On February 3, 2020 The University of Texas MD Anderson Cancer Center reported that circulating tumor cells (CTCs), a form of liquid biopsy, was independently associated with melanoma relapse, suggesting CTC assessment may be useful in identifying patients at risk for relapse who could benefit from more aggressive therapy following primary treatment (Press release, MD Anderson, FEB 3, 2020, View Source [SID1234553774]).

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Results from the study were published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). Although CTCs can be detected in melanoma patients, there is limited data regarding their significance in stage III (node-positive) disease. This prospective study was based on earlier research that found CTCs in a significant number of breast cancer patients, which was associated with relapse, independent of other existing methods for determining prognosis.

"Our findings are significant, given that there is a need for blood-based biomarkers to guide clinical decision making for stage III melanoma patients," said Anthony Lucci, M.D., professor of Breast Surgical Oncology and Surgical Oncology, and study lead. "There currently are no blood tests available to help doctors accurately tell which patients are likely to relapse, and should be given therapy, and which are low risk, and could be observed."

The researchers assessed CTCs during the patient’s first clinic visit, and relapse-free survival was compared between patients with one or more CTCs, versus those with no CTCs. CTCs were observed in 90 out of 243 patients enrolled in the study.

"Our analysis demonstrated that CTC detection was significantly associated with a decrease in relapse-free survival at six months, and persisted at a 54-month longer-term follow-up," said Lucci. "The data from this study provides support for the future pursuit of liquid biopsy techniques to help identify patients most likely to benefit from adjuvant systemic therapy."

Lucci added that this is vital given that there currently is no clear consensus on when to recommend immunotherapy for node-positive melanoma patients. Despite the development of new targeted and immune therapies to treat melanoma, many patients either do not respond to these therapies or develop resistance to therapy within six to eight months. Because such therapies also can have side effects, avoiding treatment in patients at low risk for relapse may prevent overtreatment.

The study was funded by Sheila Prenowitz, Debbie and Craig Kiefer, the Simon and Linda Eyles Foundation, the Sam and Janna Moore family, and the Wintermann Foundation. Lucci reported no disclosures.

On February 3, 2020 Nektar Therapeutics (NASDAQ: NKTR) reported the publication of preclinical data on its lead immuno-oncology candidate, NKTR-214, bempegaldesleukin (bempeg) in two manuscripts in Nature Communications (Press release, Nektar Therapeutics, FEB 3, 2020, View Source [SID1234553791]). Bempeg is an investigational CD122-preferential interleukin-2 (IL-2) pathway agonist designed to provide activation and proliferation of cancer-killing immune cells, known as CD8+ effector T cells and natural killer (NK) cells. The published data demonstrate that bempeg, in combination with immune-based therapies including checkpoint inhibition (CPI), antigen-specific vaccination and adoptive cell transfer (ACT) therapy, enhanced T-cell mediated tumor control by selectively expanding effector T cells (Teffs) over T regulatory cells (Tregs) in the tumor microenvironment.

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The first manuscript, titled "Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy," was published online and can be accessed here. The research was conducted by a team at MD Anderson Cancer Center, led by former tenured professor, Willem W. Overwijk, Ph.D., who currently serves as Vice President, Oncology Research at Nektar Therapeutics.

"Using preclinical models, we were able to demonstrate how bempeg potentiates both CPI and vaccination strategies by expanding and maintaining tumor infiltrating T cells and depleting intratumoral Tregs by a novel mechanism of cytokine release to drive efficient intratumoral Treg depletion," said Dr. Overwijk. "Our findings further define the mechanism of action of bempeg and highlight the rationale for its clinical application in combination with immune-based therapies for patients with cancer."

In the study, the activity and mechanism of action of bempeg was evaluated in combination with PD-1 and CTLA-4 CPI therapy and also with antigen-specific vaccination in preclinical animal models. The researchers concluded that bempeg in combination with PD-1 CPI therapy resulted in a higher response rate, prolonged disease control and yielded more complete responses in a variety of preclinical tumor types including colon cancer, melanoma, bladder cancer, lung cancer and breast cancer. In addition, bempeg supported the expansion and long-term maintenance of vaccination-induced anti-tumor Teffs; and bempeg treatment mediated selective depletion of intratumoral but not of peripheral Tregs, suggesting that in patients with cancer, bempeg-containing regimens could increase tumor control without exacerbating systemic inflammation. This preferential depletion of intratumoral Tregs was also observed in a small cohort of patients with renal cell cancer and melanoma receiving bempeg monotherapy, suggesting the results in mice may extend to patients receiving bempeg-based therapies.

