On December 17, 2022 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that presentations on a series of abstracts highlighting updates on its in-house discovered lenvatinib mesylate (product name: LENVIMA, the orally available kinase inhibitor, "lenvatinib") will be given at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (#GI22), taking place in-person in San Francisco, California, and virtually, from January 20 to 22, 2022 (Press release, Eisai, JAN 17, 2022, View Source [SID1234605503]).

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At this symposium, the results of a primary analysis of a prospective clinical study evaluating transcatheter arterial chemoembolization (TACE) therapy in combination strategy with lenvatinib (TACTICS-L) in patients with unresectable hepatocellular carcinoma (uHCC) in Japan (Abstract No: 417), as well as research updates on the Phase IV Study (STELLAR) to evaluate safety and tolerability of lenvatinib in patients with advanced/unresectable hepatocellular carcinoma (Abstract No: TPS485) and results from a clinical study to evaluate the efficacy of lenvatinib for conversion surgery in patients with uHCC (investigator-initiated study in Japan, Abstract No: 458), will be presented.

In addition, trial-in-progress (TiP) posters from the clinical program evaluating the combination therapy of lenvatinib plus pembrolizumab (product name: KEYTRUDA), the anti-PD-1 therapy from Merck & Co., Inc., Kenilworth, N.J., U.S.A. (known as MSD outside the United States and Canada), include the Phase III LEAP-014 Study of the combination plus chemotherapy in patients with esophageal carcinoma squamous cell carcinoma (Abstract No: TPS367), Phase III LEAP-015 Study of the combination plus chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma (Abstract No: TPS369), Phase III Study LEAP-012 of the combination plus TACE in patients with intermediate-stage hepatocellular carcinoma not amenable to curative treatment (Abstract No: TPS494), and Phase II Study of the combination plus belzutifan in patients with advanced solid tumors (Abstract No: TPS669).

In March 2018, Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A., through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of lenvatinib.

Eisai positions oncology as a key therapeutic area and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai will continue to create innovation in the development of new drugs based on cutting-edge cancer research, as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

This release discusses investigational compounds and investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

The full list of Eisai poster presentations is below.

Compound
Abstract No. Title / Scheduled Date
Lenvatinib

417
Transcatheter arterial chemoembolization therapy in combination strategy with lenvatinib in patients with unresectable hepatocellular carcinoma (TACTICS-L) in Japan: Primary analysis

January 21 (Fri)
Lenvatinib

TPS485*
A multicenter, observational, phase 4 study (STELLAR) to evaluate the safety and tolerability of lenvatinib (LEN) in patients with advanced or unresectable hepatocellular carcinoma (uHCC)

January 21 (Fri)
Lenvatinib

458
Multicenter prospective study to evaluate the efficacy of lenvatinib to achieve conversion surgery for initially unresectable hepatocellular carcinoma: LENS-HCC trial (Investigator-initiated study in Japan)

January 22 (Sat)
Lenvatinib + pembrolizumab

TPS367*
LEAP-014: an open-label, randomized, phase 3 study of first-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal carcinoma squamous cell carcinoma

January 20 (Thu)
Lenvatinib + pembrolizumab

TPS369*
LEAP-015: A randomized phase 3 study evaluating the efficacy and safety of first-line pembrolizumab plus lenvatinib plus chemotherapy versus chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma

January 20 (Thu)
Lenvatinib + pembrolizumab

TPS494*
LEAP-012 Trial in progress: Transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment

January 20 (Thu)
Lenvatinib + pembrolizumab

TPS669*
MK-6482-016： Phase 2, open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors

January 20 (Thu)
* The presentation with TPS (Trial in Progress Submission) attached to the abstract number indicates that the study is in the intermediate stage, and the presentation does not report the final study results.

1．About the Merck & Co., Inc., Kenilworth, N.J., U.S.A. and Eisai Strategic Collaboration

In March 2018, Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A., known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with KEYTRUDA, the anti-PD-1 therapy from Merck & Co., Inc., Kenilworth, N.J., U.S.A.

In addition to ongoing clinical studies evaluating the LENVIMA plus KEYTRUDA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in more than 10 different tumor types across more than 20 clinical trials.

