On September 8, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported the presentation of positive results from the Phase III clinical trial of Puma’s drug neratinib for the extended adjuvant treatment of early stage HER2-positive breast cancer following trastuzumab-based therapy (ExteNET trial) in a proffered paper oral session at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress in Madrid, Spain (Press release, Puma Biotechnology, SEP 8, 2017, View Source [SID1234520424]). Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in patients with early stage HER2-positive breast cancer. The predefined 5-year invasive disease free survival (iDFS) analysis as a follow-up to the primary 2-year iDFS analysis of the Phase III ExteNET trial was presented today.

The ExteNET trial randomized 2,840 patients in 41 countries with early stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ (DCIS), or death for a period of five years after randomization in the trial.

The patient characteristics in the trial were well balanced between the neratinib and placebo arms of the trial. For the 1,420 patients in the neratinib arm of the trial, 1,085 (76.4%) were node positive while of the 1,420 patients in the placebo arm of the trial, 1,084 (76.3%) were node positive. Additionally, in the neratinib arm of the trial, 816 patients (57.5%) were hormone receptor positive, and in the placebo arm of the trial, 815 patients (57.4%) were hormone receptor positive. The median time from the last trastuzumab dose to entry into the trial was 4.4 months for the neratinib-treated patients and 4.6 months for the placebo-treated patients.

The primary endpoint of the trial was invasive disease free survival (iDFS). The results of the trial demonstrated that after a median follow up of 5.2 years, treatment with neratinib resulted in a 27% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.73, p = 0.008). The 5-year iDFS rate for the neratinib arm was 90.2% and the 5-year iDFS rate for the placebo arm was 87.7%.

The secondary endpoint of the trial was invasive disease free survival including ductal carcinoma in situ (iDFS-DCIS). The results of the trial demonstrated that treatment with neratinib resulted in a 29% reduction of risk of disease recurrence including DCIS or death versus placebo (hazard ratio = 0.71, p = 0.004). The 5-year iDFS-DCIS rate for the neratinib arm was 89.7% and the 5-year iDFS-DCIS rate for the placebo arm was 86.8%.

For the pre-defined subgroup of patients with hormone receptor positive disease, the results of the trial demonstrated that treatment with neratinib resulted in a 40% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.60, p = 0.002). The 5-year iDFS rate for the neratinib arm was 91.2% and the 5-year iDFS rate for the placebo arm was 86.8%. For the pre-defined subgroup of patients with hormone receptor negative disease, the results of the trial demonstrated that treatment with neratinib resulted in a hazard ratio of 0.95 (p = 0.762).

The safety results were unchanged from the primary 2-year iDFS analysis of the study that showed the most frequently observed adverse event for the neratinib-treated patients was diarrhea, with approximately 39.9% of the neratinib-treated patients experiencing grade 3 or higher diarrhea (1 patient (0.1%) had grade 4 diarrhea). Patients who received neratinib in this trial did not receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. Puma is currently running the ongoing CONTROL trial to investigate the use of loperamide-based prophylaxis to reduce the incidence of grade 3 or higher diarrhea in patients with early stage HER2-positive breast cancer who have completed adjuvant trastuzumab-based treatment. The most recently reported clinical data from CONTROL in June 2017 demonstrated that the use of loperamide-based prophylaxis reduced the rate of grade 3 diarrhea with neratinib, with grade 3 diarrhea rates ranging from 8-31% when loperamide-based prophylaxis was used.

"While the use of trastuzumab in the adjuvant setting has led to a reduction in the risk of disease recurrence in patients with early stage HER2-positive breast cancer, there continues to remain a need for further reductions in the risk of disease recurrence," said Professor Miguel Martin, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC, GEICAM, Universidad Complutense in Madrid, Spain. "The longer term follow up results of the ExteNET study demonstrate that we may be able to provide this type of improvement with neratinib to further help the patients with this disease."

"We are very pleased with the results of the 5-year follow up for the ExteNET trial with neratinib. This represents the first trial with a HER2 targeted agent that has shown a benefit in the extended adjuvant setting, which we believe provides a meaningful point of differentiation for neratinib in the treatment of HER2-positive breast cancer," said Alan H. Auerbach, Chief Executive Officer and President of Puma."

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.

IMPORTANT SAFETY INFORMATION

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a 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.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

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.

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.

