On June 1, 2018 Amgen (NASDAQ:AMGN) reported results from the Phase 3 A.R.R.O.W. trial of a once-weekly KYPROLIS (carfilzomib) dosing regimen in patients with relapsed and refractory multiple myeloma (Press release, Amgen, JUN 1, 2018, View Source;p=RssLanding&cat=news&id=2352822 [SID1234527033]). In the trial, KYPROLIS administered once-weekly at 70 mg/m2 with dexamethasone (once-weekly Kd) achieved superior progression-free survival (PFS) and overall response rates (ORR), with a comparable safety profile, versus twice-weekly KYPROLIS at 27 mg/m2 and dexamethasone (twice-weekly Kd). These data were presented during an oral session at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and simultaneously published in The Lancet Oncology.

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"Proteasome inhibitors, like KYPROLIS, are essential in treating patients with multiple myeloma and have helped improve patient outcomes," said Maria-Victoria Mateos, M.D., Ph.D., director of the myeloma unit, University Hospital of Salamanca-IBSAL in Salamanca, Spain. "The A.R.R.O.W. trial showed that when given once per week at the higher dose of 70 mg/m2 with dexamethasone, KYPROLIS achieved superior progression-free survival and overall response rates, with a comparable safety profile, versus the twice-weekly regimen."

The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating this frequently relapsing and difficult-to-treat cancer. A.R.R.O.W. is the first and only randomized Phase 3 head-to-head trial to compare two different dosing schedules of KYPROLIS.

"Through our patient-centric approach, we strive to improve outcomes and experience for patients with multiple myeloma," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "Results from A.R.R.O.W. show patients can benefit from receiving KYPROLIS with a once-weekly dosing schedule. We have engaged with regulatory agencies and look forward to filing as soon as possible to potentially expand our label to include this option for patients with relapsed and refractory multiple myeloma."

A.R.R.O.W. included 478 patients with relapsed and refractory multiple myeloma who received two or three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent (IMiD). Patients in the trial treated with once-weekly Kd achieved a statistically significant 3.6 month improvement in PFS compared to the twice-weekly regimen (median PFS 11.2 months for once-weekly Kd versus 7.6 months for twice-weekly Kd; HR=0.69; 95 percent CI: 0.54-0.88; one-sided p=0.0014).The ORR in patients treated with once-weekly Kd was 62.9 percent versus 40.8 percent for those treated with the twice-weekly regimen (p<0.0001). In addition, 7.1 percent had complete responses or better in the once-weekly arm versus 1.7 percent in the twice-weekly arm in this refractory patient population.

The overall safety profiles of the two arms were comparable, with no new safety risks identified in the once-weekly arm. The most frequently reported treatment-emergent adverse events (greater than or equal to 20 percent) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia and pyrexia.

About A.R.R.O.W.
The A.R.R.O.W. (RAndomized, Open-label, Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with Dexamethasone, Comparing Once-Weekly versus Twice-weekly Carfilzomib Dosing) trial evaluated 478 patients with relapsed and refractory multiple myeloma who have received at least two but no more than three prior therapies, including bortezomib and an immunomodulatory drug. Those included in the study were randomized to receive a 30-minute infusion of once-weekly KYPROLIS (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8 and 15 of subsequent cycles) with dexamethasone (40 mg) versus a 10-minute infusion of twice-weekly KYPROLIS (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with dexamethasone (40 mg). The primary endpoint of the trial was PFS, defined as the time from randomization to disease progression or death. Secondary endpoints included ORR, overall survival, and safety and tolerability. The trial was conducted in approximately 100 sites worldwide. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT02412878.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and life-threatening disease that accounts for approximately one percent of all cancers.2,3 Worldwide, approximately 114,000 people are diagnosed with multiple myeloma each year and 80,000 patient deaths are reported on an annual basis.2

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.4 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.5 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.4,5

Since its first approval in 2012, approximately 80,000 patients worldwide have received KYPROLIS. KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and the United States. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