Key findings are summarized below:

Bempeg with anti-PD-1 CPI as combination therapy demonstrated superior efficacy over anti-PD-1 monotherapy in 8 different mouse tumor models.
Anti-PD-1 monotherapy did not change TIL frequency or clonality, while addition of bempeg increased both TIL frequency and clonality.
To delve deeper into the immune-mediated mechanism, the B16 melanoma model was used with gp100 antigen-specific CD8+ (pmel-1) T cells to track T cell numbers and persistence.
Combination of gp100 vaccination and bempeg markedly suppressed tumor growth and prolonged mouse survival.
Long-term tumor control directly correlated with the magnitude and persistence of vaccination-induced, gp100-specific CD8+ Teff in the circulation. Aldesleukin (IL-2) also synergized with vaccination but did not achieve similar potency of bempeg as measured by tumor control or T cell responses.
While bempeg increased systemic and intratumoral levels of melanoma-specific CD8+ T cells, intratumoral numbers of Tregs plummeted.
Similar depletion of intratumoral but not systemic Tregs was also observed in patients with renal cell cancer and melanoma treated with bempeg (NCT02869295).
The authors present data that CD8+ Teff-derived IFN-ɣ and TNF-α synergize to deplete intratumoral Tregs by directly inhibiting local Treg proliferation.
In the second manuscript, published this week in Nature Communications, a research team led by Antoni Ribas, Ph.D. at the UCLA Jonsson Comprehensive Cancer Center evaluated bempeg in combination with adoptively transferred T cell therapy (ACT) in melanoma models. The studies found ACT therapy supported by bempeg increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in the B16 melanoma model.

Bempeg + ACT showed preferential activation of tumor-specific CD8 T cells over Tregs in spleen and tumors of mice, increased immune-related gene expression in the tumor microenvironment, and greatly increased animal survival compared to IL-2 + ACT.
Bempeg + ACT increased tumor-specific T cell polyfunctionality (secreting multiple (>2) cytokines per cell) both intratumorally and peripherally compared to IL-2 +ACT in mice.
Analysis of peripheral blood samples from patients treated with bempeg monotherapy in a Phase 1 trial (NCT02869295) also showed enhanced polyfunctionality of T cells and NK cells.
The authors conclude that bempeg may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion, tumor infiltration and polyfunctionality of the adoptively transferred T cells.
The second manuscript titled "Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist," was published online and can be accessed here. The UCLA announcement of the publication can be accessed here.

Bempeg in combination with checkpoint inhibitors and other immune-mediating agents is being evaluated in clinical trials. For more information, visit the Pipeline page on nektar.com.

On February 3, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that Rubraca (rucaparib) is now available and reimbursed in France (Press release, Clovis Oncology, FEB 3, 2020, View Source [SID1234553756]). Rubraca (rucaparib) is an option for monotherapy maintenance treatment for adults with relapsed, platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy.2 Rucaparib is indicated for eligible patients regardless of BRCA status, which means it can be prescribed for women who harbor a BRCA mutation or who are BRCA wild-type.2

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"This is excellent news as this represents an important new option for patients with relapsed ovarian cancer who have responded to platinum-based chemotherapy," said a spokesperson for IMAGYN, the only French network of patient associations involved in the fight against ovarian cancer and gynecological tumors. "For too long, ovarian cancer treatment options beyond chemotherapy, surgery and anti-angiogenic therapy have been limited, and today’s announcement means that eligible women with ovarian cancer have more choice in their treatment than ever before."

