On October 8, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, and ENGOT, the European Network for Gynaecological Oncological Trial groups, reported the presentation of the niraparib Phase 3 ENGOT-OV16/NOVA clinical trial results at the ESMO (Free ESMO Whitepaper) 2016 Congress, the congress of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper), by Dr. Mansoor Raza Mirza, M.D., Medical Director of the Nordic Society of Gynecologic Oncology (NSGO) and principal investigator on the ENGOT-OV16/NOVA trial (Press release, TESARO, OCT 8, 2016, View Source [SID:SID1234515655]). These data were discussed during the ESMO (Free ESMO Whitepaper) press briefing in Copenhagen as part of the congress, and were simultaneously published online in the New England Journal of Medicine.1 The results will also be presented by Dr. Mirza later today during Presidential Symposium 1 (Abstract #LBA3_PR) at ESMO (Free ESMO Whitepaper).

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An infographic accompanying this announcement is available at
View Source

ENGOT-OV16/NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled 553 patients with recurrent ovarian cancer who were in response to their most recent platinum-based chemotherapy. This trial was designed to assess progression free survival (PFS) in a broad population of patients who were assigned to one of two cohorts based upon germline BRCA mutation status. The ENGOT-OV16/NOVA trial successfully achieved its primary endpoint in both cohorts, demonstrating that niraparib treatment significantly prolonged PFS compared to control in patients who were germline BRCA mutation (gBRCAmut) carriers and in patients who were not germline BRCA mutation (non-gBRCAmut) carriers. In addition, within the non-gBRCA cohort, niraparib treatment significantly prolonged PFS compared to control for the prospectively defined patient population with tumors deficient in homologous recombination (HRDpos) as determined by the Myriad myChoice HRD test. A high proportion of patients in both treatment groups in both cohorts had received three or more prior lines of chemotherapy.

"These landmark results are extremely encouraging for the ovarian cancer community," said Dr. Mirza. "The effectiveness of platinum-based chemotherapy diminishes over time, and PFS and platinum-free intervals generally become shorter after each round of platinum treatment. In addition, the incidence of infection and risk of neuropathy and hypersensitivity with certain chemotherapy agents rises with subsequent cycles. An oral maintenance treatment that could lengthen the PFS interval between rounds of platinum-based chemotherapy would be very meaningful for patients with ovarian cancer, who often live with a fear of recurrence after ending active treatment."

"We would like to thank the patients, their families and the caregivers that participated in the ENGOT-OV16/NOVA study, as well as our partners at ENGOT for their diligence in executing this trial," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "We believe the results of this Phase 3 study demonstrated a meaningful benefit for women with platinum sensitive, recurrent ovarian cancer."

Primary Endpoint Results:

Statistically Significant PFS Results in the gBRCAmut Cohort
Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.27 (95% CI, 0.173-0.410). The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p<0.0001).

Statistically Significant PFS Results in the non-gBRCAmut Cohort
Niraparib showed statistical significance for patients in the non-germline BRCA mutant cohort. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45 (95% CI, 0.338-0.607). The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p<0.0001).

Statistically Significant PFS Results in non-gBRCAmut Cohort for Patients with HRD-Positive Tumors
For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive using the Myriad myChoice HRD test, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.38 (95% CI, 0.243-0.586). The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p<0.0001).

Secondary Endpoint Results:

Secondary endpoint analyses, including chemotherapy-free interval, time to first subsequent treatment, and PFS 2 were all statistically significant and favored niraparib over control for patients in both the gBRCAmut and non-gBRCAmut cohorts. Patient-reported outcome results from validated survey tools indicated that niraparib-treated patients reported no difference from control in measures associated with quality of life. Data for overall survival are immature (HR 0.73; 95% CI, 0.480 to 1.125; p=0.1545), as fewer than 20% of events had occurred at the time of analysis.

Safety Results:

The most common (≥10%) treatment-emergent grade 3/4 adverse events in the niraparib arm were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%) with treatment discontinuation for these events of 3.3%, 1.4% and 1.9%, respectively. Thrombocytopenia was not associated with grade 3/4 bleeding events. The majority of these hematological laboratory abnormalities occurred within the first three cycles; following dose modifications the incidence of these lab abnormalities decreased and thrombocytopenia and neutropenia were infrequent beyond cycle 3. The rates of MDS/AML in the niraparib (1.4%) and control (1.1%) arms were similar. There were no deaths among patients during study treatment.