Important U.S. KYPROLIS (carfilzomib) Safety Information

Cardiac Toxicities

New onset or worsening of pre‐existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with KYPROLIS and remain under close follow‐up.
Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug‐induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. It is recommended to control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life‐threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro‐radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant‐ineligible Patients

In a clinical trial of transplant‐ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KYPROLIS in combination with melphalan and prednisone is not indicated for transplant‐ineligible patients with newly diagnosed multiple myeloma.
Embryo‐fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia

On June 1, 2018 Elios Therapeutics, a biopharmaceutical company developing innovative autologous, particle-delivered, dendritic cell cancer vaccines, reported interim data from the ongoing prospective, randomized, double-blind, placebo-controlled Phase IIb clinical trial of the TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine in patients with Stage III and IV, resected melanoma will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 4, 2018 in Chicago, Illinois (Abstract # 9525) (Press release, Orbis Health Solutions, JUN 1, 2018, View Source [SID1234529912]).

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The planned interim analysis was conducted after the first 120 patients enrolled in the trial had been randomized and treated for at least 6 months. In the per treatment population, TLPLDC showed a meaningful 32 percent reduction in the relative risk of recurrence (TLPLDC 29.4 percent vs. placebo 43.3 percent, p = 0.07) with a median follow-up of 12.6 months. There was no difference in recurrence in the intent-to-treat population (TLPLDC 56.6 percent, placebo 54.1 percent, p=0.65) with 11.9 months median follow-up. Overall, TLPLDC was safe and well-tolerated. In the study, only 33 percent of participants experienced any adverse event, and 98.6 percent of those were grade 1 and 2 events that included injection site reactions and flu-like symptoms. No serious adverse events were reported.

"The interim data evaluating the TLPLDC vaccine as an adjuvant treatment to prevent melanoma recurrences are very encouraging, suggesting clinical activity and demonstrating an attractive safety profile," said George E. Peoples, M.D., chief medical officer at Elios Therapeutics. "These data, combined with the recently reported results of our open label Phase II study demonstrating the synergistic effects of the TLPLDC vaccine in combination with checkpoint inhibitors, suggest a strong rationale for further clinical development in a Phase III program."

Detailed results from the ongoing Phase IIb study evaluating TLPLDC will be presented on Monday, June 4, 2018:

Abstract 9525 (Poster #352): Interim analysis of a prospective, randomized, double-blind, placebo-controlled, Phase IIb trial of the TLPLDC vaccine to prevent recurrence in resected Stage III or IV melanoma patients
Presenter: John W. Myers, M.D., San Antonio Military Medical Center, Houston, TX
Data/Time: Monday, June 4, 2018 from 1:15 PM – 4:45 PM CDT
Session: Melanoma/Skin Cancers Poster Session – Hall A
About the Study Design
Elios Therapeutics is conducting a prospective, randomized, double-blind, placebo-controlled Phase IIb trial to evaluate the safety and efficacy of TLPLDC in patients with resected Stage III and IV melanoma. The primary endpoint is 2 year disease-free survival (DFS).

In the study, 120 participants were randomized (2:1) to receive either TLPLDC vaccine or placebo to prevent recurrence. TLPLDC or placebo vaccines were initiated within 3 months of completion of standard of care (SoC) therapies and were given at 0, 1, 2, 6, 12, and 18 months. Study participants were followed for recurrence per SoC. The interim analysis was pre-specified at 6 months from randomization of the 120th study participant. Survival analysis was performed on the intent-to-treat and per treatment populations. The latter excludes early recurrences during the primary vaccine series (up to 6 months).

About TLPLDC
The TLPLDC (tumor lysate, particle-loaded, dendritic cell) vaccine is an autologous, personalized, therapeutic cancer vaccine designed to stimulate the immune system to recognize tumor cells and fight a patient’s specific cancer. TLPLDC is made from a patient’s own tumor and dendritic cells – the most potent antigen-presenting cells in the body. Once TLPLDC is injected, the tumor lysate-loaded dendritic cells present the tumor antigens to the immune system, stimulating the induction of tumor-specific, activated T cells that are able to find and destroy tumor cells that may remain in the body. TLPLDC is currently being studied as a monotherapy and in combination with SoC checkpoint inhibitor therapy in a Phase IIb clinical trial for the treatment of late-stage melanoma at leading academic cancer centers in the United States.