2. Eisai’s Focus on Cancer

Eisai focuses on the development of anticancer drugs, targeting the tumor microenvironment (with experience and knowledge from existing in-house discovered compounds) and the driver gene mutation and aberrant splicing (leveraging RNA Splicing Platform) as areas (Ricchi) where real patient needs are still unmet, and where Eisai can aim to become a frontrunner in oncology. Eisai aspires to discover innovative new drugs with new targets and mechanisms of action from these Ricchi, with the aim of contributing to the cure of cancers.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., U.S.A.

On January 17, 2022 AstraZeneca and Daiichi Sankyo reported that they have received notification of acceptance of the supplemental Biologics License Application (sBLA) of Enhertu (trastuzumab deruxtecan) for the treatment of adult patients in the US with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen. The application has also been granted Priority Review (Press release, AstraZeneca, JAN 17, 2022, View Source [SID1234605502]).

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Enhertu is a HER2-directed antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.1 The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is during the second quarter of 2022.

The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) programme and Project Orbis, two initiatives of the FDA which are designed to bring effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines among participating international partners.

Breast cancer is the most common cancer worldwide, with more than two million cases diagnosed in 2020, resulting in nearly 685,000 deaths globally.2 Approximately one in five cases of breast cancer are considered HER2-positive.3 Despite initial treatment with trastuzumab and a taxane, patients with HER2-positive metastatic breast cancer will often experience disease progression.4 More treatment options are needed to further delay progression and extend survival.4-6

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "This review across geographies and the Priority Review in the US as part of Project Orbis is so important because it speaks to the transformative potential of Enhertu based on the unprecedented progression-free survival benefit in this setting. The news reinforces the importance of bringing this potential new option to patients as quickly as possible."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "This regulatory review of Enhertu in the US marks the first time this medicine is participating in both the Real-Time Oncology Review and Project Orbis programmes. The FDA’s prioritisation of our application underscores the potential of this medicine and the continued need to expedite the availability of new treatment options, while making it possible to potentially receive approvals in several countries concurrently."

The sBLA is based on data from the DESTINY-Breast03 trial presented during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021.

In the trial, Enhertu demonstrated a 72% reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio [HR] 0.28; 95% confidence interval [CI]: 0.22-0.37; p=7.8×10-22) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

DESTINY-Breast03 also recorded that nearly all patients treated with Enhertu during the trial were alive at one year (94.1%) compared to 85.9% of patients treated with T-DM1. Confirmed objective response rate (ORR) more than doubled in the Enhertu arm versus the T-DM1 arm (79.7% vs. 34.2%). The safety profile of Enhertu was consistent with previous clinical trials, with no new safety concerns identified and no Grade 4 or 5 treatment-related interstitial lung disease events.

In September 2021, Enhertu received its fourth Breakthrough Therapy Designation (BTD) in the US for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens.

Enhertu is approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in more than 30 countries based on the results from the DESTINY-Breast01 trial.

Enhertu is being further assessed in a comprehensive clinical development programme evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.

Notes

HER2-positive breast cancer
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths in women worldwide.2 More than two million patients with breast cancer were diagnosed in 2020, resulting in nearly 685,000 deaths globally.2 Approximately one in five cases of breast cancer are considered HER2-positive.3

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast, gastric, lung and colorectal cancers.7 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer.8

Despite initial treatment with trastuzumab and a taxane, people with HER2-positive metastatic breast cancer will often experience disease progression.4 More treatment options are needed to further delay progression and extend survival.4-6

DESTINY-Breast03
DESTINY-Breast03 is a global head-to-head, randomised, open-label, registrational Phase III trial evaluating the safety and efficacy of Enhertu (5.4mg/kg) versus T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

The primary efficacy endpoint of DESTINY-Breast03 is progression-free survival (PFS) based on blinded independent central review. Secondary efficacy endpoints include overall survival, ORR, duration of response, PFS based on investigator assessment and safety.

