On August 30, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported the release of two abstracts on its drug neratinib that will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress, which will be held September 8 – 12 in Madrid, Spain (Press release, Puma Biotechnology, AUG 30, 2017, View Source [SID1234520342]). Abstracts are available to the public online on the ESMO (Free ESMO Whitepaper) website: www.esmo.org.

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Abstract #1490: Neratinib after trastuzumab-based adjuvant therapy in early stage HER2-positive breast cancer: 5-year analysis of the Phase III ExteNET trial.
The abstract will be presented as a proffered paper oral session on Friday, September 8.

Abstract #177P: Effects of neratinib on health-related quality of life in early stage HER2-positive breast cancer.
The abstract will be displayed as a poster on Monday, September 11.

The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in women with early stage HER2-positive breast cancer.

U.S. Approval of Neratinib (NERLYNX)

Neratinib was approved by the U.S. Food and Drug Administration in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

Indication

NERLYNX is a tyrosine kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

The full prescribing information for NERLYNX is available at www.NERLYNX.com . The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

Important Safety Information

There are possible side effects of NERLYNX. Patients must contact their doctor right away if they experience any of these symptoms. NERLYNX treatment may be stopped or the dose may be lowered if the patient experiences any of these side effects.

Diarrhea

Diarrhea is a common side effect of NERLYNX. The diarrhea may be severe, and you may get dehydrated. Your healthcare provider should prescribe the medicine loperamide for you during your first 2 cycles (56 days) of NERLYNX and then as needed. To help prevent or reduce diarrhea:

You should start taking loperamide with your first dose of NERLYNX.
Keep taking loperamide during the first 2 cycles (56 days) of NERLYNX treatment and then as needed. Your healthcare provider will tell you exactly how much and how often to take loperamide.
While taking loperamide, you and your healthcare provider should try to keep the number of bowel movements that you have at 1 or 2 bowel movements each day.
Tell your healthcare provider if you have more than 2 bowel movements in 1 day, or if you have diarrhea that does not go away.
Contact your healthcare provider right away if you have severe diarrhea or if you have diarrhea along with weakness, dizziness or fever.

Liver Problems

Changes in liver function tests are common with NERLYNX. The patient’s doctor will do tests before starting treatment, monthly during the first 3 months, and then every 3 months as needed during treatment with NERLYNX. NERLYNX treatment may be stopped or the dose may be lowered if your liver tests show severe problems. Symptoms of liver problems may include tiredness, nausea, vomiting, pain in the right upper stomach area (abdomen), fever, rash, itching or yellowing of your skin or whites of your eyes.

Pregnancy

Patients should tell their doctor if they are planning to become pregnant, are pregnant, plan to breastfeed, or are breastfeeding. NERLYNX can harm your unborn baby. Birth control should be used while a patient is receiving NERLYNX and for at least 1 month after the last dose. If patients are exposed to NERLYNX during pregnancy, they must contact their healthcare provider right away.

Common side effects in patients treated with NERLYNX

In clinical studies, the most common side effects seen in patients taking NERLYNX were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis (dry or inflamed mouth, or mouth sores), decreased appetite, muscle spasms, dyspepsia, changes in liver blood test results, nail problems, dry skin, abdominal distention, weight loss and urinary tract infection.

Patients should tell their doctor right away if they are experiencing any side effects. Report side effects to the FDA at 1-800-FDA-1088 or View Source . Patients and caregivers may also report side effects to Puma Biotechnology at 1-844-NERLYNX (1-844-637-5969).

Please see Full Prescribing Information, available at www.NERLYNX.com .

On August 30, 2017 Incyte Corporation (Nasdaq:INCY) reported that the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) has published an abstract (#1214O) containing new and updated data from the ongoing Phase 1/2 ECHO-202 trial evaluating epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with the anti-PD-1 KEYTRUDA (pembrolizumab), marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in patients with advanced melanoma (Press release, Immune Design, AUG 30, 2017, View Source [SID1234520341]).

