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BeiGene Announces First Patient Dosing in China with Investigational PARP Inhibitor BGB-290

On December 21, 2016 BeiGene, Ltd. (NASDAQ:BGNE), a clinical-stage biopharmaceutical company developing molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the dosing of the first patient in a Phase I clinical trial of BGB-290, a potent and selective PARP inhibitor, in Chinese patients with advanced solid tumors (Press release, BeiGene, DEC 21, 2016, View Source [SID1234517156]).

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"We are pleased to announce the start of clinical development for BGB-290 in China, and we look forward to its rapid development following this Phase I study. BGB-290 entered clinical evaluation in Australia in July 2014, and proof of principle data were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC meeting in 2015. We look forward to developing BGB-290 for patients in China, where this class of agents is still not available," commented John V. Oyler, Founder, Chief Executive Officer, and Chairman.

The Phase I open-label, multi-center dose escalation and expansion study of BGB-290 is designed to investigate the safety, pharmacokinetics, and antitumor activity of BGB-290 in Chinese patients with advanced solid tumors and to determine the recommended Phase II dose in these patients. Professor Binghe Xu from The Chinese Academy of Medical Sciences Cancer Hospital is the principal investigator of the study.

About BGB-290

BGB-290 is a potent and highly selective inhibitor of PARP1 and PARP2. BGB-290 is being developed as a monotherapy and in combination with other therapies for the treatment of several cancers including ovarian cancer, prostate cancer, breast cancer, glioblastoma multiforme, small cell lung cancer, and gastric cancer.

Incyte and Merus Announce Global Strategic Research Collaboration to Discover and Develop Bispecific Antibodies

On December 21, 2016 Incyte Corporation (NASDAQ:INCY) and Merus N.V. (NASDAQ:MRUS) reported that they have entered into a global, strategic collaboration agreement focused on the research, discovery and development of bispecific antibodies utilizing Merus’ proprietary Biclonics technology platform (Press release, Incyte, DEC 21, 2016, View Source [SID1234517155]). The Collaboration and License Agreement grants Incyte the exclusive rights for up to eleven bispecific antibody research programs, including two of Merus’ current preclinical immuno-oncology discovery programs.

Biclonics retain the IgG format of antibodies that are produced naturally by the immune system and, by binding to two targets, enable multiple modes of action that cannot otherwise be obtained with conventional monoclonal antibodies.

"By virtue of a unique ability to simultaneously engage multiple protein targets, we believe bispecific antibodies have the potential to play an important role in the future of biotherapeutics," said Reid Huber, Ph.D., Incyte’s Chief Scientific Officer. "This collaboration with Merus expands our large molecule discovery capabilities into an innovation-rich area of research, creating additional opportunities for us to deliver on our commitment to improving and extending the lives of patients with cancer and other serious diseases."

"This transformative, global collaboration further underscores the potential of Merus’ Biclonics technology platform and establishes a strong relationship with Incyte, a leader in innovative drug development," said Ton Logtenberg, Ph.D., Chief Executive Officer of Merus. "We look forward to expanding our pipeline under this agreement, as we efficiently exploit our preclinical discovery engine and progress our most advanced, proprietary assets in the clinic."

Terms of the Collaboration
Under the terms of the collaboration, Incyte has agreed to pay Merus an upfront payment of $120 million. In addition, Incyte has agreed to purchase 3.2 million shares of Merus stock at $25 per share, for a total equity investment of $80 million.

The parties have agreed to collaborate on the development and commercialization of up to 11 bispecific antibody programs. For one current preclinical program, Merus will retain all rights to develop and commercialize approved products in the United States, and Incyte will develop and commercialize approved products arising from the program outside the United States. Following any regulatory approval of a product candidate for this particular pre-clinical program, each company has agreed to pay the other tiered royalties ranging from 6 to 10 percent on net sales of products in their respective territories.