DESTINY-Breast03 enrolled approximately 500 patients at multiple sites in Asia, Europe, North America, Oceania and South America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial. A Type II Variation is currently under review by the European Medicines Agency (EMA) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast03 trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial. A Type II Variation is currently under review by the EMA for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior anti-HER2-based regimen.

Enhertu development programme
A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Enhertu was highlighted in the Clinical Cancer Advances 2021 report as one of two significant advancements in the "ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers," based on data from both the DESTINY-CRC01 and DESTINY-Gastric01 trials, as well as one of the targeted therapy advances of the year in non-small cell lung cancer (NSCLC), based on the interim results of the HER2-mutated cohort of the DESTINY-Lung01 trial.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment. AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation oral selective oestrogen receptor degrader (SERD) and potential new medicine camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research Lynparza in metastatic breast cancer patients with an inherited BRCA mutation and are exploring new opportunities to treat these patients earlier in their disease.

Building on the first approval of Enhertu, a HER2-directed ADC, in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings.

To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, evaluating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On January 16, 2022 Jacobio reported that it’s self-developed global first-in-class drug Aurora A inhibitor JAB-2485 received IND (Investigational New Drug) from the FDA (Food and Drug Administration) in US (Press release, Jacobio Pharmaceuticals, JAN 16, 2022, View Source [SID1234605499]). Jacobio plans to initiate a Phase I/IIa clinical trial in patients with advanced solid tumors in the US .

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JAB-2485 is a highly selective small molecule Aurora A inhibitor. JAB-2485 can inhibit Aurora A activity at the cellular level, induce apoptosis and inhibit tumor growth. At present, there is no commercialized Aurora A inhibitor globally. Jacobio’s self-developed JAB-2485 is the third Aurora A inhibitor enter into clinical stage in the United States.

JAB-2485 has good anti-tumor activity. Preclinical data show that JAB-2485 is highly selective at biochemical and cellular levels. The inhibitory activity of Aurora A is one thousand times higher than that of Aurora B, and has potential to benefit patients with small cell lung cancer and triple negative breast cancer.

Relevant studies have shown that Aurora A and SHP2 inhibitors may be one of the therapies to solve the drug resistance of KRAS G12C inhibitors, Jacobio has these three self-developed drugs in clinical stage, including SHP2 inhibitors (JAB-3068 and JAB-3312), Aurora A inhibitor (JAB-2485) and KRAS G12C inhibitors (JAB-21822), which has potential to provide more combination therapies to patients.

On January 15, 2022 GlaxoSmithKline (GSK) plc reported that it has received three unsolicited, conditional and non-binding proposals from Unilever plc to acquire the GSK Consumer Healthcare business (Press release, GlaxoSmithKline, JAN 15, 2022, View Source [SID1234605495]). The latest proposal received on 20th December 2021 was for a total acquisition value of £50 billion comprising £41.7 billion in cash and £8.3 billion in Unilever shares. The Consumer Healthcare business is a Joint Venture between GSK and Pfizer, with GSK holding a majority controlling interest of 68% and Pfizer 32%.

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GSK rejected all three proposals made on the basis that they fundamentally undervalued the Consumer Healthcare business and its future prospects.

The Board of GSK is strongly focused on maximising value for GSK shareholders and has carefully evaluated each Unilever proposal. In doing so, the Board and its advisers assessed the proposals relative to the financial planning assessments completed to support the proposed demerger of the business in mid-2022, including the sales growth outlook set out below.

Global leader in Consumer Healthcare
The Consumer Healthcare business has been transformed since 2014 through the successful integrations of GSK’s business with the Novartis consumer health portfolio in 2015 and the Pfizer portfolio in 2019. Importantly, this transformation has also provided a platform to scale and optimise many aspects of the Consumer Healthcare business including divesting lower growth brands, introducing a new R&D/innovation model, optimising the supply chain and manufacturing network, alongside continued investment in new digital, data and analytic platforms and capabilities.

This has resulted in the creation of a leading global consumer healthcare business with annual sales of £9.6 billion in 20211. The business has an exceptional portfolio of world-class, category-leading brands; global scale with footprint and distribution capability to serve more than 100 markets; strong brand building, innovation and digital capabilities; and offers a unique proposition that combines trusted science with human understanding.

