On July 31, 2015 Eisai Inc. reported that its parent company Eisai Co., Ltd. (Headquarters: Tokyo, President and CEO: Haruo Naito, "Eisai") and Halozyme Therapeutics, Inc. (Headquarters: San Diego, California, President and CEO: Dr. Helen Torley, "NASDAQ: HALO") have signed a clinical collaboration agreement to evaluate Eisai’s agent eribulin mesylate (brand name: Halaven, "eribulin") in combination with Halozyme’s investigational drug PEGPH20 (PEGylated recombinant human hyaluronidase) in first line HER2-negative metastatic breast cancer (Press release, Halozyme, JUL 31, 2015, View Source [SID:1234506778]).

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The companies will jointly share the costs of a phase 1b/2 clinical trial to assess whether or not eribulin, in combination with PEGPH20, can improve overall response rate (ORR) — the proportion of women that have a predefined reduction in tumor burden — as compared with eribulin alone as a therapy in women with advanced breast cancer.

PEGPH20 (PEGylated recombinant human hyaluronidase) is an investigational drug administered intravenously that targets the degradation of hyaluronan, a glycosaminoglycan – or chain of natural sugars throughout the body – that can accumulate around cancer cells to inhibit other therapies. The collaborative study will seek to determine whether or not the combination therapy of eribulin and PEGPH20 can improve the overall response rate in patients with high levels of hyaluronan. In hyaluronan-rich triple-negative breast preclinical animal models, the addition of PEGPH20 to eribulin showed a significantly higher tumor growth inhibition and overall tumor regression when compared to eribulin alone.

Eribulin is not indicated for first-line therapy for patients with HER2-negative metastatic breast cancer.

Eribulin is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally, eribulin is a modified and synthetically produced analog of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin is believed to work by inhibition of the growth phase of microtubule dynamics which prevents cell division.

"This is a very important collaboration, one that speaks to our continued commitment to address the unmet medical needs of patients with advanced breast cancer," said RuiRong Yuan, MD, Vice President and Chief Medical Officer, Eisai Global Oncology. "We look forward to enrolling patients in the clinical trial and assessing the results."

"This agreement marks the first clinical collaboration agreement for Halozyme and extends the study of PEGPH20 to a substantially wider population of patients with a partner that is a clear leader in the treatment of metastatic breast cancer," said Dr. Helen Torley, President and CEO, Halozyme Therapeutics.

The information discussed in this release presents an investigational use for an FDA-approved product (eribulin). It is not intended to convey conclusions about efficacy or safety. There is no guarantee that the investigational use of the combination of eribulin and PEGPH20 will successfully gain FDA approval.

About Advanced Breast Cancer
Advanced or metastatic breast cancer is a very difficult condition to treat and only 25.9% of women will survive beyond five years.

About PEGPH20
PEGPH20 is currently under development in combination with chemotherapies for the treatment of metastatic pancreatic cancer and non-small cell lung cancer with plans for it to be studied in combination with an immunotherapy agent later this year.

About Eribulin Mesylate Injection (Available as Halaven)
Eribulin mesylate injection is indicated for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic breast cancer. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Eribulin is a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai. First in the halichondrin class, eribulin is a microtubule dynamics inhibitor with a distinct binding profile. Based on in vitro studies, eribulin exerts its effect via a tubulin-based antimitotic mechanism ultimately leading to apoptotic cell death after prolonged and irreversible mitotic blockage.

Important Safety Information

Neutropenia

Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days
Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels
Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received eribulin. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy

Patients should be monitored closely for signs of peripheral motor and sensory neuropathy
Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received eribulin. Delay administration of eribulin until resolution to Grade 2 or less
Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)
Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Pregnancy Category D

Eribulin is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation

In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities
Correct hypokalemia or hypomagnesemia prior to initiating eribulin and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment

For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate or severe (CrCl 15-49 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions

Most common adverse reactions (=25%) reported in patients receiving eribulin were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)
The most common serious adverse reactions reported in patients receiving eribulin were febrile neutropenia (4%) and neutropenia (2%)
For more information about eribulin, click here for the full Prescribing Information.

On July 31, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission (EC) has approved the use of Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and chemotherapy for the neoadjuvant treatment (use before surgery) of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence (Press release, Hoffmann-La Roche , JUL 31, 2015, View Source [SID:1234506772]).

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The Perjeta regimen is the first neoadjuvant breast cancer treatment approved by the EC based on pCR data.

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Every year in Europe nearly 100,000 people are diagnosed with HER2-positive breast cancer, an aggressive type of the disease that is more likely to progress than HER2-negative cancer.1,2 Treating people with breast cancer early, before the cancer has spread, may improve the chance of preventing the disease from returning. Neoadjuvant treatment is given before surgery and is aimed at reducing tumour size so it is easier to surgically remove. pCR is achieved when there is no tumour tissue detectable at the time of surgery in the affected breast or in the affected breast and local lymph nodes. It is a common measure of neoadjuvant treatment effect in breast cancer and it can be assessed more quickly than traditional endpoints in eBC.

"Today’s approval is a significant milestone in the neoadjuvant treatment of HER2-positive early breast cancer, bringing Perjeta to patients years earlier than typical adjuvant treatment," said Sandra Horning, M.D., Roche’s Chief Medical Officer and Head, Global Product Development. "We are committed to making the Perjeta regimen available to appropriate patients in the EU as early as possible."