Merus also has the option to co-fund development of product candidates arising from two other programs. For any program for which Merus exercises its co-development option, Merus would be responsible for 35 percent of global development costs in exchange for a 50 percent share of U.S. profits and losses and tiered royalties ranging from 6 to 10 percent on ex-U.S. sales by Incyte for these programs. Merus also has the right to elect to provide up to 50 percent of detailing activities for product candidates arising from one of these programs in the United States.

For each of the other eight programs, Incyte has agreed to independently fund all development and commercialization activities. For these programs, Merus will be eligible to receive potential development, regulatory and sales milestone payments of up to $350 million per program, which could result in an aggregate milestone opportunity of approximately $2.8 billion if all development, regulatory and sales milestones are achieved across all such eight other programs in all territories. Merus will also be eligible to receive tiered royalties ranging from 6 to 10 percent on global sales of any approved products under these eight programs.

Merus will retain rights to both of its clinical candidates and MCLA-158, as well as its technology platform and future programs emerging from Merus’ platform that are outside the scope of this agreement.

The transaction is expected to close in the first quarter of 2017, subject to the early termination or expiration of any applicable waiting periods under the Hart-Scott Rodino Act and customary closing conditions.

BioInvent announces Cancer Immunotherapy Research Collaboration and License Agreement with Pfizer and issues new shares to Pfizer

On December 21, 2016 BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel immuno-regulatory antibodies to treat cancer, reported that it has entered into a cancer immunotherapy research collaboration and license agreement with Pfizer Inc. ("Pfizer") (NYSE: PFE) to develop antibodies targeting tumour-associated myeloid cells (Press release, BioInvent, DEC 21, 2016, View Source [SID1234517154]).

Under the terms of the deal, Pfizer will pay BioInvent approximately $10 million in early payments, including an upfront payment, early research funding, and a $6 million equity investment in new shares of BioInvent at a subscription price of SEK 2.56 per share, which corresponds to an approximately 30% premium to the average volume weighted price for the share during the 10 trading days prior to 21 December 2016.

Assuming five antibodies are developed through to commercialization, BioInvent would be eligible for potential future payments related to certain development milestones, which could amount to more than $0.5 billion through the term of the deal, as well as up to double digit royalties related to any potential products that may result from the collaboration. Pfizer will have the right to develop and commercialize any antibodies generated to an undisclosed number of tumour-associated myeloid cell targets.

Commenting on the agreement, Michael Oredsson, CEO of BioInvent said: "We are very pleased to announce this discovery and development collaboration with Pfizer which will leverage our cancer antibody biology and immuno-oncology expertise. We are looking forward to working with Pfizer to deliver a number of first-in-class antibodies to potentially treat a range of cancer indications addressing unmet patient needs."

BioInvent will leverage its cancer biology expertise, combined with its unbiased translational drug discovery approach ("F.I.R.S.T"), to identify novel oncology targets and therapeutic antibodies that inhibit cancer growth either by reversing the immunosuppressive activity of tumour-associated myeloid cells or by reducing the number of tumour-associated myeloid cells in the tumour.

"We believe co-targeting of tumour-associated myeloid cells has the potential to significantly improve the efficacy of currently available checkpoint inhibitor therapies, and may help activate anti-cancer immunity in currently non-responding patients and cancer types" said Björn Frendéus, CSO of BioInvent.

"We look forward to collaborating with BioInvent, as we believe that modulating the activity of tumour-associated myeloid cells presents an opportunity to help us expand our portfolio in oncology and ultimately deliver on our mission to bring innovative new medicines to cancer patients," said Robert Abraham, Ph.D., Senior Vice President and Head of Pfizer’s Oncology Research & Development Group, Pfizer.

Directed Share Issue
As part of the agreement, the Board of Directors of BioInvent on 21 December 2016 resolved, based on the authorization of the annual general meeting on 12 May 2016, on a directed issue of 21,973,594 new shares to Pfizer at a subscription price per share of SEK 2.56, corresponding to a total investment of $6 million. The subscription price corresponds to an approximately 30% premium to the average volume weighted price for BioInvent’s share during the 10 trading days prior to 21 December 2016. The reason for the derogation from the shareholders’ preferential right is that the investment, in addition to providing BioInvent with new capital, brings Pfizer as a new strategic partner, in alignment with shareholders’ interests as a new shareholder.