The business is led by a highly skilled management team with deep experience in consumer healthcare and FMCG with strong commitment to delivery on its purpose and growth ambitions.

Superior growth and highly attractive financial profile
The business is well-positioned to sustainably grow ahead of its categories in the years to come. The fundamentals for the £150 billion consumer healthcare sector are strong, reflecting an increased focus on health and wellness, significant demand from an ageing population and emerging middle class, and sizeable unmet consumer needs.

Over the period 2019-2021 the Consumer Healthcare business delivered a 4% organic sales growth CAGR2 outpacing its categories and despite the adverse impact of the COVID pandemic.

Superior sales growth for the business is expected to result from a strategy that puts the consumer at the heart of the business to better address every-day health and wellness needs, in particular by increasing household penetration of its leading brands and capitalising on new and emerging growth opportunities arising from innovation and the use of new technologies and digital platforms, all underpinned by continued strong execution and financial discipline. Over the medium term, superior sales growth is expected to be primarily driven by continued momentum of key brands in Oral Care, VMS, and Pain Relief; accelerating innovation in the US and China; and further growth in emerging markets.

Reflecting these trends, and the investments made and planned for the business, the Board of GSK is confident that the Consumer Healthcare business can sustainably deliver annual organic sales growth in the range of 4-6% (CER) over the medium term.

The combination of superior organic sales growth, operating margin expansion and consistent high cash generation will, we believe, offer both existing and prospective shareholders a highly attractive financial profile that facilitates continued investment in growth, the delivery of attractive returns and the opportunity of continued participation in long-term value creation.

Proposals fundamentally failed to reflect the intrinsic value of the business and its potential
The Board of GSK unanimously concluded that the proposals were not in the best interests of GSK shareholders as they fundamentally undervalued the Consumer Healthcare business and its future prospects.

The Board of GSK therefore remains focused on executing its proposed demerger of the Consumer Healthcare business, to create a new independent global category-leading consumer company which, subject to approval from shareholders, is on track to be achieved in mid-2022.

Capital Markets event
GSK intends to share further details of the strategy, brands, capabilities and operations, including detailed financial information and future growth ambitions for the new Consumer Healthcare business at a virtual Capital Markets Day for investors and analysts on Monday 28th February 2022.

On January 14, 2022 Gilead Sciences reported that Zydelig (idelalisib) received accelerated approval from the U.S. Food and Drug Administration (FDA) to treat relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) (Press release, Gilead Sciences, JAN 14, 2022, View Source [SID1234606718]). Approval was based on a Phase 2 study in indolent non-Hodgkin lymphoma showing that 54% of those with FL and 58% of those with SLL had an objective response as assessed by an Independent Review Committee.

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Continued approval for these indications was contingent upon providing evidence supporting confirmation of clinical benefit in FL and SLL. As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge. As a result, Gilead Sciences, Inc. (Nasdaq: GILD) formally notified the FDA of its decision to voluntarily withdraw these indications from the U.S. market.

Zydelig was also approved in 2014 to treat relapsed chronic lymphocytic leukemia (CLL) in the U.S. Additionally, Zydelig has marketing authorization to treat CLL and FL in the EU, UK, Canada, Australia, New Zealand and Switzerland. None of these approvals are affected by the proposed withdrawal. Thus, Zydelig will remain on the market in the U.S. for CLL and for CLL and FL in the EU, UK, Canada, Australia, New Zealand, and Switzerland.

Gilead continues to work collaboratively with the FDA to complete the withdrawal of the FL and SLL indications in the U.S. and with healthcare professionals to support those currently being treated with Zydelig. People receiving Zydelig for relapsed FL or SLL in the U.S. should discuss their treatment options with their healthcare provider.

About Zydelig
Zydelig (idelalisib) is approved in the U.S. for the treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities. Currently, Zydelig is also approved under the accelerated approval pathway for relapsed FL and SLL in patients who have received at least two prior systemic therapies. Accelerated approval was granted for FL and SLL based on overall response rate since an improvement in patient survival or disease-related symptoms has not been established. Zydelig is not indicated or recommended for first-line treatment for any use or in combination with bendamustine and/or rituximab for the treatment of FL. The Zydelig U.S. Prescribing Information has a Boxed Warning for the risks of fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation; see below for Important Safety Information.