On September 8, 2017 Janssen-Cilag International NV reported additional data from the pivotal Phase 3 LATITUDE clinical trial, which showed that treatment with Zytiga (abiraterone acetate) plus prednisone, in combination with androgen deprivation therapy (ADT), demonstrated clinically meaningful and statistically significant improvements in a range of patient reported outcomes (PRO) in patients with newly diagnosed, high-risk, metastatic hormone-sensitive prostate cancer (mHSPC), compared to ADT alone (Press release, Johnson & Johnson, SEP 8, 2017, View Source [SID1234520423]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Abiraterone acetate, in combination with prednisone or prednisolone, is currently indicated for the treatment of mCRPC (metastatic castration-resistant prostate cancer) in adult men who are asymptomatic or mildly symptomatic after failure of ADT in whom chemotherapy is not yet clinically indicated, and in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.1

The LATITUDE study findings, presented at the 2017 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Conference, indicate that treatment with abiraterone acetate plus prednisone, in combination with ADT, significantly delayed time to progression of worst pain intensity (HR 0.63; 95% CI 0.52-0.77; P < 0.0001), pain interference (HR 0.67; 95% CI 0.56-0.80; P < 0.0001), worst fatigue (HR 0.65; 95% CI 0.53-0.81; P = 0.0001) and fatigue interference (HR 0.59; 95% CI 0.47-0.75; P < 0.0001) compared to ADT plus placebos. Findings also show a significant improvement in health-related quality of life (HRQoL), which includes several measures such as physical and emotional wellbeing, demonstrating a reduction in risk of HRQoL degradation (HR 0.85; 95% CI 0.74-0.99; P = 0.0322) compared to ADT plus placebos.2

"In combination with the significant benefits in survival and disease progression, the new data from the LATITUDE clinical trial suggests that abiraterone acetate plus prednisone, in combination with androgen deprivation therapy, offers a much-needed efficacious treatment option for patients with newly diagnosed metastatic disease," said Dr Karim Fizazi, Principal Investigator of the trial and Head of the Medical Oncology Department at Institute Gustave Roussy, France. "These results build upon previous LATITUDE findings published in the New England Journal of Medicine in June and presented during ASCO (Free ASCO Whitepaper) 2017, which found a significant improvement in overall survival and radiographic progression-free survival in patients with newly diagnosed high-risk metastatic hormone-sensitive prostate cancer."

In addition, an indirect comparison of abiraterone acetate plus prednisone and docetaxel for the treatment of mHSPC was also presented at ESMO (Free ESMO Whitepaper). The systematic review, which examined results from LATITUDE as well as several other studies, suggests that abiraterone acetate plus prednisone, in combination with ADT, produces greater reductions in the risk of progression and in risk of death vs ADT plus docetaxel for patients with high risk or high volume disease.3

In addition to the benefits of abiraterone acetate plus prednisone seen in early stage disease, additional findings presented at ESMO (Free ESMO Whitepaper) support the use of abiraterone acetate plus prednisone in its current, mCRPC indications. Preliminary results from the AQUARiUS observational study, which prospectively collects PROs on quality of life, cognition, fatigue and pain, suggest more favourable outcomes for perceived cognitive impairments, functioning and fatigue for mCRPC patients treated with abiraterone acetate plus prednisone compared to those treated with enzalutamide, within the first three months after treatment initiation.4

"Janssen remains dedicated to addressing the challenges around treatments and quality of life for both early and late stage prostate cancer, including the thousands of patients with metastatic prostate cancer in Europe that are diagnosed each year," said Dr Ivo Winiger-Candolfi, Oncology Solid Tumour Therapy Area Lead, Janssen Europe, Middle East, Africa. "We are encouraged by the patient reported outcomes from the AQUARiUS and LATITUDE trials, which further support the use of abiraterone acetate plus prednisone in its current indications, as well as the potential for use in an earlier stage of prostate cancer, respectively. These new results suggest that abiraterone acetate plus prednisone in combination with ADT has the potential to become a standard of care for the treatment of newly diagnosed, high-risk metastatic prostate cancer patients."