As a result of the new share issue, the number of shares in BioInvent will increase from 282,721,619 shares to 304,695,213 shares, and the share capital will increase from 22,617,730 to 24,375,617. The new shares are expected to be registered with the Swedish Companies Registration Office and admitted for trade on Nasdaq Stockholm on 28 December 2016. Pfizer have undertaken, on customary terms and conditions, not to sell or otherwise dispose of the shares of the investment during a period of 90 days from the share issue. Following the directed share issue, Pfizer will own approximately 7,2% of BioInvent’s share capital.

Sumitomo Dainippon Pharma to Acquire Tolero Pharmaceuticals, Inc.(US Biotechnology Company)

On December 21, 2016 Sumitomo Dainippon Pharma Co., Ltd. (Head office: Osaka, Japan; President: Masayo Tada; Securities Code: 4506, First Section of TSE, "Sumitomo Dainippon Pharma") reported that the company and Tolero Pharmaceuticals, Inc. (Head office: Lehi, UT, U.S., CEO: David J. Bearss., "Tolero") have reached an agreement on December 21, 2016 on the acquisition of Tolero through U.S. Holding company wholly owned by Sumitomo Dainippon Pharma (Press release, Dainippon Sumitomo Pharma, DEC 21, 2016, View Source [SID1234517153]).

According to the terms of the agreement, Sumitomo Dainippon Pharma will make an upfront payment of US$ 200 million to the shareholders of Tolero on closing of the acquisition, and thereafter it will make development milestone payments up to US$ 430 million related to the compounds being developed by Tolero based on its progress. Furthermore, after the launch, Sumitomo Dainippon Pharma will also make commercial milestone payments up to US$ 150 million, based on the net sales of the compounds.

1. Objectives of acquisition
Tolero is a biotechnology company in the U.S. specializing in research and development of therapeutic agents in the areas of oncology and hematological disorders. Tolero possesses excellent drug discovery capabilities for kinase inhibitors and other drug targets, and is developing the six compounds below, including cyclin-dependent kinase 9 (CDK9) inhibitor alvocidib, which is under clinical development for hematologic malignancies.

Compound Mechanism Stage alvocidib CDK9 inhibitor Phase 2 study completed / Acute myeloid leukemia Phase 2 study ongoing / Acute myeloid leukemia with biomarker Preclinical Myelodysplastic syndromes with biomarker TP-0903 AXL Kinase inhibitor Phase 1 study ongoing / Solid tumors TP-1287 Oral CDK9 inhibitor Preclinical TP-0184 ALK2 inhibitor Preclinical

In addition to the above list, Tolero possesses two compounds in the preclinical stage.

Torelo has demonstrated POC (Proof of Concept) of alvocidib in a randomized Phase 2 study for acute myeloid leukemia (AML). Tolero is also currently conducting a Phase 2 study for 2 biomarker-positive patients of the disease in the U.S. Tolero aims for a New Drug Application to the FDA in fiscal 2018 at the earliest.

Masayo Tada, Representative Director, President and CEO of Sumitomo Dainippon Pharma, stated that "Oncology, which is one of our focus therapeutic areas, has extremely high unmet medical needs, and we believe that it is the vital mission of any R&D-oriented pharmaceutical company to deliver innovative treatment options to patients and their families. As Tolero possesses a group of attractive development compounds, including alvocidib, we expect that this acquisition will help us to reinforce our oncology pipeline and achieve sustained growth of the Sumitomo Dainippon Pharma Group after the expiry of the exclusivity period of our mainstay atypical antipsychotic LATUDA. Now that Tolero’s high drug discovery abilities are on our side, we also expect to create a continuous flow of development compounds going forward."