Approximately 5,000 women are diagnosed with ovarian cancer in France every year, which equates to roughly 14 every day.3 Ovarian cancer is the eighth most common cancer in women and the fourth most fatal cancer in France.4 In addition, approximately 25 percent of ovarian cancer patients harbor a BRCA1/2 mutation in the tumor, correlating to improved outcomes to platinum and PARP inhibitors therapy.5,6 The majority of women diagnosed with ovarian cancer are BRCA wild-type; these patients typically have a worse prognosis.5,6 Of those treated with surgery and first line chemotherapy, approximately 70 percent of patients will relapse within the first three years.7

"The availability of rucaparib is good news, as ovarian cancer is a disease often diagnosed at an advanced stage and many women may have a poor prognosis," said Professor Isabelle Ray-Coquard, President of the GINECO Group, which specializes in clinical and translational research in the field of women’s cancers, and sets up and coordinates clinical trials in France and abroad. "Patients with relapsed ovarian cancer may have many debilitating symptoms, and it is important that new treatments such as rucaparib are made available to the eligible patients that may benefit from them."

The European Union (EU) authorization is based on data from the pivotal phase 3 ARIEL3 clinical trial, which found that rucaparib significantly improved PFS in all ovarian cancer patient populations studied.1 ARIEL3 successfully achieved its primary endpoint of extending investigator-assessed PFS versus placebo in all patients treated (intention-to-treat, or ITT), population, regardless of BRCA status (median 10.8 months vs 5.4 months).1,2 In this population, the risk of progression or death has been decreased by 64%.1 In addition, it successfully achieved the key secondary endpoint of extending PFS by independent radiological review versus placebo in all patients treated (ITT), regardless of BRCA status (median 13.7 months vs 5.4 months).2 The overall safety profile of rucaparib is based on data from 937 patients with ovarian cancer treated with rucaparib monotherapy in clinical trials.2

"The fact that rucaparib is now reimbursed and available in France means there is a new treatment for patients with platinum-sensitive relapsed ovarian cancer," said Dr. Anne Floquet, President of the SFOG, the French Society for Gyneco-Oncology. "I am very proud to have been able to participate in the ARIEL3 study, which demonstrates the effectiveness of rucaparib in improving patients’ progression-free survival. I am also delighted to be able to prescribe this treatment as it may offer benefits for eligible patients."

"We are working to make Rubraca available in multiple countries across Europe, and with the reimbursement and availability of Rubraca in France, it is now a treatment option for eligible patients in Germany, England, Italy, and in France," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "Rubraca is effective across a broad population of women with relapsed ovarian cancer and is an important step in the ovarian cancer treatment pathway for eligible patients."

About Rubraca (rucaparib)

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 that is being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancer (mCRPC), as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca (rucaparib) European Union (EU) authorized use and Important Safety Information

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Rubraca is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with ≥2 prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Efficacy of Rubraca as treatment for relapsed or progressive EOC, FTC, or PPC has not been investigated in patients who have received prior treatment with a PARP inhibitor. Therefore, use in this patient population is not recommended.

Summary warnings and precautions:

Hematological toxicity

During treatment with Rubraca, events of myelosuppression (anemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8–10 weeks of treatment with Rubraca. These reactions are manageable with routine medical treatment and/or dose adjustment for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from hematological toxicities caused by previous chemotherapy (CTCAE grade ≥1).

Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see Posology and Method of Administration [4.2] of the Summary of Product Characteristics [SPC]) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE grade 1 or better after 4 weeks, the patient should be referred to a hematologist for further investigations.

MDS/AML

MDS/AML, including cases with fatal outcome, have been reported in patients who received Rubraca. The duration of therapy with Rubraca in patients who developed MDS/AML varied from less than 1 month to approximately 28 months.

If MDS/AML is suspected, the patient should be referred to a hematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged hematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued.

Photosensitivity

Photosensitivity has been observed in patients treated with Rubraca. Patients should avoid spending time in direct sunlight because they may burn more easily during Rubraca treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor of 50 or greater.

Gastrointestinal toxicities

Gastrointestinal toxicities (nausea and vomiting) are frequently reported with Rubraca, and are generally low grade (CTCAE grade 1 or 2), and may be managed with dose reduction (refer to Posology and Method of Administration [4.2], Table 1 of the SPC) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e. preventative) use prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalization.

Embryofetal toxicity

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of Rubraca to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see Preclinical Safety Data [5.3] of the SPC).

Pregnancy/contraception

Pregnant women should be informed of the potential risk to a fetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy test before initiating treatment is recommended in women of reproductive potential.