On June 1, 2018 Cambrex Corporation (NYSE: CBM), a leading manufacturer of small molecule innovator and generic Active Pharmaceutical Ingredients (APIs), reported that Steven Klosk, President and Chief Executive Officer, will present at the Jefferies 2018 Global Healthcare Conference on June 7, 2018 at 9:30 a.m. EDT in New York City (Press release, Cambrex, JUN 1, 2018, View Source [SID1234527035]).

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The live audio webcast and slide presentation can be accessed from the Cambrex website at www.cambrex.com in the Investors section under "Webcasts & Presentations", and a replay will be available for 90 days after the live event concludes

On June 1, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that long-term phase 1 safety and efficacy data for DS-8201, an investigational HER2-targeting antibody drug conjugate (ADC), in 241 heavily pretreated patients with HER2-expressing breast, gastric and other solid cancers who received recommended expansion doses of 5.4 mg/kg or 6.4 mg/kg, will be presented today during an Oral Abstract Session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Abstract 2501; 2:57 – 3:09 PM CDT) (Press release, Daiichi Sankyo, JUN 1, 2018, View Source [SID1234527018]).

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Updated preliminary results in a subgroup analysis of 34 patients with heavily pretreated HER2-low-expressing metastatic breast cancer (defined as IHC 2+/ISH- or IHC 1+/ISH- tumors) showed that DS-8201 demonstrated a confirmed overall response rate of 50.0 percent (17/34 patients) and a disease control rate of 85.3 percent (29/34 patients). Preliminary estimates of median duration of response have reached 11 months (95 percent CI: NA) and median progression-free survival has reached 12.9 months (95 percent CI: NA). A total of 14 patients (41.2 percent) were continuing to receive treatment at the time of data cutoff, which was April 18, 2018.

"HER2-targeted treatments historically have not been effective in treating metastatic breast cancer with low levels of HER2 expression," said Hiroji Iwata, MD, PhD, Vice Director and Chief of Breast Oncology at Aichi Cancer Center Hospital, Nagoya, Japan. "While these results of DS-8201 in the HER2-low-expressing subgroup need to be further confirmed in a larger clinical setting, the preliminary data are intriguing in that we may need to begin rethinking how we approach HER2 as a cell surface target for precision medicine treatment in metastatic breast cancer."

In an updated preliminary subgroup analysis in 99 efficacy evaluable patients with HER2-positive metastatic breast cancer pretreated with ado-trastuzumab emtansine (T-DM1) (as well as trastuzumab and pertuzumab in the majority of cases), DS-8201 demonstrated a confirmed overall response rate of 54.5 percent (54/99 patients) and a disease control rate of 93.9 percent (93/99 patients). Median duration of response and median progression-free survival have not yet been reached. Out of 111 patients with HER2-positive metastatic breast cancer who received at least one dose of DS-8201, 65 (55.1 percent) were continuing to receive treatment at the time of data cut off.

Updated overall safety data across all subgroups of the phase 1 study were reported. The most common adverse events (>30 percent, any Grade), included nausea (68.9 percent), decreased appetite (55.6 percent), alopecia (36.1 percent), vomiting (34.9 percent) and anemia (32.0 percent). Grade 3 adverse events occurring in ≥10 percent of patients included decreased neutrophil count (15.4 percent), anemia (14.9 percent), decreased white blood cell count (12.4 percent) and decreased platelet count (10.4 percent). Twenty-three patients (9.5 percent) discontinued treatment due to adverse events, which included ten (10) Grade 5 adverse events: pneumonitis (4), disease progression (2), interstitial lung disease (ILD) (1), ileus (1), pneumonia aspiration (1) and pneumonia (1). All reported or suspected cases of ILD or pneumonitis currently are under review by an independent ILD adjudication committee.