-ENDS-

NOTES TO EDITORS

About high-risk metastatic hormone-sensitive prostate cancer (mHSPC)

There are approximately 420,000 men diagnosed with prostate cancer in Europe per year.5 Around 2%-43% (up to 180,000) have metastatic prostate cancer.6,7,8 Not all prostate cancer is the same. It ranges from cancer confined to the prostate gland to cancer that has spread outside of the prostate to the lymph nodes, bones, or other parts of the body. The extent or spread of prostate cancer determines the stage.9 Hormone-sensitive prostate cancer (HSPC) refers to a stage of the disease when the patient has not been treated with ADT.10 Patients with newly diagnosed mHSPC, particularly with high-risk characteristics, have a poor prognosis.10 ADT plus docetaxel has shown improved outcomes in mHSPC, but many patients are not candidates for docetaxel and may benefit from alternative therapy.11

About the LATITUDE Trial12

The Phase 3, multinational, multicentre, randomised, double-blind, placebo-controlled LATITUDE study enrolled 1,199 newly diagnosed patients with mHSPC (no prior treatment with ADT or ≤3 months treatment with ADT before baseline) and was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada. A total number of 597 patients were randomised to receive ADT in combination with abiraterone acetate plus prednisone (n=597), while 602 patients were randomised to receive ADT and placebos (n=602). Patients included had high-risk mHSPC documented by positive bone scan or metastatic lesions at the time of diagnosis on computed tomography (CT) or magnetic resonance imaging (MRI). Additionally, patients had to have at least two of the three following high-risk factors associated with poor prognosis:

Gleason score ≥8
≥3 bone lesions
presence of measurable visceral metastases
These results served the basis for Janssen’s Type II variation application submission to the European Medicines Agency (EMA), seeking to expand the existing marketing authorisation for abiraterone acetate plus prednisone or prednisolone to include the treatment of men with newly-diagnosed, high-risk, metastatic hormone-sensitive prostate cancer (mHSPC). If approved, this will broaden the use of abiraterone acetate plus prednisone to include an earlier stage of prostate cancer than its current indications.

Overall, the safety profile of ADT in combination with abiraterone acetate plus prednisone was consistent with prior studies in patients with metastatic castration-resistant prostate cancer (mCRPC). The most common and anticipated adverse events were elevated incidences of mineralocorticoid-related hypertension and hypokalaemia in the ADT in combination with abiraterone acetate plus prednisone arm compared with ADT and placebos. The incidence rate of grade 3 or higher hypertension (20% vs. 10%) was greater than that observed in prior studies of abiraterone acetate in mCRPC patients. There were no serious sequelae from the increased rate of hypertension. The incidence of hypokalaemia was higher than that reported in prior Phase 3 studies of abiraterone acetate in mCRPC; however, only two patients discontinued treatment due to hypokalaemia and there were no hypokalaemia-related deaths.

The observed degrees of hypertension and hypokalaemia were both medically manageable with antihypertensive medications and potassium supplements as needed, only rarely required treatment discontinuation, and seldom led to serious consequences.

About the AQUARiUS Trial13

The prospective, multinational, observational AQUARiUS study investigates the impact that both abiraterone acetate plus prednisone and enzalutamide have on HRQoL, PROs, and medical resource use in patients with mCRPC. The study enrolled 210 patients with mCRPC and has been conducted at 27 sites in three countries in Europe. The estimated study completion date is March 2018. Primary outcomes being measured are HRQoL, fatigue, pain, cognitive function and medical resource use.

About abiraterone acetate

Abiraterone acetate plus prednisone / prednisolone is the only approved therapy in mCRPC that inhibits production of androgens (which fuel prostate cancer growth) at all three sources that are important in prostate cancer – the testes, adrenals and the tumour itself.1,14,15

Abiraterone acetate plus prednisone / prednisolone has been approved in more than 90 countries to date, and has been prescribed to approximately 330,000 men worldwide.16,17

Indications1

In 2011, abiraterone acetate in combination with prednisone / prednisolone was approved by the European Commission (EC) for the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

In December 2012, the EC granted an extension of the indication for abiraterone acetate permitting its use, in combination with prednisone or prednisolone, for the treatment of mCRPC, in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.1

Further Information1

The most common adverse reactions seen with abiraterone acetate plus prednisone / prednisolone include urinary tract infection, hypokalaemia, hypertension, and peripheral oedema.