On February 3, 2020 Calibr, the drug discovery and development division of Scripps Research, reported that the U.S. Food and Drug Administration has given clearance to the Investigational New Drug (IND) application for Calibr’s "switchable" CAR-T cell therapy, which is being evaluated for the treatment of certain cancers, including relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma and chronic lymphocytic leukemia (Press release, The Scripps Research Institute, FEB 3, 2020, View Source [SID1234553776]).

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Having achieved this regulatory milestone, Calibr can begin clinical trials for its novel cell therapy candidate, CLBR001 + SWI019. The therapy leverages a patient’s own immune cells to treat cancer, putting them under the control of a novel molecular "switch" that seeks to eliminate life-threatening side effects that have hampered the use of cell therapies to date.

"CLBR001 + SWI019 is a first-in-class switchable CAR-T cell platform designed to confer the efficacy associated with engineered T cell therapies, while potentially affording greater safety and versatility through the incorporation of a control switch," says Travis Young, PhD, Calibr’s vice president of biologics and leader of its CAR-T development program. "If successful, this approach holds promise to be universally applied to other types of cancer, including solid tumor cancers that have yet to reap the benefits of CAR-T therapies."

CAR-T, short for chimeric antigen receptor T-cell, is a relatively new form of cancer therapy that has achieved remarkable responses in patients with blood- or bone marrow-based diseases such as leukemias and lymphomas. It works by genetically engineering a patient’s own T cells—which play a key role in immune response—to seek and destroy cancer within the body. However, some patients who receive T-cell therapies experience an adverse effect, which can be severe, called cytokine release syndrome, which occurs when the immune system reacts too strongly and causes dangerous inflammation.

Calibr’s switchable CAR-T cell platform incorporates an antibody known as SWI019 that acts as a switch, activating the engineered cell and directing it to engage the cancer target. This may allow doctors to more precisely regulate the potency of the therapy and is expected to provide a significant safety advantage. In preclinical studies, the approach proved highly effective at eliminating tumors while controlling the level of cytokines produced in response to treatment.

"AbbVie continues to be impressed by Calibr’s progress on advancing this innovative switchable cell therapy technology," says Mohit Trikha, Ph.D., vice president, head of Oncology Early Development and Bay Area site head at AbbVie. "This milestone is an important step forward for this potential CAR-T therapy and our recently expanded collaboration with Scripps Research, which holds promise to rapidly advance additional treatment options for patients."

The launch of the clinical study—the third being run independently by the institute and the fifth study to originate from Calibr’s research—is another major landmark for Scripps Research’s pioneering nonprofit drug development model. News of the FDA’s decision comes on heels of another recent IND acceptance for Calibr’s first-in-class bispecific antibody for prostate cancer; that drug candidate, CCW702, is now being tested in a phase I trial for patients with metastatic, castrate resistant prostate cancer.

The switchable CAR-T cell platform was invented at Scripps Research and progressed to the Investigational New Drug stage with support from the Wellcome Trust. Calibr recently partnered its platform with biopharmaceutical company AbbVie, which holds certain rights to commercialization.

"AbbVie has been an outstanding partner for Scripps Research on this CAR-T cell program," says Scripps Research President and CEO Peter Schultz, PhD. "We look forward to continuing to bring novel therapies to the clinic through this collaboration."

Clinical development of CLBR001 + SWI019 will be led by Calibr’s Chief Medical Officer Pamela D. Garzone, PhD. Calibr expects to begin enrolling patients for the phase 1 clinical trial in the first half of 2020, with the potential to expand the platform to solid tumors in coming years.

On February 3, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported multiple data presentations from a robust solid tumor portfolio that will be featured at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium, taking place February 13-15 in San Francisco (Press release, Janssen Pharmaceuticals, FEB 3, 2020, View Source [SID1234553792]). Company-sponsored data presentations will include clinical results for ERLEADA (apalutamide) and niraparib in prostate cancer; and BALVERSA (erdafitinib) in bladder cancer.