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"We are encouraged by these additional data from our ECHO-202 trial, which demonstrate robust and durable responses in patients with advanced melanoma treated with the combination of epacadostat and KEYTRUDA," said Steven Stein, M.D., Chief Medical Officer, Incyte. "These results further underscore the potential of this novel immunotherapy combination, and we look forward to reporting more detailed results from this study at ESMO (Free ESMO Whitepaper) next month."

Key Findings from the ECHO-202 Advanced Melanoma Cohort
Results of efficacy evaluable patients (N=54) as of February 27, 2017 include:

ECHO-202 Overall Response Rates (ORR), Disease Control Rates (DCR) and Durability of Response (DoR) in Advanced Melanoma
n/N
(%) All Patients
Treatment-Naïve
Advanced Melanoma
Patients

Treatment-Naïve
Advanced Melanoma
Patients
(epacadostat 100 mg BID)
ORR
30/54
(56)
25/45
(56)
18/30
(60)
8 CR (15)
22 PR (41)
6 CR (13)
19 PR (42)
2 CR (7)
16 PR (53)
DCR
42/54
(78)
35/45
(78)
Not yet reported
DoR 28/30 responses ongoing
Median (range) duration of response: 287.5+ (1+ to 763+) days

Across all efficacy-evaluable advanced melanoma patients, median progression-free survival (PFS) was 12.4 months, with PFS rates of 70 percent, 54 percent, and 50 percent at 6 months, 12 months, and 18 months respectively. In patients who were treatment-naïve for advanced disease, median PFS has not been reached, with landmark PFS rates of 68 percent, 52 percent, and 52 percent at 6 months, 12 months, and 18 months respectively.

Epacadostat in combination with KEYTRUDA was well-tolerated. The most common (≥15 percent) all grade treatment-related adverse events (TRAEs) were fatigue (39 percent), rash (33 percent), pruritus (27 percent), and arthralgia (16 percent). Grade ≥3 TRAEs were observed in 17 percent of patients; the most common were increased lipase (n=4), rash (n=3), and increased amylase (n=2). Three patients discontinued for TRAEs. No treatment-related deaths occurred.

The abstract was made available today on the ESMO (Free ESMO Whitepaper) Congress website at View Source

Updated data from ECHO-202 will be highlighted in an oral presentation on Saturday, 9 September 2017 from 15:00 – 15:15 CET at the ESMO (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain. Following the presentation, Incyte will host an investor conference call and webcast at 17:00 CET (11:00 a.m. ET) on 9 September 2017—the call and webcast can be accessed via the Events and Presentations tab of the Investor section of www.incyte.com.

About ECHO-202 (KEYNOTE-037)
The ECHO-202 study (NCT02178722) is evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with KEYTRUDA. Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + KEYTRUDA 2 mg/kg IV Q3W and epacadostat 300 mg BID + KEYTRUDA 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + KEYTRUDA 200 mg IV Q3W) portions of the trial. For more information about ECHO-202, visit View Source

About ECHO
The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies are evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study investigating KEYTRUDA in combination with epacadostat or placebo for the treatment of patients with unresectable or metastatic melanoma, is also ongoing and fully recruited. For more information about the ECHO clinical trial program, visit www.ECHOClinicalTrials.com.

About Epacadostat (INCB024360)
The immunosuppressive effects of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity on the tumor microenvironment help cancer cells evade immunosurveillance. Epacadostat is an investigational, highly potent and selective oral inhibitor of the IDO1 enzyme. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck and bladder cancer. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitors KEYTRUDA or nivolumab improved response rates compared with studies of the immune checkpoint inhibitors alone.

On August 30, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported more than 60 presentations, including seven late-breaking abstracts, from its Oncology portfolio will be featured at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain, September 8-12 (Press release, Bristol-Myers Squibb, AUG 30, 2017, View Source [SID1234520340]). Presentations of data from company-sponsored studies, clinical collaborations and investigator-sponsored research will explore the potential role of Opdivo (nivolumab) as monotherapy and in combination with Yervoy (ipilimumab); with relatlimab (formerly known as BMS-986016), a fully human monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3); or with chemotherapy in 13 types of cancer and analyses that provide insights into the potential role of biomarkers to predict patients’ treatment response.