For a full list of side effects and for further information on dosage and administration, contraindications and other precautions when using abiraterone acetate plus prednisone / prednisolone please refer to the summary of product characteristics, which is available at: View Source

On September 8, 2017 Ipsen (Euronext: IPN; ADR: IPSEY) reported that the European Medicines Agency (EMA), the European regulatory authority, has validated the application for variation to the Cabometyx (cabozantinib) marketing authorization for the addition of a new indication in first-line treatment of advanced renal cell carcinoma (Press release, Ipsen, SEP 8, 2017, View Source [SID1234520422]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The filing is based on the results of CABOSUN, a phase II trial demonstrating that Cabometyx prolongs progression free survival (PFS) in treatment-naive patients with intermediate- or poor-risk aRCC compared to sunitinib, the standard of care for more than 10 years. If approved, Cabometyx would be the first and only single-agent treatment to demonstrate superior clinical efficacy over the standard of care in both first line (vs. sunitinib) and second line (vs. everolimus) aRCC.

Alexandre Lebeaut, MD, Executive Vice-President, R&D, Chief Scientific Officer, Ipsen, said: "The filing is based on the results of CABOSUN, a phase II trial demonstrating that Cabometyx prolongs progression free survival (PFS) in a statistically and clinically meaningful way in treatment-naive patients with intermediate- or poor-risk advanced RCC compared to sunitinib, the standard of care for more than 10 years. Ipsen’s commitment to oncology and developing innovative therapies for cancer patients is stronger than ever. We continue to be excited about our partnership with Exelixis to investigate new indications for cabozantinib."

In September 2016, Cabometyx was approved in the EU for the treatment of aRCC in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. As of today, Cabometyx is commercially available for the treatment of eligible patients with advanced RCC in Austria, Denmark, Germany, Luxembourg, Norway, The Netherlands, Spain and UK.

About advanced Renal Cell Carcinoma

With the incidence predicted to rise 22% by 2020, renal cell carcinoma (RCC) threatens to become one of the fastest growing cancers in the world.[i] Targeted therapies including tyrosine kinase inhibitors (TKIs) of the VEGF receptor (VEGFR) introduced a decade ago, significantly transformed the treatment landscape of aRCC.[ii]

The American Cancer Society’s 2017 statistics cite kidney cancer as one of the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.[iii] Clear cell RCC is the most common type of kidney cancer in adults.[iv] If detected in its early stages, the five-year survival rate for RCC is high. For patients with advanced- or late-stage metastatic RCC, however, the five-year survival rate is only 12% with no identified cure for the disease.[v] Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.[vi]

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL, and VEGF.[vii]–[viii] These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness, and metastasis.[ix], [x], [xi], [xii] MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors. xii – xv

About Cabometyx (cabozantinib)

Cabometyx is the tablet formulation of cabozantinib. Its targets include MET, AXL, and VEGFR receptors in tumor cells. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis, and drug resistance. Cabometyx is available in 20 mg, 40 mg, or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved Cabometyx tablets for the treatment of patients with aRCC who have received prior anti-angiogenic therapy. On August 16, 2017, Ipsen’s partner Exelixis has submitted a U.S. supplemental new drug application for cabometyx (cabozantinib) for the treatment of previously untreated advanced kidney cancer. On September 9, 2016, the European Commission approved Cabometyx tablets for the treatment of aRCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway, and Iceland. On September 8, 2017, the EMA validated the application for Cabometyx for the treatment in first line aRCC.

About the CABOSUN study

On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with intermediate- or poor-risk aRCC per IMDC (International Metastatic RCC Carcinoma Database Consortium) criteria as determined by investigator assessment. CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the NCI-CTEP. These results were first presented by Dr. Toni Choueiri at the meeting of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2017).[xiii]

On June 19th 2017 Exelixis announced that the analysis of the review by a blinded independent radiology review committee (IRC) has confirmed the primary efficacy endpoint results of investigator-assessed progression-free survival (PFS) from the CABOSUN randomized phase 2 trial of cabozantinib as compared with sunitinib in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Per the IRC analysis, cabozantinib demonstrated a clinically meaningful and statistically significant reduction in the rate of disease progression or death as measured by PFS. The incidence of adverse events (any grade) and the incidence of grade 3 or 4 adverse events between cabozantinib and sunitinib were comparable.