"Despite diagnostic and treatment advances, ovarian cancer remains the deadliest gynecologic cancer, and the need for new therapeutic options that prolong response remains critical," said David Barley, CEO of the National Ovarian Cancer Coalition. "The results of the NOVA trial are encouraging, and could offer patients and their families a treatment option during the stressful period that follows platinum-based chemotherapy where the majority of patients receive no treatment."

Investor Briefing and Webcast
TESARO will webcast an investor and analyst briefing in Copenhagen on Saturday, October 8 at 7:00 PM local time in Copenhagen in conjunction with the ESMO (Free ESMO Whitepaper) annual meeting. At this briefing, TESARO management will review the niraparib development program and data presented at ESMO (Free ESMO Whitepaper) and answer questions from investors and analysts. This event will be webcast live and archived for 30 days, and may be accessed from the TESARO Investor Events and Presentations webpage at www.tesarobio.com. A reception will begin at 6:30 PM local time for those institutional investors and analysts attending this event in Copenhagen; please RSVP to [email protected] in order to attend.

About the Phase 3 ENGOT-OV16/NOVA Clinical Trial of Niraparib
NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled 553 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. Patients were enrolled into one of two independent cohorts based on germline BRCA mutation status. One cohort enrolled patients who were germline BRCA mutation carriers (gBRCAmut), and the second cohort enrolled patients who were not germline BRCA mutation carriers (non-gBRCAmut) and included patients with HRD-positive and HRD-negative tumors. Within each cohort, patients were randomized 2:1 to receive niraparib or placebo and were treated continuously with placebo or 300 milligrams of niraparib, dosed as three 100 milligram tablets once per day, until progression. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints include patient-reported outcomes, chemotherapy-free interval length, PFS 2, overall survival, and other measures of safety and tolerability. More information about this trial is available at View Source

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in four ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients with platinum-sensitive, recurrent ovarian cancer (the NOVA trial); a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial); a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial); and a Phase 3 trial for the treatment of patients with BRCA-mutant breast cancer (the BRAVO trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab and bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to niraparib for the treatment of patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. TESARO has initiated a rolling submission of a New Drug Application (NDA) for niraparib to the FDA, and intends to complete this submission during the fourth quarter. The Marketing Authorization Application (MAA) for niraparib is planned for submission to the European Medicines Agency (EMA) in the fourth quarter.

Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA, the European Medicines Agency (EMA), or any other regulatory agencies.

About Ovarian Cancer
Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and more than 65,000 women are diagnosed annually in Europe. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years. If approved, niraparib may address the difficult "watchful waiting" periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.

On October 8, 2016 Novartis reported data from the Phase III COMBI-v study demonstrating an overall survival (OS) and a progression-free survival benefit for patients with BRAF V600 mutation-positive advanced melanoma when treated first-line with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib) compared to vemurafenib monotherapy[1] (Press release, Novartis, OCT 8, 2016, View Source [SID:SID1234515678]). The results of this study, which was conducted in 704 patients[1], are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen.

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"The three-year overall survival follow-up data from COMBI-v is remarkable because it is the second Phase III study this year to demonstrate a significant long-term survival benefit for BRAF mutation-positive melanoma patients treated with Tafinlar + Mekinist combination therapy compared to BRAF inhibitor monotherapy," said Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy. "The results of this trial continue to reinforce Tafinlar + Mekinist as a standard of care and sets a new benchmark for treating patients with BRAF V600 mutation-positive advanced melanoma."

Results from the COMBI-v study found the estimated three-year survival rate to be 45% of patients receiving the combination of Tafinlar + Mekinist (95% CI, 39.1%-49.8%) compared with 31% of patients who received vemurafenib monotherapy (95% CI, 26.1%-36.4%)[1]. There were 34 patients who crossed over from the vemurafenib monotherapy arm to the combination arm after the combination demonstrated a significant OS benefit in a prior analysis[1]. Additionally, the estimated three-year progression-free survival rate was 24% (95% CI, 19.4%-28.8%) for the combination arm and 10% (95% CI, 5.9%-14.5%) for the vemurafenib monotherapy arm[1].