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Presentations that illustrate the company’s approach include the following:

Late-breaking research to be featured in Presidential Symposia from CheckMate -238 evaluating the safety and efficacy of adjuvant Opdivo in resected high-risk melanoma, and from CheckMate -214 on Opdivo in combination with Yervoy in previously untreated advanced renal cell carcinoma.
Additional late-breaking presentations featuring the first disclosures of data on Opdivo in advance of surgery in squamous cell cancer of the head and neck, from CheckMate -358, and for Opdivo following induction treatment in triple-negative breast cancer.
Late-breaking updated efficacy results from an ongoing study of relatlimab in combination with Opdivo in patients with melanoma who progressed during prior anti-PD-1/PD-L1 therapy in all-comer and biomarker-enriched populations.
Analyses of emerging biomarkers, including tumor mutation burden, microsatellite instability, LAG-3, T cell infiltration and immune cell profiles, that may help inform more precise treatment approaches. Data on the clinical impact of a fixed duration of Opdivo in non-small cell lung cancer from CheckMate -153 will also be presented.
Additional data evaluating Opdivo-based combinations that are rationally designed based on BMS’ deep understanding of cancer biology, including studies of Opdivo in combination with Yervoy, and the first disclosure of data from ONO-37 on the safety and clinical activity of Opdivo in combination with chemotherapy in previously untreated gastric/gastroesophageal junction cancer.
The full set of data from research investigating the company’s I-O medicines includes the following:

Gastrointestinal Malignancies

•

A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer: updated results and subset analysis by PD-L1 expression (ATTRACTION-02/ONO-4538-12)
Author: N. Boku
Abstract #617O
Proffered Paper Session: Gastrointestinal Tumors, Non-Colorectal 1
Friday, September 8, 2:51–3:03 PM CEST, Barcelona Auditorium

•
Two-year survival and safety update for esophageal squamous cell carcinoma treated with nivolumab (ATTRACTION-01/ONO-4538-07)
Author: Y. Kitagawa
Abstract #638P
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
Interim safety and clinical activity of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated unresectable advanced or recurrent gastric/gastroesophageal junction cancer: part 1 study of ATTRACTION-04/ONO-4538-37
Author: Y-K. Kang
Abstract #671P
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
Nivolumab in patients with advanced chemotherapy-refractory esophagogastric cancer according to microsatellite instability status: CheckMate -032
Author: P. Ott
Abstract #674P
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
ATTRACTION-04/ONO-4538-37: A randomized, multicenter, phase 2/3 study of nivolumab plus chemotherapy in patients with previously untreated advanced or recurrent gastric or gastroesophageal junction cancer
Author: L.-T. Chen
Abstract #777TiP
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
ATTRACTION-05/ONO-4538-38/BMS CA209844: A randomized, multicenter, double-blind, placebo- controlled phase 3 study of nivolumab in combination with adjuvant chemotherapy in Stage III gastric and esophagogastric junction cancer
Author: M. Terashima
Abstract #778TiP
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
Real-world productivity, healthcare resource utilization, and quality of life in patients with advanced gastric cancer in Canada and Europe
Author: G. Maglinte
Abstract #1112PD
Poster Discussion Session: Public Health Policy and Health Economics
Saturday, September 9, 4:30–5:45 PM CEST, Tarragona Auditorium

•
Analysis of tumor PD-L1 expression and biomarkers in relation to clinical activity in patients with deficient DNA mismatch repair/high microsatellite instability metastatic colorectal cancer treated with nivolumab + ipilimumab: CheckMate -142
Author: T. André
Abstract #484PD
Poster Discussion Session: Gastrointestinal Tumors, Colorectal
Sunday, September 10, 3–4 PM CEST, Sevilla Auditorium