U.S. Important Safety Information for Zydelig
BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig.
Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig.
Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig.
Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig if intestinal perforation is suspected.
Contraindications

History of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis (TEN) with any drug.
Warnings and Precautions

Hepatotoxicity: Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.
Severe diarrhea or colitis: Severe diarrhea or colitis (Grade ≥3) occurred in 14% of patients treated with Zydelig monotherapy and 20% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.
Pneumonitis: Fatal and serious pneumonitis occurred in 4% of patients treated with Zydelig compared to 1% on the comparator arms in randomized clinical trials of combination therapies. Time to onset of pneumonitis ranged from <1 to 15 months. Clinical manifestations included interstitial infiltrates and organizing pneumonia. Monitor patients on Zydelig for pulmonary symptoms. In patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5%, interrupt Zydelig until the etiology has been determined. If symptomatic pneumonitis or organizing pneumonia is diagnosed, initiate appropriate treatment with corticosteroids and permanently discontinue Zydelig.
Infections: Fatal and/or serious infections occurred in 21% of patients treated with Zydelig monotherapy and 48% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. The most common infections were pneumonia, sepsis, and febrile neutropenia. Treat infections prior to initiation of Zydelig therapy and interrupt Zydelig for Grade 3 or higher infection. Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in <1% of patients treated with Zydelig. Provide PJP prophylaxis during treatment with ZYDELIG. Interrupt Zydelig in patients with suspected PJP infection of any grade, and permanently discontinue Zydelig if PJP infection of any grade is confirmed. Regular clinical and laboratory monitoring for CMV infection is recommended in patients with a history of CMV infection or positive CMV serology at the start of treatment with Zydelig. Interrupt Zydelig in the setting of positive CMV PCR or antigen test until the viremia has resolved. If Zydelig is subsequently resumed, patients should be monitored (by PCR or antigen test) for CMV reactivation at least monthly.
Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Zydelig permanently in patients who experience intestinal perforation.
Severe cutaneous reactions: Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with Zydelig. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also occurred. If suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS or TEN, or DRESS is confirmed, permanently discontinue Zydelig. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and permanently discontinue Zydelig.
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients on Zydelig. Zydelig is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis. Permanently discontinue Zydelig and institute appropriate supportive measures if a reaction occurs.
Neutropenia: Grade 3-4 neutropenia occurred in 25% of patients treated with monotherapy and 58% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Monitor blood counts at least every 2 weeks for the first 6 months, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L. Interrupt Zydelig until resolution and resume at reduced dose.
Embryo-fetal toxicity: Zydelig may cause fetal harm. Females who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.
Adverse Reactions

Most common adverse reactions in patients treated with Zydelig in combination trials (incidence ≥30%, all grades) were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea; and in the monotherapy trial (incidence ≥20%, all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash.
Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (23%), diarrhea (10%), pyrexia (9%), sepsis (8%) and febrile neutropenia (5%); SAR were reported in 59% of patients, and 17% discontinued therapy due to adverse reactions. Most frequent SAR in clinical studies when used alone were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients, and 53% discontinued due to adverse reactions.
Most common lab abnormalitiesinclude neutropenia, ALT elevations, and AST elevations.
Drug Interactions

CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
CYP3A inhibitors: Avoid coadministration with strong CYP3A inhibitors. If unable to use alternative drugs, monitor patients more frequently for Zydelig adverse reactions.
CYP3A substrates: Avoid coadministration with sensitive CYP3A substrates.
Dosage and Administration

Recommended Dosage: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.
Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: ALT/AST elevations, bilirubin elevations, diarrhea, pneumonitis, infections, intestinal perforation, severe cutaneous reactions, hypersensitivity reactions, neutropenia, and thrombocytopenia. For other severe or life-threatening adverse reactions, withhold Zydelig until resolution. If resuming Zydelig after interruption for other severe or life-threatening toxicities, reduce the dosage to 100 mg twice daily. Permanently discontinue Zydelig for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.