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"We are committed to improving outcomes in patients with prostate and bladder cancer where high unmet needs continue to persist despite advancements in treatment," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. "At this year’s meeting, we look forward to highlighting results from our GU portfolio and pipeline, including a new analysis of time to second progression or death after initial treatment with ERLEADA from the Phase 3 TITAN study in patients with metastatic castration-sensitive prostate cancer; and new data for BALVERSA in combination with an anti-PD-1 monoclonal antibody."

Highlights from the Janssen oncology portfolio and pipeline will include:

New Analyses from the Phase 3 TITAN Study of ERLEADA in Metastatic Castration-Sensitive Prostate Cancer (mCSPC)
An oral presentation will feature a post hoc analysis of data from the Phase 3 TITAN study on the time to second progression (PFS2) or death at any time for patients receiving hormone versus taxane therapy after initial treatment with ERLEADA (Abstract #82).

A poster presentation will highlight ERLEADA efficacy and safety results in high- versus low-risk patients with mCSPC (Abstract #87).

Niraparib Results in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and Biallelic DNA-Repair Gene Defects
A poster presentation will include an updated analysis from the Phase 2 GALAHAD study evaluating correlative measures of tumor response in patients with mCRPC and biallelic DNA-repair gene defects, including patients with BRCA1/2 gene mutations (Abstract #118).

BALVERSA and Cetrelimab Combination Results in Metastatic Urothelial Carcinoma (mUC) in Patients with Genetic Alterations
A poster presentation (Abstract #511) will report results from the Phase 1b/2 NORSE study evaluating BALVERSA in combination with cetrelimab, an anti-PD-1 monoclonal antibody, in patients with locally advanced or mUC with select fibroblast growth factor receptor (FGFR) genetic alterations.

Company-sponsored abstracts to be presented at the meeting include:

Abstract No.

Title

Date/Time

ERLEADA (apalutamide)

Oral Presentation

Abstract #82

Time to Second Progression (PFS2) in Patients
from TITAN with Metastatic Castration-Sensitive
Prostate Cancer by First Subsequent Therapy
(Hormonal vs Taxane)

Thursday, February 13

1:35 PM – 1:45 PM PST

Poster Presentations

Abstract #87

Apalutamide for Metastatic Castration-Sensitive
Prostate Cancer in TITAN: Outcomes in Patients
with Low- and High-Risk Disease

Thursday, February 13

11:30 AM – 1:00 PM and
5:30 PM – 6:30 PM PST

Abstract #320

A Randomized Phase 2 Study of Apalutamide,
Androgen Deprivation Therapy, or APA + ADT in
Patients with Biochemically Relapsed Prostate
Cancer

Thursday, February 13

11:30 AM – 1:00 PM and
5:30 PM – 6:30 PM PST

Abstract #156

Linking the Aggressive Variant Prostate Cancer
Molecular Signature to Androgen Indifference in a
Prospective Clinical Trial

Thursday, February 13

11:30 AM – 1:00 PM and
5:30 PM – 6:30 PM PST

Abstract #TPS383

PROTEUS: A Randomized, Double-Blind, Placebo –
Controlled, Phase 3 Trial of Apalutamide Plus
Androgen Deprivation Therapy vs PBO Plus ADT
Prior to Radical Prostatectomy in Patients with
Localized High-Risk or Locally Advanced Prostate
Cancer

Thursday, February 13

11:30 AM – 1:00 PM and
5:30 PM – 6:30 PM PST

Niraparib

Poster Presentations

Abstract #118

GALAHAD: Niraparib in Patients with Metastatic
Castration-Resistant Prostate Cancer and Biallelic
DNA-Repair Gene Defects: Correlative Measures of
Tumor Response in Phase 2 GALAHAD Study

Thursday, February 13

11:30 AM – 1:00 PM
and 5:30 PM – 6:30 PM PST

Abstract #122

BEDIVERE: Phase 1b Study of Niraparib Plus
Androgen Receptor-Targeted Therapy in Patients
with Metastatic Castration Resistant Prostate
Cancer

Thursday, February 13

11:30 AM – 1:00 PM
and 5:30 PM – 6:30 PM PST

Abstract #TPS257

MAGNITUDE: A Phase 3 Randomized, Placebo-
Controlled, Double-Blind Study of Niraparib Plus
Abiraterone Acetate and Prednisone Versus
Abiraterone Acetate and Prednisone in Patients
with Metastatic Prostate Cancer