The EC approval is based primarily on data from the neoadjuvant Phase II NeoSphere study, which showed that nearly 40% of people receiving the combination of Perjeta, Herceptin and chemotherapy achieved pCR in the affected breast and local lymph nodes compared to 21.5% of people who received Herceptin and taxane chemotherapy alone.3 The approval was also supported by data from the Phase II neoadjuvant TRYPHAENA study, in which pCR rates ranging from 54.7% to 63.6% were achieved across the three Perjeta-containing study arms.4 Long-term safety results from the Phase III CLEOPATRA trial in people with previously untreated HER2-positive advanced breast cancer also supported the approval.5 Data from the ongoing Phase III APHINITY study in the adjuvant (post-surgery) setting will provide additional insights into the broader role of Perjeta in the treatment of HER2-positive eBC.

Follow-up data from the NeoSphere trial were presented last month at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). These data suggested that people who received the Perjeta regimen prior to surgery were 31% less likely to experience disease worsening, recurrence or death (PFS HR=0.69; 95% CI, 0.34–1.40) compared to those who received Herceptin and chemotherapy.6 People treated with the Perjeta regimen were also 40% less likely to experience disease recurrence or death (DFS HR=0.60; 95% CI, 0.28–1.27). These new data suggest that the pCR benefit seen with the Perjeta regimen may translate into longer-term improvements in patient outcomes.6

Perjeta is already approved as neoadjuvant treatment for people with HER2-positive eBC in the U.S. and 21 other countries.

About Perjeta
Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers. Perjeta is designed specifically to prevent the HER2 receptor from pairing (or ‘dimerising’) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumour growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive blockade of HER signalling pathways, thus preventing tumour cell growth and survival.

About the NeoSphere trial
The NeoSphere trial3 (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomised, multicentre, international Phase II study in 417 people with newly diagnosed HER2-positive, operable, locally advanced, or inflammatory eBC. Participants were randomised to one of four study arms and received four cycles (12 weeks) of neoadjuvant treatment followed by surgery and a year of adjuvant treatment with Herceptin plus chemotherapy. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, PFS, DFS, breast-conserving surgery rate and biomarker assessment. Study data showed the following:
Treatment with Perjeta, Herceptin and docetaxel chemotherapy significantly improved the rate of pCR in the affected breast and local lymph nodes by 17.8% compared to Herceptin and chemotherapy alone (39.3% vs. 21.5%, p=0.0063)
– pCR of 21.5% for Herceptin and chemotherapy
– pCR of 39.3% for Perjeta, Herceptin and chemotherapy
– pCR of 11.2% for Perjeta and Herceptin
– pCR of 17.7% for Perjeta and chemotherapy

The Perjeta regimen was not associated with a significant increase in adverse events (AEs), compared to Herceptin and chemotherapy alone

The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9%), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4%), leukopenia (decrease in overall white blood cells, 4.7%) and diarrhoea (5.6%)

pCR means that there is no tumour tissue detectable at the time of surgery either in the affected breast or in the affected breast and local lymph nodes following completion of neoadjuvant treatment.

About the TRYPHAENA trial
The TRYPHAENA trial4 (ToleRabilitY of Pertuzumab, Herceptin and AnthracyclinEs in NeoAdjuvant breast cancer) is a randomised, multicentre Phase II study that was conducted in 225 people with HER2-positive, operable, locally advanced or inflammatory eBC with tumours greater than two centimetres. Participants were randomised to one of three neoadjuvant Perjeta regimens. The primary endpoint was cardiac safety. Secondary endpoints included pCR, clinical response, breast-conserving surgery rate, DFS, PFS, overall survival (OS) and biomarker assessment. Study data showed the following:

The study was not powered to compare the three study arms. The rates of total pCR in the breast and local lymph nodes in the three arms were as follows:
– pCR of 56.2% for Perjeta, Herceptin and anthracycline-based chemotherapy, followed by Perjeta, Herceptin and chemotherapy
– pCR of 54.7% for anthracycline-based chemotherapy, followed by Perjeta, Herceptin and chemotherapy
– pCR of 63.6% for the anthracycline-free arm (Perjeta, Herceptin, chemotherapy and carboplatin chemotherapy)
No new or unexpected cardiac AEs, or other AEs, were observed in any of the study arms. AEs observed were consistent with those seen in previous studies of Perjeta, Herceptin and chemotherapy, either in combination or alone.
The most common severe (Grade 3 or higher) AEs in any of the three study arms were:
– In the concurrent arm: neutropenia (47.2%), leukopenia (19.4%) and febrile neutropenia (18.1%)
– In the sequential arm: neutropenia (42.7%), leukopenia (12.0%), febrile neutropenia (9.3%), diarrhoea (5.3%) and left ventricular dysfunction (4.0%)
– In the anthracycline-free arm: neutropenia (46.1%), febrile neutropenia (17.1%), anaemia (decrease in red blood cells, 17.1%); the AEs of diarrhoea, leukopenia, anaemia and thrombocytopenia (decrease in platelets) all had an incidence of 11.8%

About Roche’s medicines for HER2-positive breast cancer

Roche has been leading research into the HER2 pathway for over 30 years and is committed to improving the health, quality of life and survival of people with both early and advanced HER2-positive disease. Roche has developed three innovative medicines that have helped transform the treatment of HER2-positive breast cancer: Herceptin, Perjeta and Kadcyla. HER2-positive breast cancer is a particularly aggressive form of the disease that affects approximately 20% of patients.2 Over the past 15 years, the outlook for people with HER2-positive disease has improved to the extent that those with this form of the disease treated with these innovative medicines now typically experience better outcomes than people with less aggressive HER2-negative disease.7
Eligibility for treatment with Roche’s HER2-targeted medicines is determined via a diagnostic test, saving time from the outset by identifying patients who will likely benefit from these medicines at the onset of their disease.