2. Outline of the acquisition After the acquisition, Tolero will become a wholly-owned subsidiary of Dainippon Sumitomo Pharma America Holdings, Inc. (Head office: MA, U.S., "Holding company"), a holding company wholly-owned by Sumitomo Dainippon Pharma, and continue its research and development in Lehi, Utah. The boards of directors of Sumitomo Dainippon Pharma and Tolero have each approved this acquisition. However, fulfillment of the terms and conditions of the U.S. Antitrust Law and completion of statutory procedures (including approval from Tolero’s shareholders) are required to complete the acquisition. After completion of these procedures, the acquisition is expected to be deemed closed in February 2017. In this transaction, Lazard Frères K.K. serves as Sumitomo Dainippon Pharma’s financial advisor and Jones Day serves as its legal advisor. The acquisition will be implemented by way of a merger between Tolero and a special purpose company which has been established under the Holding company for facilitating this deal. Tolero will be the surviving company. The existing shareholders of Tolero will receive cash in compensation for the merger.

3. Outline of Tolero (1) Company Name Tolero Pharmaceuticals, Inc. (2) Address of Headquarters 2975 Executive Parkway Suite # 320 Lehi, UT 84043, U.S. (3) Representative CEO：David J. Bearss (4) Business Description Research and Development of pharmaceuticals in the areas of oncology and hematological disorders. (5) Share Capital US$ 866 (As of December 14,2016) (6) Date Established June 2011 (7) Major shareholders and shareholding ratio David J. Bearss (22.1%), Orelot LLC (15.2%), Alger Health Sciences Fund（8.9%）and others (As of December 14, 2016) › (8) Relationship with Nothing particular in terms of capital tie, personal connection. 3 Sumitomo Dainippon Pharma In November 2016, Sumitomo Dainippon Pharma and Tolero entered into a loan agreement (where Sumitomo Dainippon Pharma is a creditor) with the upper limit being set at US$ 6 million. (9) Financial status for recent business years (consolidated) Fiscal Year (US$) FY2013 FY2014 FY2015 Shareholder’s equity △7,691thousand △14,461 thousand △25,473 thousand Total assets 844 thousand 13,172 thousand 3,546 thousand Shareholder’s equity per share △0.9 △1.7 △2.9 Revenue 142 thousand －－ Operating profit △2,958 thousand △4,557 thousand △9,742 thousand Net income △4,473 thousand △6,328 thousand △9,340 thousand Earnings per share △0.5 △0.7 △1.1 Dividend per share －－－ › Shown the name of the representative investor and shareholding ratio of aggregate amount of shares jointly held by the joint holders where applicable

4. Number of owned shares and percentage of ownership before and after acquisition (1) Number of shares already acquired 0 shares Percentage of voting rights: 0% (2) Number of shares to be acquired 100 shares ›Note 1 Percentage of voting rights: 100% (Planned) (3) Total value for the acquisition Approximately up to US$ 780 million ›Note 2 Details: Upfront payment: US$ 200 million Development and commercial milestone: up to US$ 580 million Note 1: This acquisition will be made through a cash merger. Sumitomo Dainippon Pharma will not acquire Tolero’ shares because all outstanding shares of Tolero will be extinguished in exchange for cash payment to existing shareholders as consideration for the merger. Note 2: Total value for the acquisition does not include advisory fees and so forth (approximately ￥700 million).

5. Schedule (1) Sumitomo Dainippon Pharma’s Board Meeting Resolution December 21, 2016 (2) Signing Date December 21, 2016 (3) Completion of Acquisition February, 2017 (will be completed) › › As stated in (2) above, fulfillment of the terms and conditions of the U.S. Antitrust Law and the completion of statutory procedures (including approval from Tolero’s shareholders) are 4 required to complete the acquisition.