Thursday, February 13

11:30 AM – 1:00 PM
and 5:30 PM – 6:30 PM PST

BALVERSA (erdafitinib)

Poster Presentations

Abstract #511

Dose Escalation Results from Phase 1b/2 NORSE
Study of Erdafitinib + PD-1 Inhibitor JNJ-
63723283 (Cetrelimab [CET]) in Patients with
Metastatic or Locally Advanced Urothelial
Carcinoma and Selected Fibroblast Growth Factor
Receptor (FGFR) Gene Alterations

Friday, February 14

12:15 PM – 1:45 PM
and 5:15 PM – 6:15
PM PST

Abstract #493

BRIDGE + GeneCentric: Predictive Value of
Fibroblast Growth Factor Receptor Alterations on
Anti-PD-(L)1 Treatment Outcomes in Patients with
Advanced Urothelial Cancer: Pooled Analysis of
Real-World Data

Friday, February 14

12:15 PM – 1:45 PM
and 5:15 PM – 6:15
PM PST

Abstract #TPS603

BLC2003 Trial in Progress (TiP): A Randomized
Phase 2 Study of Erdafitinib Versus Intravesical
Chemotherapy in Patients with High-Risk Non-
Muscle Invasive Bladder Cancer with FGFR
Mutations or Fusions, Who Recurred After Bacillus
Calmette-Guérin Therapy

Friday, February 14

12:15 PM – 1:45 PM
and 5:15 PM – 6:15
PM PST

About ERLEADA (apalutamide)
ERLEADA is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and for the treatment of patients with mCSPC. ERLEADA received U.S. Food and Drug Administration (FDA) approval for nmCRPC on February 14, 2018 and was approved for mCSPC on September 17, 2019.1 ERLEADA is taken orally, once daily, with or without food.1 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide (ERLEADA) as a treatment option for patients with non-metastatic (M0) CRPC with a Category 1 recommendation for those with a PSA doubling time ≤10 months.*2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) include apalutamide (ERLEADA) with androgen deprivation** as a Category 1 treatment option for patients with metastatic (M1) castration-naive prostate cancer.†5 The American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) recommend clinicians offer apalutamide (ERLEADA) with continued androgen deprivation therapy (ADT) as one of the treatment options for patients with nmCRPC at high risk for developing metastatic disease. (Standard; Evidence Level Grade A)***.3 ERLEADA is being studied in five Phase 3 clinical trials.

For more information about ERLEADA, visit www.ERLEADA.com.

* Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer V.4.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed January 2020. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

** Orchiectomy, LHRH agonist, or LHRH antagonist

† The term "castration-naive" is used to define patients who are not on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term "castration-naive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of radiation therapy provided they have recovered testicular function.

***Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.

***Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

About Niraparib
Niraparib is an orally-administered selective poly ADP ribose polymerase (PARP) inhibitor that is currently being studied by Janssen for the treatment of patients with prostate cancer. Ongoing studies include the Phase 3 MAGNITUDE study evaluating niraparib in combination with ZYTIGA (abiraterone acetate) and prednisone in adults with metastatic prostate cancer; and QUEST, a Phase 1b/2 study of niraparib combination therapies for the treatment of mCRPC. On October 3, 2019 niraparib received Breakthrough Therapy Designation from the U.S. FDA based on the Phase 2 GALAHAD study in patients with mCRPC.

In April 2016, Janssen entered a worldwide (except Japan) collaboration and license agreement with TESARO, Inc. (now GSK), for exclusive rights to niraparib in prostate cancer. In the U.S., niraparib is indicated for the treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy; and for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency positive status.4 Niraparib is currently marketed by GSK as ZEJULA. GSK is focused on maximizing patient survival through transformational medicines for patients living with cancer. Please refer to the full Prescribing Information available at View Source

About BALVERSA (erdafitinib)
BALVERSA is a once-daily, oral FGFR kinase inhibitor indicated for the treatment of adults with locally advanced or mUC that has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.5

This indication was approved by the U.S. FDA on April 12, 2019 under an accelerated approval based on tumor response rate. BALVERSA is the first FGFR kinase inhibitor to receive U.S. FDA approval for the treatment of mUC. Patients may be eligible for BALVERSA based on an FDA-approved companion diagnostic. Continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trials.5 In 2008, Janssen entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize BALVERSA.