"These updated results further support our broad and comprehensive development program underway exploring the potential of DS-8201 in HER2-low-expressing breast cancer, which represents about half of all breast cancers, as well as in HER2-positive metastatic breast cancer, where unmet treatment needs remain," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Our pivotal phase 2 trial in HER2-positive metastatic breast cancer is underway, and we are planning phase 3 trials in HER2-low-expressing and HER2-positive metastatic breast cancer in order to determine whether the smart delivery of chemotherapy with DS-8201 may be an effective treatment option against breast tumors that express varying levels of HER2 as a cell surface antigen. A similar biological paradigm is being tested in our other ongoing phase 2 studies of DS-8201 in gastric and colorectal cancer."

HER2-Expressing Gastric Cancer and Other Solid Cancer Subgroup Analyses

Updated preliminary results of two additional subgroup analyses were reported in addition to the two breast cancer subgroups. In the subgroup of 44 patients with HER2-expressing (defined as IHC 3+ or IHC 2+/

ISH-) gastric cancer or gastroesophageal junction adenocarcinoma previously treated with trastuzumab and chemotherapy, DS-8201 demonstrated a confirmed overall response rate of 43.2 percent (19/44 patients) and a disease control rate of 79.5 percent (35/44 patients). Preliminary estimates of median duration of response has reached 7.0 months (95 percent CI: NA) and median progression-free survival has reached 5.6 months (95 percent CI: 3.0, 8.3).

In an updated preliminaryanalysis in 31 evaluable patients with other HER2-expressing solid tumors such as colorectal and non-small cell lung cancer, DS-8201 demonstrated a confirmed overall response rate of 38.7 percent (12/31 patients) and a disease control rate of 83.9 percent (26/31 patients). Preliminary estimates of median duration of response has reached 12.9 months (95 percent CI: 2.8, 12.9) and median progression-free survival has reached 12.1 months (95% CI: 2.7, 14.1).

Unmet Need in HER2-Expressing Breast and Gastric Cancer

About one in five breast and gastric cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.1,2 To be considered HER2-positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH).1,3 IHC test results are reported as: 0, IHC 1+, IHC 2+ or IHC 3+.1,3 A finding of IHC 3+ is considered HER2-positive.1,3 A finding of IHC 2+ is borderline and typically is confirmed by a positive FISH test.1,3

Several unmet needs remain today in HER2-expressing metastatic breast cancer. Many HER2-positive tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease, and there is no current standard of care for HER2-positive tumors after treatment with trastuzumab, pertuzumab and T-DM1.4 Additionally, there are no anti-HER2 therapies indicated for HER2 low-expressing tumors (IHC 2+/FISH- or IHC 1+).

HER2-expressing gastric cancer also is an area of unmet medical need as advances in the treatment of the disease have been limited, largely due to its genetic complexity and heterogeneity.5 Currently, there are no approved HER2-targeting therapy options for patients with HER2-positive advanced gastric cancer after treatment with trastuzumab.

About the DS-8201 Phase 1 Study

The open-label, two-part phase 1 study is currently evaluating DS-8201 in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of the study was to assess the safety and tolerability of DS-8201 and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology.6

In the dose expansion part of the phase 1 study, DS-8201 is given to patients with HER2-positive advanced or metastatic breast cancer and gastric cancer, HER2-low-expressing breast cancer and other HER2-expressing or mutant solid tumors. Patient enrollment in the two breast cancer cohorts and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan. For more information about the study, please visit ClinicalTrials.gov.

About DS-8201

DS-8201 is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in pivotal phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01) in North America, Europe and Asia; pivotal phase 2 development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01) in Japan and South Korea; phase 2 development for HER2-expressing advanced colorectal cancer in North America, Europe and Japan; phase 2 development for unresectable and/or metastatic non-squamous HER2-overexpressing or HER2-mutated non-small cell lung cancer (NSCLC) in North America, Europe and Japan; and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors in the U.S. and Japan.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 has also been granted SAKIGAKE Designation by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of HER2-positive advanced gastric or gastroesophageal junction cancer.

DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

On June 1, 2018 Celgene Corporation (NASDAQ:CELG) reported results from the OPTIMISMM study, a phase III, randomized, open-label, international clinical study of the investigational combination regimen of POMALYST (pomalidomide), bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one prior treatment including lenalidomide (Press release, Celgene, JUN 1, 2018, View Source [SID1234527036]). The results were presented at the 54th Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Scientific Sessions (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois on June 1-5, 2018.

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OPTIMISMM evaluated the efficacy and safety of POMALYST/IMNOVID (pomalidomide) plus bortezomib and low-dose dexamethasone (PVd) versus bortezomib and low-dose dexamethasone (Vd) in patients with early RRMM (1-3 prior lines of therapy). It is the only phase III trial to report results with a triplet combination in patients who have all received prior lenalidomide therapy. With lenalidomide becoming a standard of care, this represents a patient population for which there is a growing unmet medical need.

An analysis of the results found that the treatment with PVd resulted in significantly improved progression-free survival (PFS) and an earlier, deeper, more durable response in these patients compared to Vd treatment. The study, which included a high percentage of patients refractory to lenalidomide (71% in the PVd arm, 69% in the Vd arm), met its primary endpoint of PFS. Those receiving PVd achieved a statistically significant longer PFS than those in the Vd treatment arm (11.20 months vs. 7.10 months, respectively [P= < .0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease progression or death by 39% in the PVd arm. The PFS benefit was observed in the following subgroups of patients: LEN-refractory, LEN-nonrefractory, prior PI exposure or high-risk cytogenetics. Overall response rate (ORR), one of the study’s secondary endpoints, was also significantly higher in the PVd treatment arm, compared to those receiving Vd (82.2% vs. 50.0%, p < 0.001). Additionally, time to treatment response was longer in the PVd arm (0.9 months PVd vs. 1.4 months Vd), complete response was higher in the PVd arm (15.7% PVd vs. 4.0% Vd) and those receiving PVd experienced a longer duration of response than those in the Vd arm (13.7 months PVd vs. 10.9 months Vd.)

In an exploratory sub-group analysis, patients who had received one prior line of therapy reported longer PFS (20.73 months in PVd arm (n=40) vs. 11.63 months in Vd arm (n=41)) and ORR (90.1% in PVd arm vs. 54.8% in Vd arm) with a 46% reduction in the risk of disease progression or death in the PVd treatment arm compared with Vd. Other secondary endpoints included overall survival and safety.

"In the early relapse setting, there remains a need for a deeper understanding of potential treatment options, and in particular for patients who have received prior lenalidomide-based therapy. These are the first phase III clinical findings to report a significant and clinically meaningful progression-free survival improvement in patients who have previously received lenalidomide, a majority of whom are lenalidomide refractory," said Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute.

The most common Grade 3/4 treatment-emergent adverse events (TEAE) were neutropenia (PVd: 42% vs. Vd: 9%), infections (PVd: 31% vs. Vd: 18%) and thrombocytopenia (PVd: 27% vs. Vd: 29%.) Rates of grade 3 or 4 deep vein thrombosis in the PVd vs. Vd arms were 0.7% vs. 0.4% and rates of grade 3 or 4 pulmonary embolism in PVd vs. Vd were 4.0% vs. 0.4%. No events were fatal. SPMs occurred in 3.2% (2.7 per 100 person years) of patients treated with PVd and 1.5% (1.2 per 100 person years) of patients treated with Vd. The most common reason for treatment discontinuation was progressive disease.

"The results of the OPTIMISMM trial continue to bolster the growing body of research into combination regimens based on the foundation of our IMiD therapies," said Nadim Ahmed, President of Hematology and Oncology for Celgene. "We are excited by the findings, as they illustrate the potential for a pomalidomide-based triplet regimen to be used earlier in the treatment course. The study also included patients who received PVd immediately following progression after lenalidomide treatment, a growing and clinically relevant patient population for which no phase III data were available until now."

Pomalyst plus dexamethasone in combination with bortezomib is not approved in any country for any use.