CABOSUN is a randomized, open-label, active-controlled phase II trial that enrolled 157 patients with aRCC determined to be intermediate- or poor-risk per IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, four weeks on followed by two weeks off). The primary endpoint was PFS. Secondary endpoints included overall survival and objective response rate. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2, and had to be intermediate- or poor-risk per IMDC criteria (Heng, JCO, 2009).[xiv] Prior systemic treatment for RCC was not permitted.

On September 8, 2017 Foundation Medicine, Inc. (NASDAQ:FMI) reported presentations at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting highlighting validation data for its novel assay to measure tumor mutational burden from blood (bTMB) (Press release, Foundation Medicine, SEP 8, 2017, View Source [SID1234520421]). These presentations will highlight retrospective data analysis from Roche/Genentech’s Phase II POPLAR and Phase III OAK studies that enabled analytic and clinical validation for the bTMB assay. The studies demonstrate that high bTMB as measured by Foundation Medicine’s assay is associated with response to atezolizumab in individuals with previously-treated non-small cell lung cancer (NSCLC), potentially offering a new option to expand personalized care options for patients with advanced cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Based on these findings, Foundation Medicine also announced today that its bTMB assay will be integrated as part of Roche/Genentech’s prospective, randomized Phase III Blood First Assay Screening Trial (BFAST) as a companion diagnostic assay to investigate bTMB as a non-invasive biomarker of response to first-line atezolizumab in advanced NSCLC patients.

"Foundation Medicine has previously shown that measuring tumor mutational burden from tissue samples can help reliably predict responses to immunotherapies. However, a critical need exists for measuring TMB via a non-invasive solution for cancer patients for whom tissue is not available or when a biopsy is not feasible," said Vincent Miller, M.D., chief medical officer at Foundation Medicine. "Our data at ESMO (Free ESMO Whitepaper) provide the first evidence that response to immunotherapy can be predicted using only a blood sample and we’re pleased that we recently received FDA clinical trial approval for the Phase III study to validate bTMB as a biomarker in first-line immunotherapy. Based on the study results, we expect further development of our bTMB assay as a companion diagnostic, providing an important predictive and complementary solution to FoundationACT liquid biopsy, and ultimately enabling physicians to make informed selection of targeted or immunotherapy treatments in the absence of tissue."

In the studies presented at ESMO (Free ESMO Whitepaper), Foundation Medicine’s bTMB assay was analytically validated to determine TMB with high precision and accuracy from as little as one percent tumor content in a blood sample. The assay was used to retrospectively analyze a total of 794 plasma samples from the Phase II POPLAR and Phase III OAK clinical trials. The analysis showed that atezolizumab demonstrated a clear benefit for overall survival. Additionally, there was a correlation between patients with high bTMB in those studies and longer progression-free survival (PFS) when treated with atezolizumab. In addition, bTMB was not found to correlate with PD-L1 expression levels as measured by tissue-based immunohistochemistry, suggesting that bTMB, like tissue TMB, provides independent and critical predictive information in addition to the information furnished by PD-L1 testing.

The bTMB assay validation presentations will take place during the following times:

Abstract #1295O — Blood-based biomarkers for cancer immunotherapy: Tumor mutational burden in blood (bTMB) is associated with improved atezolizumab (atezo) efficacy in 2L+ NSCLC (POPLAR and OAK), Sept 8, 4:00pm – 5:30pm, Madrid Auditorium (Oral Presentation)

Abstract #102P — Analytic validation of a next generation sequencing assay to identify tumor mutational burden from blood (bTMB) to support investigation of an anti-PD-L1 agent, atezolizumab, in a first line non-small cell lung cancer trial (BFAST), Sept 11, 1:15pm – 2:15pm, Hall 8 (Poster Presentation)

In totality, the company and its collaborators will present a total of 19 studies at the ESMO (Free ESMO Whitepaper) Annual Meeting, including three oral presentations, seven poster discussions and nine posters, which support the integration of comprehensive genomic profiling (CGP) and biomarkers such as tissue- and blood-based TMB to help guide personalized cancer care. These new data include insights into the landscape of tissue-based TMB across various types of cancer, which may help further stratify molecular subtypes of disease and guide more personalized treatment. Results will be presented from a study of more than 80,000 solid tumors, a study of more than 22,000 gastrointestinal cancers and a study of more than 2,000 melanoma cases (the largest known cohort of metastatic melanoma cases with comprehensive genomic profiling released to date). Together these results reveal pan-tumor and disease-specific alterations that may inform rational selection of immunotherapy.