6. Financial impact on group performance Financial impact on the Sumitomo Dainippon Pharma’s consolidated financial results for fiscal year ending March 31, 2017 and beyond is currently under review. We will make an announcement if any other disclosure is required. (Reference)

Cyclin-dependent kinase (CDK) 9 inhibitor; alvocidib

Alvocidib targets CDK9, a member of cyclin-dependent kinase family, which activates transcription of cancer-related genes. The subsequent down-regulation of MCL-1, an anti-apoptotic gene, may be responsible for the potential clinical anti-cancer activity observed with alvocidib.
Alvocidib is an investigational intravenous small-molecule agent and it received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the treatment of acute myeloid leukemia (AML). National Cancer Institute (NCI) conducted alvocidib’s Phase 2 study（J-1101/NCI-8972, Haematologica 2015;100(9)） comparing ACM regimen (alvocidib, cytarabine and mitoxantrone) to the standard-of-care (cytarabine and daunorubicin), in front line AML patients who had one or more poor-risk features. In this study, ACM regimen (alvocidib combination therapy) demonstrated a statistically significant improvement in the complete remission (CR) rate, one of primary endpoints for AML therapy, compared to the standard-of-care, 70 % and 46 %, respectively. Moreover, the tolerability of both regimens was similar.
Alvocidib is licensed from Sanofi S.A. (Head office: France) to Tolero for exclusive worldwide rights to develop and commercialize. Torelo will make payments to Sanofi on the successful achievement of milestones related to the commercialization and pay tiered royalties on sales of alvocidib.

Torelo is also developing TP-1287 (oral delivery), a prodrug of alvocidib.

AXL receptor tyrosine kinase inhibitor; TP-0903

AXL is known to be involved in acquiring resistance to conventional agents and developing metastatic capacity in cancer cells. TP-0903 targeting AXL is a potential anti-cancer agent for a variety of cancer types. ALK2 inhibitor; TP-0184 TP-0184 inhibits enzymatic activity of activin receptor-like kinase-2(ALK2）, a member of bone morphogenetic protein (BMP) receptor family, leading to decreased expression of hepcidin, which is a circulating peptide overexpressed in hepatic cells in response to chronic inflammation related to cancer and auto immune diseases. TP-0184 has a potential to ameliorate anemia of chronic disease.

FDA Accepts Supplemental New Drug Application for Pfizer’s IBRANCE® (palbociclib) in HR+, HER2- Metastatic Breast Cancer

On December 21, 2016 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has accepted for review a supplemental New Drug Application (sNDA) for its first-in-class CDK 4/6 inhibitor, IBRANCE (palbociclib) (Press release, Pfizer, DEC 21, 2016, View Source [SID1234517152]). The sNDA supports the conversion of the accelerated approval of IBRANCE in combination with letrozole to regular approval and includes data from the Phase 3 PALOMA-2 trial, which evaluated IBRANCE as initial therapy in combination with letrozole for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer. This is the same patient population as the randomized Phase 2 PALOMA-1 trial upon which the accelerated approval of IBRANCE plus letrozole was granted in February 2015.

The sNDA was granted Priority Review status, which accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing.1 The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in April 2017.

"Since its introduction in 2015, more than 45,000 patients have been prescribed IBRANCE by more than 9,000 providers in the U.S.," said Liz Barrett, global president and general manager, Pfizer Oncology. "We are pleased that the PALOMA-2 trial has further demonstrated the significant clinical benefit of IBRANCE in the first-line setting, providing additional evidence for its continued use as a standard of care medicine."

PALOMA-2 is a randomized (2:1), multicenter, double-blind Phase 3 study that evaluated a total of 666 women from 186 global sites in 17 countries. The results of PALOMA-2 were presented at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June and recently published in the November 17, 2016 issue of The New England Journal of Medicine. The study demonstrated that IBRANCE in combination with letrozole improved progression-free survival compared to letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. The adverse events observed with IBRANCE in combination with letrozole in PALOMA-2 were generally consistent with their respective known adverse event profiles.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is the first and only FDA approved oral inhibitor of CDKs 4 and 6,2 which are key regulators of the cell cycle that trigger cellular progression.3,4 IBRANCE is approved in more than 50 countries.

In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.2 The indication in combination with letrozole is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).