"We are pleased to see the continued benefit of Tafinlar + Mekinist targeted combination therapy beyond three-years in another study," said Alessandro Riva, MD, Global Head, Oncology Development & Medical Affairs. "As we’ve come to understand, this combination of targeted inhibitors has demonstrated an unprecedented ability to block the known resistance pathways and extend overall survival for BRAF mutation-positive patients. These results underscore our commitment to advancing the practice of precision oncology and extending patients’ lives through treatment options that target the root cause of their cancer."

At three years of follow up, the combination of Tafinlar + Mekinist continued to demonstrate a benefit on the measures of duration of response (DoR) and overall response rate (ORR), in line with results seen at the two-year follow up analysis[1].

The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for vemurafenib monotherapy; no new safety concerns were observed.

About the COMBI-v Study
COMBI-v is a two-arm, open-label, Phase III study comparing the combination of Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS. The Independent Data Monitoring Committee (IDMC) stopped the trial early based on efficacy results observed in the Tafinlar + Mekinist study arm as part of a planned interim analysis[1].

About Melanoma
Advanced melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates[2],[3]. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease[2]. There are about 200,000 new cases of melanoma diagnosed worldwide each year[4], approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma[2],[5]. Gene tests can determine whether a tumor has a BRAF mutation[2],[6].

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and other countries.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in non-small cell lung cancer (NSCLC) and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indication.

Tafinlar and Mekinist are also indicated in more than 40 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information for Metastatic Melanoma
Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat melanoma with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause fever which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.

Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Rash is a common side effect of Tafinlar in combination with Mekinist, or with Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can also cause other skin reactions which can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness or a swelling of their muscles should contact their healthcare provider immediately.

Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

Mekinist, alone or in combination with Tafinlar, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognised risk of gastrointestinal perforation.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, tiredness, nausea, headache, chills, diarrhea, rash, joint pain, high blood pressure, vomiting and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar. Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

Please see full Prescribing Information for Tafinlar and Mekinist.

On October 8, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that its myChoice HRD test identified more than double the number of patients who may benefit from treatment with niraparib than were identified by germline BRCA testing alone (Press release, Myriad Genetics, OCT 8, 2016, View Source [SID:SID1234515681]). The myChoice HRD test was evaluated in the NOVA study (NCT01847274) of nirarapib, an investigational oral PARP inhibitor being developed by TESARO (Nasdaq:TSRO).

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Today’s announcement follows publication of the NOVA study in the New England Journal of Medicine. NOVA is a well-controlled Phase 3 trial of niraparib that enrolled 553 patients with recurrent ovarian cancer who responded to their most recent platinum-based chemotherapy. This trial was designed to assess progression free survival (PFS) in a broad population of patients who were assigned to one of two cohorts based upon germline BRCA mutation status.

"Patients with ovarian cancer who tested positive with myChoice HRD experienced a clinically meaningful improvement in PFS," said Johnathan Lancaster, M.D., Ph.D., gynecologic oncologist and chief medical officer of Myriad Genetic Laboratories. "We estimate that myChoice HRD identifies more than double the number of patients who may benefit compared to germline BRCA testing alone."

The NOVA results showed that in patients who were germline BRCA mutation carriers, the median PFS for patients treated with niraparib was 21.0 months compared to 5.5 months for the control group (p<0.0001; HR 0.27,95% CI, 0.173-0.410). The median PFS benefit for patients with HRD-positive tumors who were treated with niraparib was 12.9 months compared to 3.8 months for the control group (P<0.0001; HR 0.38, 95% CI, 0.243-0.586). Additionally, the exploratory analysis showed that for patients who were determined to be HRD negative, the median PFS for patients treated with niraparib was 6.9 months compared to 3.8 months for the control group (p<0.0226; HR 0.58, 95% CI, 0.361-0.922).

The key findings are illustrated in the chart below.
View Source

The myChoice HRD test is being developed in parallel with the clinical development of niraparib. The collaboration with TESARO began in March 2014 and includes several ongoing clinical trials in a variety of tumor types.