ABOUT OPTIMISMM

OPTIMISMM is the first phase III trial to compare the efficacy and safety of PVd vs. Vd as an early line of therapy in patients with RRMM (with 1-3 prior lines of therapy) and prior lenalidomide (LEN) exposure, including LEN-refractory patients. The study was a multi-center, international, open-label, randomized phase III clinical trial to compare the efficacy and safety of a POMALYST (lenalidomide), bortezomib and low-dose dexamethasone (PVd) treatment regimen to a bortezomib and low-dose dexamethasone (Vd) treatment regimen in patients with relapsed or refractory multiple myeloma.

This global study evaluated 559 patients with relapsed or refractory multiple myeloma who had received up to three prior lines of therapy, including two or more cycles of lenalidomide treatment, who had an ECOG score of PS ≤ 2. Prior treatment with bortezomib was allowed, except for patients whose disease progressed while on a regimen containing bortezomib 1.3 mg/m2 twice weekly dosing. Patients were stratified based on age (≤ 75 years old vs > 75 years old), number of prior antimyeloma regimens (1 vs. > 1), and β2-microglobulin levels ( < 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L) at screening. The median age of the patients was 67 years in the PVd group and 68 years in the Vd group.

Patients were randomized 1:1 to receive PVd or Vd. In 21-day cycles, patients received POMALYST 4 mg/d on days 1-14 (PVd arm only); bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of cycles 1-8 and on days 1 and 8 of cycles 9 and beyond; and dexamethasone 20 mg/d (10 mg if aged > 75 years) on the days of and after receiving bortezomib treatment.

About POMALYST

Indication

POMALYST (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution program called POMALYST REMS.

Venous and Arterial Thromboembolism
Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS
Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm.
Blood Donation: Patients must not donate blood during treatment with POMALYST and for 4 weeks following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.
POMALYST REMS Program: See Boxed WARNINGS
Prescribers and pharmacies must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive POMALYST. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous and Arterial Thromboembolism: See Boxed WARNINGS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hematologic Toxicity: Neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction in patients taking POMALYST in clinical trials, followed by anemia and thrombocytopenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe cutaneous reactions such as SJS, TEN or DRESS, and do not resume therapy.
Dizziness and Confusional State: In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy: In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
ADVERSE REACTIONS

The most common adverse reactions for POMALYST (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.

In the phase III trial, nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥2% higher than control) included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), back pain (19.7%), cough (20%), pneumonia (19.3%), bone pain (18%), edema peripheral (17.3%), peripheral neuropathy (17.3%), muscle spasms (15.3%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥1% higher than control) included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%).

DRUG INTERACTIONS

Avoid concomitant use of POMALYST with strong inhibitors of CYP1A2. Consider alternative treatments. If a strong CYP1A2 inhibitor must be used, reduce POMALYST dose by 50%.

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a POMALYST pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Lactation: There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed child, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST, advise women not to breastfeed during treatment with POMALYST.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients > 65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
Renal Impairment: Reduce POMALYST dose by 25% in patients with severe renal impairment requiring dialysis. Take dose of POMALYST following hemodialysis on hemodialysis days.
Hepatic Impairment: Reduce POMALYST dose by 25% in patients with mild to moderate hepatic impairment and 50% in patients with severe hepatic impairment.
Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces the AUC of pomalidomide by 32% by CYP1A2 induction.
Please see full Prescribing Information, including Boxed WARNINGS.

About Celgene’s Immunomodulatory Drugs

Immunomodulatory Drugs (IMiDs) are Celgene’s proprietary small molecule, orally available compounds for the treatment of some blood cancers. IMiD agents are hypothesized to have multiple mechanisms of action. They have been found to increase activation and proliferation of T cells, and proliferation of the IL-2 protein and activity of CD8+ effector T cells. IMiD agents have also been found to affect the stimulation and expression of natural killer (NK) cells, working within the environment of the cell to stimulate the immune system to attack the cancer cells, as well as attack the cancer cells directly. In addition to immunomodulatory properties, IMiD agents are hypothesized to have tumoricidal and antiangiogenic activity. Celgene’s portfolio of IMiD agents have become a foundation of multiple myeloma research, with a growing number of studies exploring these compounds as combination partners across a range of settings of the disease.