Genitourinary Cancer
•
Medical costs and health care resource use in elderly U.S. patients with newly diagnosed metastatic or surgically unresectable urothelial carcinoma using Surveillance, Epidemiology, and End Results (SEER) Medicare data
Author: A. Aly
Abstract #1131P
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
A phase 3, randomized, double-blind, multicenter study of adjuvant nivolumab vs placebo in patients with high-risk invasive urothelial carcinoma (CheckMate -274)
Author: D. Bajorin
Abstract #921TiP
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Impact of tumor mutation burden on nivolumab efficacy in second-line urothelial carcinoma patients: exploratory analysis of the phase 2 CheckMate -275 study
Author: M. Galsky
Abstract #848PD
Poster Discussion Session: Genitourinary Tumors, Non-Prostate
Sunday, September 10, 2:45–4:15 PM CEST, Cordoba Auditorium

•
Epithelial-mesenchymal transition, T cell infiltration, and outcomes with nivolumab in urothelial cancer
Author: M. Galsky
Abstract #850PD
Poster Discussion Session: Genitourinary Tumors, Non-Prostate
Sunday, September 10, 2:45–4:15 PM CEST, Cordoba Auditorium

•
CheckMate -214: Efficacy and safety of nivolumab + ipilimumab v sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups
Author: B. Escudier
Abstract #LBA5
Presidential Symposium II
Sunday, September 10, 4:30–6:20 PM CEST, Madrid Auditorium

Glioblastoma
•
Nivolumab in combination with radiotherapy ± temozolomide: updated safety results from CheckMate -143 in patients with methylated or unmethylated newly diagnosed glioblastoma
Author: M. Lim
Abstract #325O
Proffered Paper Session: CNS Tumors
Friday, September 8, 4–4:12 PM CEST, Alicante Auditorium

Head and Neck Cancer
•
An open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate -358): safety and efficacy of neoadjuvant nivolumab in squamous cell carcinoma of the head and neck
Author: R. Ferris
Abstract #LBA46
Poster Discussion Session: Head and Neck Cancer
Saturday, September 9, 2:45–4:15 PM CEST, Alicante Auditorium

•
Nivolumab vs investigator’s choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: treatment effect on clinical outcomes by best overall response in CheckMate -141
Author: L. Licitra
Abstract #1055P
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Estimated costs of treatment-related adverse events for recurrent or metastatic squamous cell carcinoma of the head and neck in the CheckMate -141 trial
Author: M. Venkatachalam
Abstract #1056P
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Treatment beyond progression with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in the phase 3 CheckMate -141 study: a biomarker analysis and updated clinical outcomes
Author: R. Haddad
Abstract #1043O
Proffered Paper Session: Head and Neck Cancer
Monday, September 11, 3:12–3:24 PM CEST, Granada Auditorium

Melanoma
•
Characterization of complete responses in patients with advanced melanoma who received the combination of nivolumab and ipilimumab, nivolumab or IPI alone
Author: C. Robert
Abstract #1213O
Proffered Paper Session: Melanoma and Other Skin Tumors
Saturday, September 9, 2:45–3 PM CEST, Madrid Auditorium

•
Cost-effectiveness of nivolumab + ipilimumab in first-line treatment of advanced melanoma: analysis using 28-month overall survival from CheckMate -067
Author: J. Sabater
Abstract #1115P
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Late physical, psychological and social consequences of ipilimumab treatment in advanced melanoma
Author: A. Boekhout
Abstract #1260TiP
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Real-world use of ipilimumab and nivolumab monotherapy or in combination in patients with advanced melanoma: results from a retrospective chart review
Author: A. Tarhini
Abstract #1250P
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Regional differences in overall survival in patients with advanced melanoma who received nivolumab combined with ipilimumab or nivolumab alone in a phase 3 trial (CheckMate -067)
Author: J.-J. Grob
Abstract #1222PD
Poster Discussion Session: Melanoma and Other Skin Tumors
Monday, September 11, 11 AM–12:15 PM CEST, Pamplona Auditorium

•
Quality-adjusted survival of combined nivolumab plus ipilimumab or NIVO alone vs IPI among treatment-naïve patients with advanced melanoma: a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis
Author: M. Botteman
Abstract #1223PD
Poster Discussion Session: Melanoma and Other Skin Tumors
Monday, September 11, 11 AM–12:15 PM CEST, Pamplona Auditorium

•
Adjuvant therapy with nivolumab versus ipilimumab after complete resection of Stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate -238)
Author: J. Weber
Abstract #LBA8
Presidential Symposium III
Monday, September 11, 5:15–5:30 PM CEST, Madrid Auditorium

Thoracic Malignancies
•
Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients with advanced non-small cell lung cancer
Author: D. Spigel
Abstract #1297O
Proffered Paper Session: NSCLC, Metastatic 1
Friday, September 8, 4:39–4:51 PM CEST, Madrid Auditorium

•
Efficiency of nivolumab in the treatment of second-line advanced non-squamous non-small cell lung cancer in Spain
Author: P. González
Abstract #1319P
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
Three-year follow-up from CheckMate -017/-057: nivolumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer
Author: E. Felip
Abstract #1301PD
Poster Discussion Session: NSCLC, Metastatic
Sunday, September 10, 4:30–6 PM CEST, Barcelona Auditorium

•
Nivolumab in previously treated patients with metastatic squamous NSCLC: results of a European single-arm, phase 2 trial (CheckMate -171) including patients aged ≥70 years and with poor performance status
Author: S. Popat
Abstract #1303PD
Poster Discussion Session: NSCLC, Metastatic
Sunday, September 10, 4:30–6 PM CEST, Barcelona Auditorium

Early Assets & Cross-tumor
•
Impact of licensing and reimbursement discrepancies on patient access to cancer treatments across Europe and Canada
Author: J. McKendrick
Abstract #1124P
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

•
Anti-CC-chemokine receptor 4 (CCR4) antibody mogamulizumab and nivolumab combination phase 1 study in patients with advanced or metastatic solid tumors
Author: N. Yamamoto
Abstract #LBA17
Proffered Paper Session: Developmental Therapeutics
Sunday, September 10, 4:30–4:45 PM CEST, Cordoba Auditorium

•
Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in patients with melanoma who progressed during prior anti–PD-1/PD-L1 therapy in all-comer and biomarker-enriched populations
Author: P. Ascierto
Abstract #LBA18
Proffered Paper Session: Developmental Therapeutics
Sunday, September 10, 4:45–5 PM CEST, Cordoba Auditorium

•
Initial results of BMS-986012, a first-in-class fucosyl-GM1 mAb, in combination with nivolumab, in patients with relapsed/refractory small-cell lung cancer
Author: Q. Chu
Abstract #1528PD
Poster Discussion Session: Non-metastatic NSCLC and Other Thoracic Malignancies
Monday, September 11, 2:45–4:15 PM CEST, Pamplona Auditorium

Clinical Collaborations
•
A phase 1/2 study on safety of rovalpituzumab tesirine in combination with nivolumab or nivolumab + ipilimumab in small cell lung cancer
Author: C. Scripture
Abstract #1538TiP
Poster Display Session
Saturday, September 9, 1:15–2:15 PM CEST, Hall 8

•
PIVOT-02: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and nivolumab in patients with select, locally advanced or metastatic solid tumor malignancies
Author: A. Diab
Abstract #1212TiP
Poster Display Session
Sunday, September 10, 1:15–2:15 PM CEST, Hall 8

On August 30, 2017 FUJIFILM Corporation (President: Kenji Sukeno) reported that it has decided to start clinical trials in the United States in 2018 for its anti-cancer agent FF-10832 to assess it as a potential treatment for advanced solid tumors (Press release, Fujifilm, AUG 30, 2017, View Source [SID1234520339]). FF-10832 is a liposome-based agent which harnesses the advanced nano-dispersion technology, analysis technology and process technology nurtured through the photographic film business in order to incorporate the existing water-soluble anti-cancer agent gemcitabine*1 into liposomes.