About myChoice HRD
Myriad’s myChoice HRD is the most comprehensive homologous recombination deficiency test to detect when a tumor has lost the ability to repair double-stranded DNA breaks, resulting in increased susceptibility to DNA-damaging drugs such as platinum drugs or PARP inhibitors. The myChoice HRD score is a composite of three proprietary technologies: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions. Positive myChoice HRD scores, reflective of DNA repair deficiencies, are prevalent in all breast cancer subtypes, ovarian and most other major cancers. In previously published data, Myriad showed that the myChoice HRD test predicted drug response to platinum therapy in certain patients with triple-negative breast and ovarian cancers. It is estimated that 1.4 million people in the United States and Europe who are diagnosed with cancers annually may be candidates for treatment with DNA-damaging agents.

On October 7, 2016 Cambrex Corporation (NYSE:CBM), a leading manufacturer of small molecule innovator and generic Active Pharmaceutical Ingredients (APIs), reported that it has completed the acquisition of PharmaCore, Inc., a privately-owned company located in High Point, North Carolina, specializing in developing, manufacturing and scaling up small molecule APIs for clinical phase projects. This completes the transaction initially announced on September 26, 2016 (Press release, Cambrex, OCT 7, 2016, View Source [SID:SID1234515685]). With the acquisition of PharmaCore, which has been renamed Cambrex High Point, Inc., Cambrex enhances its capabilities and expertise to efficiently develop early clinical phase products and new technologies.

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On October 7, 2016 Celgene Corporation (NASDAQ:CELG) reported results from multiple sponsored and independent studies will be presented during the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Annual Meeting evaluating the use of ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) as a foundational treatment, either alone or in combination with novel agents and novel regimens, for patients with traditionally challenging cancers, including metastatic pancreatic cancer (mPAC), metastatic breast cancer (MBC) and advanced non-small cell lung cancer (NSCLC) (Press release, Celgene, OCT 7, 2016, View Source [SID:SID1234515645]).

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"Celgene continues to evaluate the safety and efficacy of ABRAXANE in patients with particularly challenging advanced diseases or with co-morbidities that limit their treatment options," said Michael Pehl, President, Hematology and Oncology for Celgene. "These data continue to shape our understanding of these difficult to treat diseases which will help evolve the current and future treatment landscapes in areas where there have been historically limited treatment options available to patients."

Investigational Research Evaluates ABRAXANE as a Foundational Treatment in mPAC, NSCLC, and MBC

The cancer treatment landscape has rapidly evolved over the last several years, with the introduction of targeted therapies and immunotherapy. While these advances have generated a lot of excitement, there are patients who may not benefit from these therapies. Celgene remains committed to continuing to explore treatments for these patients and at ESMO (Free ESMO Whitepaper) 2016, several studies evaluating treatment with ABRAXANE as a foundation therapy in these patients are being presented.

New data being presented from the ABOUND trials demonstrate the continued benefit of ABRAXANE/carboplatin doublet therapy in NSCLC. ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. The ABOUND trials included patients 70 years and older, as well as those with poorer performance status or squamous disease.1,2,3

An interim analysis of the ABOUND.70+ study (Poster 1280P) will be presented that evaluated the quality of life impact of elderly patients (aged 70+) with advanced NSCLC and an ECOG status of 0 or 1 treated with an ABRAXANE + carboplatin regimen through 4 cycles of treatment.1

The ABOUND.PS2 study (Poster 1278P) evaluated radiological response following treatment with ABRAXANE + carboplatin in 31 patients with advanced NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status 2.2
Similarly, interim quality of life results from the ABOUND.sqm study (Poster 1279P) will be presented that evaluated the quality of life in squamous NSCLC patients treated with ABRAXANE + carboplatin.3
Real-world outcomes data will also be presented for patients with metastatic breast cancer (MBC) including in the HR+/Her2- and TNBC subsets treated with ABRAXANE. 4,5

A study of 176 MBC patients (Poster 1030P) reports on time to treatment discontinuation (TTD) and time to next treatment (TTNT) with ABRAXANE compared with eribulin.4

Another retrospective analysis (Poster 1029P) will be presented that evaluated TTD in 411 MBC patients in the second line setting with ABRAXANE vs paclitaxel.5
The use of ABRAXANE in first line mPAC is further investigated by multiple independent studies being reported at ESMO (Free ESMO Whitepaper).