Furthermore, new studies show the prevalence of TMB in subtypes of certain cancers where immunotherapy is not often considered, such as breast and thymic cancers. These findings may help expand the utility of TMB into new indications.

The European Society for Medical Oncology Annual Meeting will be held from September 8-12, 2017 in Madrid, Spain.

On September 8, 2017 Celgene Corporation (NASDAQ:CELG) reported that data from multiple studies evaluating investigational uses of ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) will be presented during the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Annual Meeting between September 8-12 in Madrid, Spain (Press release, Celgene, SEP 8, 2017, View Source [SID1234520420]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data presented at ESMO (Free ESMO Whitepaper) highlight investigational uses of ABRAXANE to potentially treat patients with particularly challenging diseases, either alone or in combination with other agents," said Nadim Ahmed, President, Hematology and Oncology for Celgene. "Through these data, we are able to continue advancing our understanding and treatment of these cancers especially in patient populations with historically limited treatment options."

In advanced non-small cell lung cancer (NSCLC), abstracts from three studies in the ABOUND program continue to evaluate investigational uses of ABRAXANE. ABOUND 2L+ is a Phase II trial evaluating second-line monotherapy or combination treatment with an immune checkpoint inhibitor or epigenetic therapy. ABOUND.SQM is a Phase III study evaluating ABRAXANE as combination treatment with carboplatin as induction therapy for those with squamous disease. ABOUND 70+ is a Phase IV study evaluating the first-line treatment of ABRAXANE + carboplatin in patients 70 years and older.

Additionally, updated data from the Phase II LAPACT study evaluating the investigational use of ABRAXANE in patients with locally advanced, non-resectable pancreatic cancer will be presented.

Selected abstracts include*:

Non-Small Cell Lung Cancer

Abstract LBA48; Oral; Friday, September 8, 4:00 p.m., Madrid Auditorium, ABOUND.2L+: nab-paclitaxel (nap-P) +/- CC-486 or durvalumab in previously treated patients with advanced non-small cell lung cancer (NSCLC) (Morgensztern)

Abstract 1369P; Poster; Saturday, September 9, 1:15 p.m., Hall 8, nab-Paclitaxel/carboplatin (nab-P/C) induction therapy in squamous (SCC) non-small cell lung cancer (NSCLC): interim safety results from ABOUND.sqm (Gridelli)

Abstract 1366P; Poster; Saturday, September 9, 1:15 p.m., Hall 8, Effect of nab-paclitaxel/carboplatin (nab-P/C) induction therapy on quality of life (QoL) of patients with squamous (SCC) non-small cell lung cancer (NSCLC) (ABOUND.sqm) (Ponce Aix)

Abstract 1367P; Poster; Saturday, September 9, 1:15 p.m., Hall 8, Quality of Life (QoL) in Elderly NSCLC Patients (pts) Treated with nab-Paclitaxel/Carboplatin (nab-P/C) in the ABOUND.70+ Trial (Langer)

Pancreatic Cancer

Abstract 622PD; Poster Discussion; Monday, September 11, 4:30 p.m., Cordoba Auditorium, nab-Paclitaxel (nab-P) plus gemcitabine (G) for patients (Pts) with locally advanced pancreatic cancer (LAPC): Interim efficacy and safety results from the Phase 2 LAPACT Trial (Philip)

Abstract 730P; Poster; Saturday, September 9, 1:15 p.m., Hall 8, Interim Health-Related Quality of Life (QoL) From LAPACT, a Phase 2 Trial of nab-Paclitaxel (nab-P) Plus Gemcitabine (G) for Patients (pts) With Locally Advanced Pancreatic Cancer (LAPC) (Portales)

In advanced NSCLC, Abraxane is not approved for use as monotherapy or in combination with CC-486 or durvalumab. Abraxane is also not approved for use as a second-line therapy in advanced NSCLC. Abraxane is not approved for patients with locally advanced pancreatic cancer. The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

*All times Central European Standard Time (CEST)

A complete listing of abstracts can be found on the ESMO (Free ESMO Whitepaper) website at View Source

About ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

ABRAXANE is an albumin-based nanotechnology therapy approved for the treatment of metastatic breast cancer, advanced non-small cell lung cancer and metastatic 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.