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Liposomes are artificially constructed vesicles made from the same organic phospholipids that make up cell membranes and bio membranes. As one of a variety of drug delivery system (DDS) technologies, liposomes are used to deliver the required amount of a drug to the specified part of the body on the necessary schedule. Certain anti-cancer agents act on healthy tissue in addition to the tumor that can result in severe adverse effects. Liposomes are currently attracting significant attention as an effective means of avoiding these adverse effects on healthy tissue. Preparing pharmaceuticals in the form of liposomes allows the pharmaceutical to be delivered selectively to the tumor, which can be expected to improve pharmacological efficacy and suppress adverse effects. In order to achieve this, the following conditions must all be met: (1) improve the stability of the pharmaceutical agent in the blood (2) the achievement of the Enhanced Permeability and Retention (EPR) effect*2 (namely the long-term, sustainable concentration of the agent within the tumor as a result of ensuring that the agent does not leak from healthy blood vessels) and (3) the release of the agent within the tumor. Generally, it is difficult to simultaneously achieve both (1) the improved stability of the pharmaceutical agent in the blood and (3) the release of the agent within the tumor. This is particularly the case with water-soluble drugs, where the technical barriers are very high, and these considerations have been an issue affecting the production of effective liposomes.

FF-10832 harnesses Fujifilm’s expertise including nano-dispersion technology, analysis technology and process technology in order to incorporate gemcitabine, a drug with a short half-life*3 in blood, into liposomes, which is expected to lead to a significant increase in the stability of the agent within the blood. Furthermore, to achieve EPR benefits, the liposomes are designed to have a uniform size of approximately 80 nm, raising the concentration of the agent within the tumor. In experiments on mice transplanting human-derived pancreatic cancer cells, concentrations of FF-10832 within the pancreatic cancer cells reach higher levels than with the original preparation of gemcitabine – confirming the long-term sustainable presence of the agent within the tumor (in mice experiments).

Furthermore, the same experiments on mice also demonstrate that when FF-10832 is administered, it is possible to obtain a pharmacological benefit in excess of that produced by the original preparation of gemcitabine with only 1/60th of the dose. In addition, the release of the agent within the tumor was confirmed by demonstrating the efficacy including in the case of human-derived pancreatic cancer cells, which included a subtype that does not usually respond well to the original gemcitabine treatment, as well as in other mice experiments involving the transplantation of cancer cells other than pancreatic cancer cells. From these results, it can be expected that FF-10832 fulfills the conditions required of liposome preparations for human, and provides effective treatment not only for pancreatic cancer, a condition for which the number of promising treatments is currently limited, but also potentially in further applications for the treatment of other solid tumors.

Fujifilm plans to submit an investigational new drug (IND) application for FF-10832 in the US before the end of 2017 and plans to start clinical trials in 2018.

[Schematic diagram showing how FF-10832 is released into tumor]

Fujifilm is defining oncology as its focal area and the company is actively engaged in the research and development of pharmaceuticals by combining the technologies and knowledge accumulated in the photographic film business in fields including the synthesis and design of compounds in addition to nano-dispersion technology and analysis technology. Going forward, the company is committed not only to the development of new drugs, but also to the development of new Drug Delivery Systems, as the company works to address social issues through the provision of innovative pharmaceutical products.

*1 Gemcitabine (Gemzar) is an anti-cancer agent developed by the US company Eli Lilly and Company. It is used as a drug of first choice for the treatment of pancreatic cancer, and is also indicated for the treatment of a wide range of other cancers including lung cancer and ovarian cancer.

*2 Tumors produce new blood vessels for the purpose of nourishing the tumor, but these new blood vessels are immature, with the walls of the vessels containing gaps that do not exist in normal healthy vessels. When a high concentration of liposomes and high-molecular weight drugs is observed in these vessels, there is no leakage from the healthy vessels that do not contain these gaps, with the liposomes and high-molecular-weight drugs leaking only from the blood vessel walls of the tumor. In addition, since the lymphatic tissue within tumor is also immature, it is difficult to remove the liposomes and high-molecular-weight drugs that have permeated the surrounding tissue, causing the drug to accumulate within the tumor. This effect is called Enhanced Permeability and Retention effect. The effect was originally reported in 1986 by Hiroshi Maeda, Professor at the Sojo University DDS research center and Honorary Professor at Kumamoto University, and Yasuhiro Matsumura, Director at Division of Development Therapeutics at the National Cancer Center’s Exploratory Oncology Research & Clinical Trials Center (NCC-EPOC) in the paper " A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs." In 2016, Maeda and Matsumura were recognized as Thomson Reuters Citation Laureates, distinction conferred by Thomson Reuters on researchers considered to be likely candidates for future Nobel prizes on the basis of an analysis of research literature and citations.

