 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.

Immune-mediated hepatitis occurred in 16 (1%) of 1567 patients, including Grade 2 (0.1%), 3 (0.7%), 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.

Hypophysitis occurred in 13 (0.8%) of 1567 patients, including Grade 2 (0.3%), 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 for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1567 patients, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients, including Grade 3 (0.1%) hypothyroidism. Thyroid disorders can occur at any time during treatment. 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.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in 7 (0.4%) of 1567 patients, including Grade 2 (0.2%), 3 (0.2%), 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.

Other clinically important immune-mediated adverse reactions can occur. 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 (pembrolizumab) 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 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 1567 patients: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 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.

In Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions with KEYTRUDA (pembrolizumab) vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

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 Oncology, 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 more than 270 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.