Safety and efficacy results from novel Abraxane regimens like GABRINOX (Abraxane-gemcitabine followed by FOLFIRINOX), and PAXG (Abraxane, cisplatin, capecitabine and gemcitabine) are being reported at ESMO (Free ESMO Whitepaper) 2016 (Posters 679P and 681P).6,7
Safety and efficacy data for Abraxane in patients with elevated bilirubin (posters 684P and 683P) will also be reported.8,9
Investigating ABRAXANE as a Chemotherapy Foundation with Novel Agents

In addition, there is also emerging data that further evaluates ABRAXANE’s use in challenging oncological diseases which illustrates the medical interest in ABRAXANE as a chemotherapy foundation in research with novel agents.

Currently, there are 180 clinical studies evaluating ABRAXANE combinations, including novel agents.10 At this year’s ESMO (Free ESMO Whitepaper), 15 independent studies are presented which evaluate ABRAXANE as a combination therapy with other agents across several tumor types including: TNBC – durvalumab (Poster 221TIP), mPAC – cisplatin, capecitabine, gemcitabine, FOLFIRINOX, ipafricept, vantictumab, PEGPH20, nivolumab (Posters 681P – Reni, 367PD – Weekes, 677P – Messersmith, 682P – Giommoni, and 715 TiP – Van Cutsem), and NSCLC – nivolumab, necitumumab (Posters 1059P – George and 1298 TiP – Socinski).

In addition, Celgene is presenting preliminary tolerability data evaluating the investigational combination use of ABRAXANE with the immunotherapy agent nivolumab (Poster 1059P) in NSCLC and mPAC. The study has been expanded and patients are currently enrolling in part 2. Additional data on the safety and efficacy of this combination in multiple tumor types will be presented at a future medical meeting.11

Update of ESMO (Free ESMO Whitepaper) Clinical Practice Guidelines

The latest edition of ESMO (Free ESMO Whitepaper) lung cancer guidelines have been updated to recommend use of ABRAXANE + carboplatin in patients with stage IV NSCLC. The recommendation is based on the pivotal trial that was conducted for ABRAXANE.12

About ABRAXANE (nab-paclitaxel)

ABRAXANE is a nanotechnology agent that is currently the only albumin-based nanotechnology therapy approved for the treatment of metastatic breast cancer, non-small cell lung cancer and pancreatic cancer in the United States, Europe and other markets around the world. It contains albumin-bound paclitaxel nanoparticles and is manufactured using patented nab technology. ABRAXANE is formulated with albumin, a human protein, and is free of solvents.

ABRAXANE was first approved in January 2005 by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. In Europe, ABRAXANE was approved in January 2008 as monotherapy for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. ABRAXANE is now approved in more than 50 countries for the treatment of metastatic breast cancer.

In October 2012, ABRAXANE was approved by the FDA for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. ABRAXANE is also approved for the treatment of NSCLC in Argentina, Australia, Chile, Ecuador, Guatemala, Hong Kong, Japan, New Zealand and Singapore.

In September 2013, the FDA approved ABRAXANE as first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. In December 2013, ABRAXANE in combination with gemcitabine was approved for first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas in Europe. ABRAXANE is also approved for the treatment of metastatic pancreatic cancer in more than 40 countries.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In the case of severe neutropenia ( < 500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC
In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level > 1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3
In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, < 1%), nausea (any 30%, 22%; severe 3%, < 1%), diarrhea (any 27%, 15%; severe < 1%, 1%) and infections (24%, 20%), respectively
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, < 1%), mucositis (any 7%, 6%; severe < 1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe < 1%, < 1%), neutropenic sepsis ( < 1%, < 1%), and injection site reactions ( < 1%, 1%), respectively. Dehydration and pyrexia were also reported
Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported
Non-Small Cell Lung Cancer (NSCLC) Study

The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group
Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively
Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin
Pancreatic Adenocarcinoma Study

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years or older who received ABRAXANE for MBC in a pooled analysis of clinical studies
Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC
Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
For MBC and NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment
For adenocarcinoma of the pancreas, do not administer ABRAXANE to patients who have moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

Please refer to the Summary of Product Characteristics for full European prescribing information.