*3 The half-life is the time taken for the concentration of pharmaceutical in the blood to decrease by half.

On August 30, 2017 Amgen (NASDAQ: AMGN) reported positive results from a post-hoc analysis requested by the U.S. Food and Drug Administration (FDA) of the Phase 3 head-to-head ENDEAVOR trial, which followed patients for at least three years after enrollment (Press release, Amgen, AUG 30, 2017, View Source [SID1234520338]). The analysis evaluated overall survival (OS) and long-term safety of KYPROLIS (carfilzomib) administered at 56 mg/m2 twice weekly and dexamethasone (Kd) versus Velcade (bortezomib) and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. Kd reduced the risk of death by 24 percent over Vd (median OS 47.8 months for Kd versus 38.8 months for Vd, HR=0.76, 95 percent CI, 0.63-0.92; p=0.0017). This Kd regimen is currently approved in the U.S., European Union and other countries based on the primary analysis of progression-free survival in the ENDEAVOR study.

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"For physicians making prescribing decisions, long-term follow-up helps to further support the safety and efficacy of a therapy and instills confidence in the treatment," said Robert Orlowski, M.D., Ph.D., Florence Maude Thomas Cancer Research professor and chair, ad interim, Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center. "The current three-year follow-up analysis demonstrates that this proteasome inhibitor continues to demonstrate a prolonged overall survival benefit and consistent safety profile when combined with dexamethasone for relapsed multiple myeloma patients."

"We are excited about the three-year follow-up of the ENDEAVOR study as the overall survival benefit reflects both the efficacy and the long-term safety of this KYPROLIS regimen in patients with relapsed multiple myeloma," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These results confirm that when a patient relapses, KYPROLIS should replace Velcade as a standard-of-care."

Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were anemia, diarrhea, pyrexia, hypertension, dyspnea, fatigue, cough, insomnia, upper respiratory tract infection, nausea, bronchitis, asthenia, back pain, thrombocytopenia, edema peripheral, headache and muscle spasms.

Results from the primary ENDEAVOR OS analysis were recently published online in The Lancet Oncology. Data showed Kd reduced the risk of death by 21 percent over Vd. Patients treated with KYPROLIS lived 7.6 months longer than those treated with Velcade (median OS 47.6 months for Kd versus 40.0 months for Vd, HR=0.79, 95 percent CI, 0.65-0.96). On Aug. 30, 2017, Amgen announced the FDA accepted for review the supplemental New Drug Application (sNDA) for KYPROLIS to include OS data from the Phase 3 head-to-head ENDEAVOR trial in the product information. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of April 30, 2018.

Since its approval in 2012, more than 50,000 patients worldwide have received KYPROLIS. The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating this frequently relapsing and difficult-to-treat cancer. KYPROLIS is available for patients whose myeloma has relapsed or become resistant to another treatment and continues to be studied in a range of combinations and patient populations.

About ENDEAVOR

The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kd versus Vd in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The primary analysis was published in The Lancet Oncology and is described in the Prescribing Information.

Patients received treatment until progression with KYPROLIS as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treatment cycles, along with low-dose dexamethasone (20 mg). For cycle one only, KYPROLIS was administered at 20 mg/m2 on days 1 and 2, and if tolerated was escalated to 56 mg/m2 from day 8 cycle one onwards. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were treated with bortezomib administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regional regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide.

For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

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 very aggressive disease that accounts for approximately one percent of all cancers.2,3 In the U.S., there are nearly 95,000 people living with, or in remission from, multiple myeloma.4 Approximately 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.4

About KYPROLIS (carfilzomib)

Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.5 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.5,6

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 European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

IMPORTANT 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 and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure 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. 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.
The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see full prescribing information at www.kyprolis.com.