Ongoing studies for BALVERSA in patients with locally advanced or mUC whose tumors have certain FGFR alterations include the Phase 2 BLC2001 study evaluating efficacy and safety, and the Phase 3 BLC3001 study evaluating BALVERSA compared with vinflunine, docetaxel or pembrolizumab. The development plan for BALVERSA also includes a Phase 2 study (NCT04083976) in patients with advanced solid tumors and FGFR alterations.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer include erdafitinib (BALVERSA) as an alternative preferred regimen for locally advanced or metastatic disease (Stage IV) (post-platinum) for patients with susceptible FGFR3 or FGFR2 genetic alterations.*6 The NCCN Guidelines recommend molecular/genomic testing for FGFR3 and FGFR2 genetic alterations as part of a work-up of locally advanced or metastatic urothelial carcinoma.6

For more information about BALVERSA, visit www.BALVERSA.com.

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed January 2020. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

ERLEADA IMPORTANT SAFETY INFORMATION1
WARNINGS AND PRECAUTIONS

Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 3% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA for Grade 3 and 4 events.

Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA with increased frequency in the elderly. Evaluate patients for fall risk.

Seizure — In 2 randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA have not been established in females. Based on its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS
Adverse Reactions — The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea and fracture.

Laboratory Abnormalities — All Grades (Grade 3-4)

Hematology — In the TITAN study: white blood cell decreased ERLEADA 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)
Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA 17% (3%), placebo 12% (2%). In the SPARTAN study: hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (0.5%)
Rash — In 2 randomized studies, rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA treatment (6%) vs placebo (0.5%).

The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA.

Hypothyroidism — In 2 randomized studies, hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

DRUG INTERACTIONS

Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA on Other Drugs — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.

Please see the full Prescribing Information for ERLEADA.

BALVERSA IMPORTANT SAFETY INFORMATION5
WARNINGS AND PRECAUTIONS

Ocular Disorders – BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect. CSR/RPED was reported in 25% of patients treated with BALVERSA, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively, and 3% of patients discontinued BALVERSA. Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed. Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Withhold BALVERSATM when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)].

Hyperphosphatemia – Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8–116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA. Monitor for hyperphosphatemia and follow the dose modification guidelines when required [see Dosage and Administration (2.2, 2.3)].

Embryo-fetal Toxicity – Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In a rat embryo-fetal toxicity study, erdafitinib was embryotoxic and teratogenic at exposures less than the human exposures at all doses studied. Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Most common adverse reactions including laboratory abnormalities ≥20% were: Phosphate increased (76%), stomatitis (56%), fatigue (54%), creatinine increased (52%), diarrhea (47%), dry mouth (45%), onycholysis (41%), alanine aminotransferase increased (41%), alkaline phosphatase increased (41%), sodium decreased (40%), decreased appetite (38%), albumin decreased (37%), dysgeusia (37%), hemoglobin decreased (35%), dry skin (34%), aspartate aminotransferase increased (30%), magnesium decreased (30%), dry eye (28%), alopecia (26%), palmar-plantar erythrodysesthesia syndrome (26%), constipation (28%), phosphate decreased (24%), abdominal pain (23%), calcium increased (22%), nausea (21%), and musculoskeletal pain (20%). The most common Grade 3 or greater adverse reactions (>1%) were stomatitis (9%), nail dystrophy*, palmar-plantar erythrodysesthesia syndrome (6%), paronychia (3%), nail disorder*, keratitis†, onycholysis* (10%), and hyperphosphatemia.

*Included within onycholysis. †Included within dry eye.

An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.

Serious adverse reactions occurred in 41% of patients, including eye disorders (10%).

Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).

Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythrodysesthesia syndrome (8%).

Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythrodysesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%).

Drug Interactions

Strong CYP2C9 or CYP3A4 Inhibitors: Consider alternative agents or monitor closely for adverse reactions. (7.1)
Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. (7.1)
Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg. (7.1)
Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. (2.3, 7.1)
CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. (7.2)
OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. (7.2)
P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2)
Use in Specific Populations

Lactation – Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose.