On November 19, 2020 Novocure (NASDAQ: NVCR) reported 43 presentations on Tumor Treating Fields will be featured at the Society for Neuro-Oncology 2020 Virtual Annual Meeting on November 19 through November 21 (Press release, NovoCure, NOV 19, 2020, View Source [SID1234571440]). The presentations include two oral presentations and cover a broad and growing range of topics, with 36 of the 43 presentations prepared by external authors.

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The oral presentations on Tumor Treating Fields include:

Data from EF-19, a post-approval registry study of Tumor Treating Fields in recurrent glioblastoma (GBM), supporting results from Novocure’s EF-11 phase 3 pivotal trial in recurrent GBM and confirming the effectiveness and safety of Tumor Treating Fields as a monotherapy.
Therapeutic implications of conditional vulnerabilities caused by Tumor Treating Fields exposure in novel combination therapies for non-small cell lung cancer (NSCLC) and brain metastases from NSCLC. Study results suggest that the combination of cisplatin and etoposide together with Tumor Treating Fields may be beneficial for NSCLC patients and patients with brain metastases from NSCLC.
Highlighted topics among poster presentations include the TRIDENT study evaluating Tumor Treating Fields in combination with radiation therapy and temozolomide, long-term survival in GBM patients after Tumor Treating Fields therapy, Tumor Treating Fields in combination with immunotherapy, a subgroup analysis of the EF-14 trial focusing on efficacy of Tumor Treating Fields in elderly patients, optimizing use of Tumor Treating Fields during Covid-19, and safety and quality of life of GBM patients treated with Tumor Treating Fields in China.

"From our first presentation at the SNO Annual Meeting in 2008 to today, we and our external partners have shared nearly 300 presentations on Tumor Treating Fields, strengthening our foundational understanding of our therapy and our science every year," said Dr. Ely Benaim, Novocure’s Chief Medical Officer. "It remains an honor for us to participate and engage with our scientific colleagues at one of the most important neuro-oncology conferences worldwide. We look forward to gathering virtually to share our work and learn from our partners."

Oral Presentations

(Abstract #: CBIO-01) Therapeutic implications of conditional vulnerabilities caused by Tumor Treating Fields exposure in novel combination therapies for non-small cell lung cancer and brain metastases from non-small cell lung cancer. N, Karanam, M. Story. (Experimental and Translation Sciences Session I)

(Abstract #: CTNI-77) EF-19: a post-approval registry study of Tumor Treating Fields (TTFields) in recurrent glioblastoma (rGBM). J. Zhu, R. O’Donnell, S. Goldlust, Z. Ram. (Clinical Trials Session I)

Poster Presentations

(Abstract #: CTIM-17) Phase I study of the safety and immunogenicity of personalized neoantigen vaccines and Tumor Treating Fields in patients with newly diagnosed glioblastoma. J. Kodysh, A. Rubinsteyn, A. Blazquez, J. Mandeli, N. Bhardwaj, A. Hormigo. (Clinical trials: Immunologic)

(Abstract #: NIMG-37) Delayed pseudoprogression in two patients undergoing TTFields treatment for newly diagnosed glioblastoma. A. Lowman, S. Hurrell, S. Bobholz, J. Connelly, E. Cochran, W. Mueller, S. McGarry, M. Brehler, P. LaViolette. (Neuro-imaging)

(Abstract #: INNV-10) Effects of TTFields Usage and Duration of Usage on Cellularity and Ki67 Distributions at Autopsy. S. Bobholz, A. Lowman, J. Connelly, E. Cochran, W. Mueller, S. McGarry, M. Brehler, P. LaViolette. (Innovations in patient care)

(Abstract # NCOG-26) Impact of Gender on Tumor Treating Fields Compliance in Patients with Glioblastoma. L. Karpf, S. Chawla, L. Desiderio, S. Mohan. (Outcome measures and neuro-cognitive outcomes)

(Abstract #: CTNI-21) Scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma. R. Miller, A. Song, A. Ali, V. Bar-Ad, N. Martinez, J. Glass, D. Andrews, K. Judy, J. Evans, C. Farrell, M. Werner-Wasik, I. Chervoneva, M. Ly, J. Palmer, H. Liu, W. Shi. (Clinical trials: Non-immunologic)

(Abstract #: CTIM-04) Updates for a phase 2 open-labeled study of pembrolizumab plus TTFields plus maintenance temozolomide in patients with newly diagnosed glioblastoma (2-THE-TOP). A. Ghiaseddin, S. Warren, A. Allen, D. Sampson, D. Chen, A. Sherman, V. Greene, M. Rahman, D. Tran. (Clinical trials: Immunologic)

(Abstract #: NCOG-52) Tumor Treating Fields in Meningioma. C. Mawrin. (Outcome measures and neuro-cognitive outcomes)

(Abstract #: CTNI-59) First safety analysis of anaplastic meningioma patients treated with Tumor Treating Fields (TTFields). C Mawrin. (Clinical trials: Non-immunologic)

(Abstract #: CTNI-71) TTFields in routine clinical care of newly diagnosed GBM patients in Germany – first report on the fully enrolled TIGER study population. O. Bähr, G. Tabatabai, R. Fietkau, R. Goldbrunner, M. Glas. (Clinical trials: Non-immunologic)

(Abstract #: CTNI-46) A Phase II Trial of Tumor Treating Fields (TTFields) Concomitant with Radiosurgery for the Treatment of Recurrent, Bevacizumab-naïve Glioblastoma. M. Harat, M. Blok, M. Adamczak-Sobczak, P. Szymanski, I. Miechowicz, B. Malkowski. (Clinical trials: Non-immunologic)

(Abstract #: CTNI-79) PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. S. Kebir, L. Lazaridis, T. Schmidt, C. Oster, D. Pierscianek, N. Guberina, C. Kleinschnitz, M. Proescholdt, P. Hau, A. Grosu, U. Sure, B. Scheffler, M. Stuschke, M. Glas. (Clinical trials: Non-immunologic)

(Abstract #: RTID-06) Enhancing Tumor Treating Fields therapy for recurrent glioblastoma with targeted and individualized skull remodeling surgery. A multi-center randomized phase 2 trial. N. Mikic, A. Korshoej. (Randomized Trials in Development)

(Abstract #: RTID-12) Phase 2 trial of Tumor Treating Fields (TTFields) plus radiation therapy (RT) plus temozolomide (TMZ) compared to RT plus temozolomide in newly diagnosed glioblastoma (ndGBM). R. Grossman, D. Limon, F. Bokstein, C. Harosh, D. Blumenthal, Z. Ram. (Randomized Trials in Development)

(Abstract #: NIMG-58) The effect of cell confluence on the distribution of Tumor Treating Fields. T. Marciano, S. Levi, Z. Bomzon. (Neuro-imaging)

(Abstract #: NIMG-65) Study of local perturbation in computational modelling on Tumor Treating Fields (TTFields) therapy. O. Zeevi, Z. Bomzon, T. Marciano. (Neuro-imaging)

(Abstract #: INNV-05) Tumor Treating Fields (TTFields) treatment planning for a patient with astrocytoma in the spinal cord. J. De Los Santos, S. Arvatz, O. Zeevi, S. Levi, Z. Bomzon, T. Marciano. (Innovations in patient care)

(Abstract #: CBIO-09) Intratumoral heterogeneity of dielectric properties in glioblastoma. M. Proescholdt, A. Haj, C. Doenitz, N. Schmidt, Z. Bomzon. (Cell biology (cell cycle regulation, DNA repair/modulation))

(Abstract #: RBIO-04) New Therapeutic Delivery Methods for Tumor-Treating Fields for Higher Efficacy. K. Carlson, Z. Bomzon, J. Arle. (Radiobiology)

(Abstract #: COVD-17) Tumor Treating Fields for glioblastoma therapy during the COVID-19 pandemic: Expert consensus on use and experience. N. Gatson, J. Barnholtz-Sloan, J. Drappatz, R. Henriksson, A. Hottinger, P. Hinoul, C. Kruchko, V. Puduvalli, D. Tran, E. Wong, M. Glas. (Innovations in patient care)

(Abstract #: COVD-04) Real-world perspectives: Tumor Treating Fields (TTFields) utility to optimize treatment of patients with glioblastoma (GBM) amidst COVID-19 pandemic. P. Frongillo, M. Shackelford, L. Rain. (Innovations in patient care)

(Abstract #: NCOG-36) First health utilities of glioblastoma patients using TTFields treatment. G. Chavez, C. Proescholdt. (Outcome measures and neuro-cognitive outcomes)

(Abstract #: EXTH-76) The inovivo system: a novel preclinical tool for in vivo delivery of Tumor Treating Fields (TTFields). S. Davidi, R. Blat, A. Shteingauz, Y. Porat, M. Giladi, U. Weinberg, Y. Palti. (Preclinical Experimental Therapeutics)

(Abstract #: EXTH-69) Increased cancer cell permeability following Tumor Treating Fields (TTFields) application in vitro. T. Voloshin, Y. Porat, N. Kaynan, A. Klein-Goldberg, R. Paz, A. Volodin, M. Giladi, U. Weinberg, Y. Palti. (Preclinical Experimental Therapeutics)

(Abstract #: TAMI-04) Tumor Treating Fields (TTFields) hinder glioma cell motility through regulation of microtubule and actin dynamics. T. Voloshin, R. Schneiderman, A. Volodin, R. Shamir, N. Kaynan, E. Zeevi, L. Koren, A. Klein-Goldberg, R. Paz, M. Giladi, Z. Bomzon, U. Weinberg, Y. Palti. (Tumor Microenvironment/Angiogenesis/Metabolism/Invasion)

(Abstract #: EXTH-31) Increasing Tumor Treating Fields (TTFields) efficacy by targeting the G2 cell cycle checkpoint with combined Wee1 or Chk1 inhibitors in glioblastoma cell lines. P. Slangen, M. de Gooijer, M. van Geldorp, O. van Tellingen, G. Borst. (Preclinical Experimental Therapeutics)

(Abstract #: EXTH-33) Valproic acid enhances anti-proliferative effects of Tumor Treating Fields on patient-derived gliosarcoma cells in vitro. S. Michelhaugh, S. Mittal. (Preclinical Experimental Therapeutics)

On November 19, 2020 VBI Vaccines Inc. (Nasdaq: VBIV) ("VBI") a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, reported Phase 2a (Part B) data from its ongoing Phase 1/2a study of VBI-1901, the company’s cancer vaccine immunotherapeutic candidate designed to target cytomegalovirus (CMV) as a foreign viral antigen in recurrent glioblastoma (GBM) (Press release, VBI Vaccines, NOV 19, 2020, View Source [SID1234571439]). The data were presented in an e-poster at the Society for Neuro-Oncology (SNO) 2020 Annual Meeting, November 19-21, 2020.

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Data from Phase 2a (Part B) of the ongoing study showed:

2 partial responses (PRs) and 2 stable disease (SD) observed in the VBI-1901 + GM-CSF vaccinated group, resulting in a disease control rate of 40% (n=4/10)
A 56% disease control rate achieved in the group vaccinated with VBI-1901 + AS01, with 5 stable disease observations (n=5/9) – tumor response data for the 10th patient enrolled is pending
Presumed pseudoprogression was observed in both vaccinated groups– defined as immune infiltration into the tumor which appears initially as tumor growth, but later subsides resulting in tumor growth stabilization and/or shrinkage
Andrew B. Lassman, M.D., Chief of Neuro-oncology at Columbia University Irving Medical Center and Associate Director for Clinical Trials at the Herbert Irving Comprehensive Cancer Center, and principal investigator of the study presented the e-poster, commenting, "Tumor response data is one of the most objective measures of efficacy in open label studies, especially in this difficult-to-treat patient population. Few treatment options are available to recurrent glioblastoma patients, and the tumor response data seen to-date in this ongoing study are encouraging. Any treatment that could demonstrate clinical benefit would be incredibly meaningful."

Emmanuel Hanon, Senior Vice President, Head of R&D Vaccines at GSK, commented, "The early data seen to-date in this ongoing study are encouraging, underscoring the potential benefit of adjuvants in combination with VBI-1901 in the clinical setting. Previous research in the context of other vaccines has shown AS01’s ability to boost T cell-mediated immunity. This is the first time GSK’s adjuvant system is assessed in oncology and we are looking forward to getting more data about the potential of therapeutic vaccination to treat such an aggressive and recurring disease."

David E. Anderson, Ph.D., VBI’s Chief Scientific Officer, commented, "This ongoing study continues to demonstrate the potential of VBI-1901, with both the GM-CSF adjuvant and GSK’s AS01 adjuvant system, to be an effective cancer vaccine immunotherapeutic. The tumor responses seen to-date across both study arms, including 2 partial responses and 7 stable disease, are meaningful, especially as an outcome of a monotherapy. This data supports the continued development of the program, both as a monotherapy as well as part of a combination regimen."

Based on the available data, VBI is exploring a randomized, controlled clinical study, including a potential registration study, for the next phase of development, which could begin in 2021, pending approval from regulatory bodies.

A webcast of Dr. Anderson discussing these data with Jeff Baxter, VBI’s President and CEO, can be found here: View Source

A copy of the e-poster is available on the "Events/Presentations" page in the "Investors" section of the VBI Vaccines website.

About the Phase 1/2a Study Design

VBI’s two-part Phase 1/2a study is a multi-center, open-label, dose-escalation study of VBI-1901 in up to 38 patients with recurrent GBM:

Phase 1 (Part A)
Dose-escalation phase that defined the safety, tolerability, and optimal dose level of VBI-1901 adjuvanted with granulocyte-macrophage colony-stimulating factor (GM-CSF) in recurrent GBM patients with any number of prior recurrences.
This phase enrolled 18 recurrent GBM patients across three dose cohorts of VBI-1901: 0.4 µg, 2.0 µg, and 10.0 µg.
Enrollment completed in December 2018.
Phase 2a (Part B)
Subsequent extension of the optimal dose level, 10.0 µg, as defined in the Part A dose escalation phase.
This phase is a two-arm study, enrolling 10 first-recurrent GBM patients in each vaccinated group, assessing 10.0 µg of VBI-1901 in combination with either GM-CSF or GSK’s proprietary AS01 adjuvant system as immunomodulatory adjuvants.
Enrollment of the 10 patients in each adjuvant group is complete.
VBI-1901 is administered intradermally when adjuvanted with GM-CSF and intramuscularly when adjuvanted with GSK’s AS01 adjuvant system. Patients in both phases of the study receive the vaccine immunotherapeutic every four weeks until tumor progression.

About VBI-1901 and GBM

VBI-1901 is a novel cancer vaccine immunotherapeutic candidate developed using VBI’s enveloped virus-like particle (eVLP) technology to target two highly immunogenic cytomegalovirus (CMV) antigens, gB and pp65. Scientific literature suggests CMV infection is prevalent in multiple solid tumors, including glioblastoma (GBM). GBM is among the most common and aggressive malignant primary brain tumors in humans. In the U.S. alone, 12,000 new cases are diagnosed each year. The current standard of care for treating GBM is surgical resection, followed by radiation and chemotherapy. Even with aggressive treatment, GBM progresses rapidly and has a high mortality.

On November 19, 2020 AstraZeneca reported that it will present new research aimed at addressing key unmet needs facing patients with blood cancers at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, held virtually from 5 to 8 December 2020 (Press release, AstraZeneca, NOV 19, 2020, View Source [SID1234571438]).

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The Company will present 27 abstracts spanning five medicines and potential new medicines and eight different hematology conditions that demonstrate the Company’s commitment to advancing hematology research and treatments for patients living with hematologic malignancies.

Key data presentations include:

A pooled analysis of data from four trials – ELEVATE TN, ASCEND, ACE-CL-001 and 15-H-0016 – expanding on the cardiovascular safety profile of CALQUENCE (acalabrutinib) monotherapy treatment for patients with chronic lymphocytic leukemia (CLL)
Extended follow-up data from the pivotal Phase II ACE-LY-004 trial that support long-term treatment with CALQUENCE in adult patients with relapsed or refractory mantle cell lymphoma (MCL)
Data on CALQUENCE in combination with venetoclax and either obinutuzumab or rituximab in patients with CLL, showing a safety profile consistent with previous trials with high complete responses and undetectable minimal residual disease rates after a median follow-up of 26.9 months, with minimal to no drug-drug interactions in the Phase Ib ACE-CL-003 trial
First-in-human data from the potential new medicine B-cell maturation antigen (BCMA)-targeted antibody drug conjugate, MEDI2228, presenting data on safety and efficacy at all dose levels in relapsed or refractory multiple myeloma
Data showing pre-clinical evidence of overcoming resistance in relapsed or refractory MCL from the dual BCL2/XL inhibitor, AZD4320, which blocks the anti-apoptotic effect of BCL2 and BCLXL
Phase I data from the anti-inducible co-stimulator anti-ICOS monoclonal antibody, MEDI-570, demonstrating promising early clinical activity in poor-risk refractory and heavily pretreated patients with angioimmunoblastic T-cell lymphoma
Multiple studies on roxadustat, the first in a new class of medicines evaluating its clinical effectiveness and safety profile in both the dialysis dependent and non-dialysis dependent anemia of CKD patient populations
Data on roxadustat assessing efficacy in anemia secondary to lower-risk myelodysplastic syndrome (MDS) regardless of baseline factors. In approximately one in three patients MDS leads to acute myeloid leukemia1
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "Our data at ASH (Free ASH Whitepaper) this year continue to support CALQUENCE as a well-tolerated treatment with impressive efficacy and safety across multiple blood cancers, reinforcing physicians’ confidence in treating patients with CALQUENCE over the long term. Data at the meeting will also explore CALQUENCE combinations with commonly used therapies, showing potential across a variety of regimens in chronic lymphocytic leukemia to best suit the unique needs of each patient."

José Baselga, Executive Vice President, Oncology R&D, said: "As we rapidly expand our presence in hematology, we are focused on identifying novel targets and mechanisms of action that can address the most urgent unmet needs across various hematological malignancies. Our early portfolio at this year’s ASH (Free ASH Whitepaper) clearly demonstrates our commitment to following the science in combating treatment-resistant and rare blood cancers."

Key AstraZeneca presentations during the 62nd ASH (Free ASH Whitepaper) Annual Meeting and Exposition

Lead author

Abstract title

Presentation details

CALQUENCE (acalabrutinib)

Brown, JR

Pooled Analysis of Cardiovascular Events from Clinical Trials Evaluating Acalabrutinib Monotherapy in Patients with CLL

Abstract #3146

Oral and Poster Abstracts

Monday, 7 December

7am–3:30pm PST

Wang, M

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory MCL: Long-Term Efficacy and Safety Results from a Phase 2 Study

Abstract #2040

Oral and Poster Abstracts

Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma

Sunday, 6 December

7am– 3:30pm PST

Woyach, JA

Acalabrutinib in Combination with Venetoclax and Obinutuzumab or Rituximab in Patients with Treatment-Naïve or Relapsed/Refractory CLL

Abstract #1312

Oral and Poster Abstracts

CLL: Therapy, excluding Transplantation

Saturday, 5 December
7am – 3:30pm PST

Davids, MS

Updated Safety and Efficacy Results from a Phase 2 Study of Acalabrutinib, Venetoclax and Obinutuzumab for Frontline Treatment of CLL

Abstract #3141

Oral and Poster Abstracts

CLL: Therapy, excluding Transplantation

Monday, 7 December
7am – 3:30pm PST

Munir, T

Cost-effectiveness of Acalabrutinib Monotherapy Compared with Chlorambucil Plus Obinutuzumab for Previously Untreated CLL

Abstract #2510

Oral and Poster Abstracts

Health Services Research—Malignant Conditions

Sunday, 6 December
7am – 3:30pm PST

Roxadustat

Henry, D

Oral Roxadustat Efficacy in Anemia Secondary to Lower-risk MDS Irrespective of Ring Sideroblasts and Baseline Erythropoietin Levels

Abstract #1277

Oral and Poster Abstracts

MDS — Clinical Studies

Saturday, 5 December
7am – 3:30pm PST

Provenzano, R

Pooled Efficacy and Cardiovascular Analysis of Roxadustat Compared with Placebo in Anemia Correction in Chronic Kidney Disease Patients Not on Dialysis

Abstract #1671

Oral and Poster Abstracts

Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron

Sunday, 6 December
7am – 3:30pm PST

Fishbane, S

Pooled Efficacy and Cardiovascular Safety Results of Roxadustat Compared with Epoetin Alfa in the Treatment of Anemia in Chronic Kidney Disease Patients on Dialysis

Abstract #749

Oral and Poster Abstracts

Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron

Saturday, 5 December
7am – 3:30pm PST

Early Stage Pipeline

Kumar, S

Phase 1, First-in-Human Study of MEDI2228, a BCMA-Targeted ADC in Patients with Relapsed/Refractory Multiple Myeloma

Abstract #179

Oral and Poster Abstracts

Myeloma/Amyloidosis: Therapy, excluding Transplantation

Saturday, 5 December
12–1:30pm PST

Li, Y

AZD4320 is a Novel and Potent BCL-2/XL Dual Inhibitor in Targeting Aggressive MCL

Abstract #2094

Oral and Poster Abstracts

Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents

Sunday, 6 December
7am – 3:30pm PST

Chavez, J

A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-cell Lymphoma (PTCL) and Angioimmunoblastic T-cell Lymphoma (AITL) (NCI-9930)

Abstract #1151

Oral and Poster Abstracts

Hodgkin Lymphoma and T/NK Cell Lymphoma

Saturday, 5 December
7am – 3:30pm PST

INDICATION AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

CALQUENCE is also indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE (acalabrutinib) capsules

Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter

Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) of any grade in patients with relapsed or refractory MCL were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

Dose reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.

Please see full Prescribing Information, including Patient Information.

CALQUENCE
CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its activity.2,3 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.2

As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in more than 20 company-sponsored clinical trials. CALQUENCE is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, and other hematologic malignancies.

Roxadustat
Roxadustat is a first in a new class of investigational medications that has the potential to promote erythropoiesis through increased endogenous production of erythropoietin; improved iron absorption, transport and mobilization; and downregulation of hepcidin, which helps to overcome the negative impact of inflammation on hemoglobin synthesis and red blood cell production. The roxadustat NDA for the treatment of anemia in CKD in both NDD and DD is under review by the US Food and Drug Administration with a decision expected in Q4 2020. Roxadustat is also in clinical development for anemia associated with myelodysplastic syndromes (MDS) and for chemotherapy-induced anemia (CIA).

AstraZeneca and FibroGen Inc. (FibroGen) are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia in the US, China and other markets in the Americas and in Australia/New Zealand, as well as Southeast Asia. Astellas and FibroGen are collaborating on the development and commercialization of roxadustat for the potential treatment of anemia in territories including Japan, Europe, the Commonwealth of Independent States, the Middle East and South Africa.

AstraZeneca in hematology
Leveraging its strength in oncology, AstraZeneca has established hematology as one of four key oncology disease areas of focus. The Company’s hematology franchise includes two medicines approved by the US Food and Drug Administration and a robust global development program for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s hematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On November 19, 2020 Pfizer Inc. (NYSE:PFE) reported results from the Phase 3 CROWN trial of LORBRENA (lorlatinib, available in Europe under the brand name LORVIQUA) versus XALKORI (crizotinib) in people with previously untreated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) were published online ahead of print in the New England Journal of Medicine (Press release, Pfizer, NOV 19, 2020, View Source [SID1234571437]). At a planned interim analysis, LORBRENA treatment resulted in statistically significant and clinically meaningful improvement in progression-free survival (PFS) according to blinded independent central review (BICR), the primary endpoint, compared to XALKORI (HR 0.28: 95% CI, 0.19 to 0.41; p<0.001), corresponding to a 72% reduction in the risk of progression or death. The trial is continuing for the secondary endpoint of overall survival (OS), which was not mature at the time of analysis.

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"For nearly a decade, we have been committed to transforming the treatment of non-small cell lung cancer through the development of innovative medicines like LORBRENA, a third-generation ALK-inhibitor specifically developed to inhibit the most common tumor mutations that drive resistance to current medications and to address brain metastases," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "The prolonged progression-free survival data and intracranial responses seen in the CROWN trial highlight the potential role for LORBRENA to significantly improve outcomes for people with previously untreated ALK-positive advanced NSCLC and we are pleased that these data will be reviewed as part of the FDA’s Real-Time Oncology Review (RTOR) pilot program."

As a secondary endpoint, the confirmed objective response rate (ORR) was 76% (95% CI, 68 to 83) with LORBRENA and 58% (95% CI, 49 to 66) with XALKORI. Additionally, LORBRENA showed increased intracranial activity compared with XALKORI. In the LORBRENA arm, 96% (95% CI, 91 to 98) of people were without central nervous system (CNS) progression at 12 months compared to 60% (95% CI, 49 to 69) in the XALKORI arm (HR 0.07: 95% CI, 0.03 to 0.17). In people presenting with measurable brain metastases (n=30), the intracranial ORR was 82% (95% CI, 57 to 96, n=14) with LORBRENA and 23% (95% CI, 5 to 54, n=3) with XALKORI; intracranial complete response rates of 71% and 8% were seen in each arm, respectively.

"Biomarker-driven medicines have improved outcomes for people living with ALK-positive non-small cell lung cancer, but innovative therapies are still needed to delay disease progression," said Benjamin Solomon, M.D., Department of Medical Oncology, Peter MacCallum Cancer Centre. "The results from the CROWN trial demonstrate that LORBRENA has the potential to be a practice-changing, first-line option, and we thank the many people and their families who participated in this trial."

In this trial, adverse events (AEs) occurring in >20% of patients treated with LORBRENA were hypercholesterolemia (70%), hypertriglyceridemia (64%), edema (55%), weight increase (38%), peripheral neuropathy (34%), cognitive effects (21%), and diarrhea (21%). Grade 3 or 4 AEs occurred in 72% of people treated with LORBRENA and 56% of people treated with XALKORI. The most common Grade 3 or 4 AEs for LORBRENA were hypertriglyceridemia (20%), increased weight (17%), hypercholesterolemia (16%), and hypertension (10%). Adverse events leading to permanent treatment discontinuation occurred in 7% of people treated with LORBRENA and 9% of people treated with XALKORI.

CROWN is a global, Phase 3, randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated ALK-positive advanced NSCLC were randomized 1:1 to receive LORBRENA monotherapy (n=149) or XALKORI monotherapy (n=147). The primary endpoint of the CROWN trial is PFS based on BICR. Secondary endpoints include PFS based on investigator’s assessment, OS, ORR, intracranial objective response, and safety.

In 2018, the Food and Drug Administration (FDA) approved LORBRENA for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease. This indication is approved under accelerated approval based on tumor response rate and duration of response. CROWN is the confirmatory trial for the conversion to full approval. Based on the positive outcome of the CROWN trial, the data will be reviewed under the FDA’s Real Time Oncology Review pilot program and will be shared with other health authorities to seek approval for an indication that includes previously untreated ALK-positive advanced NSCLC.

Lung cancer is the number one cause of cancer-related death around the world.1 NSCLC accounts for approximately 80-85% of lung cancers,2 with ALK-positive tumors occurring in about 3-5% of NSCLC cases.3 In 2020, an estimated 13,000 new cases of ALK-positive NSCLC are expected to be diagnosed in the G7.4

About LORBRENA (lorlatinib)

LORBRENA is a tyrosine kinase inhibitor (TKI) that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of ALK. LORBRENA was specifically developed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier. LORBRENA is approved in the U.S. for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on:

crizotinib and at least one other ALK inhibitor for metastatic disease; or
alectinib as the first ALK inhibitor therapy for metastatic disease; or
ceritinib as the first ALK inhibitor therapy for metastatic disease.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
The full prescribing information for LORBRENA can be found here.

IMPORTANT LORBRENA (lorlatinib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Contraindications: LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity.

Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers: Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 ALT or AST elevations occurred in 50% of subjects, Grade 3 in 33% of subjects, and Grade 2 in 8% of subjects. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); median time to recovery in subjects with Grade 3 or 4 or Grade 2 ALT or AST elevations was 18 days and 7 days, respectively. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA. Avoid concomitant use of LORBRENA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating LORBRENA and at least 3 times during the first week after initiating LORBRENA. Depending upon the relative importance of each drug, discontinue LORBRENA or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity.

Central Nervous System (CNS) Effects: A broad spectrum of CNS effects can occur; overall, CNS effects occurred in 54% of 332 patients receiving LORBRENA. These included seizures (3%, sometimes in conjunction with other neurologic findings), hallucinations (7%; 0.6% severe [Grade 3 or 4]), and changes in cognitive function (29%; 2.1% severe), mood (including suicidal ideation) (24%; 1.8% severe), speech (14%; 0.3% severe), mental status (2.1%; 1.8% severe), and sleep (10%). Median time to first onset of any CNS effect was 1.2 months (1 day to 1.7 years). Overall, 1.5% and 9% of patients required permanent or temporary discontinuation of LORBRENA, respectively, for a CNS effect; 8% required dose reduction. Withhold and resume at same or reduced dose or permanently discontinue based on severity.

Hyperlipidemia: Increases in serum cholesterol and triglycerides can occur. Grade 3 or 4 elevations in total cholesterol occurred in 17% and Grade 3 or 4 elevations in triglycerides occurred in 17% of the 332 patients who received LORBRENA. Median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 7% and 3% of patients required temporary discontinuation or dose reduction of LORBRENA, respectively, for elevations in cholesterol and in triglycerides. Eighty percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 21 days. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. Withhold and resume at same dose for the first occurrence; resume at same or reduced dose of LORBRENA for recurrence based on severity.

Atrioventricular (AV) Block: PR interval prolongation and AV block can occur. In 295 patients who received LORBRENA at a dose of 100 mg orally once daily and who had a baseline electrocardiography (ECG), 1% experienced AV block and 0.3% experienced Grade 3 AV block and underwent pacemaker placement. Monitor ECG prior to initiating LORBRENA and periodically thereafter. Withhold and resume at reduced or same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur. ILD/pneumonitis occurred in 1.5% of patients, including Grade 3 or 4 ILD/pneumonitis in 1.2% of patients. One patient (0.3%) discontinued LORBRENA for ILD/pneumonitis. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis. Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity.

Embryo-fetal Toxicity: LORBRENA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORBRENA can render hormonal contraceptives ineffective, during treatment with LORBRENA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for 3 months after the final dose.

Adverse Reactions: Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). The most common (≥20%) adverse reactions were (all Grades; Grade 3 or 4): edema (57%; 3.1%), peripheral neuropathy (47%; 2.7%), cognitive effects (27%; 2.0%), dyspnea (27%; 5.4%), fatigue (26%; 0.3%), weight gain (24%; 4.4%), arthralgia (23%; 0.7%), mood effects (23%; 1.7%), and diarrhea (22%; 0.7%); the most common (≥20%) laboratory abnormalities were (all Grades; Grade 3 or 4): hypercholesterolemia (96%; 18%), hypertriglyceridemia (90%; 18%), anemia (52%; 4.8%), hyperglycemia (52%; 5%), increased AST (37%; 2.1%), hypoalbuminemia (33%; 1.0%), increased ALT (28%; 2.1%), increased lipase (24%; 10%), and increased alkaline phosphatase (24%; 1.0%).

Drug Interactions: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Avoid concomitant use with moderate CYP3A inducers and strong CYP3A inhibitors. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor ALT, AST, and bilirubin as recommended. If concomitant use with a strong CYP3A inhibitor cannot be avoided, reduce the LORBRENA dose as recommended. Avoid concomitant use of LORBRENA with CYP3A substrates and P-gp substrates, which may reduce the efficacy of these substrates.

Lactation: Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.

Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment. The recommended dose of LORBRENA has not been established for patients with moderate or severe hepatic impairment.

Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. The recommended dose of LORBRENA has not been established for patients with severe renal impairment.

About XALKORI (crizotinib)

XALKORI is a TKI indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK- or ROS1-positive as detected by an FDA-approved test. XALKORI has received approval for patients with ALK-positive NSCLC in more than 90 countries including Australia, Canada, China, Japan, South Korea and the European Union. XALKORI is also approved for ROS1-positive NSCLC in more than 60 countries.

The full prescribing information for XALKORI can be found here.

IMPORTANT XALKORI (crizotinib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1719). Increased transaminases generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop increased transaminases. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.

Interstitial Lung Disease/Pneumonitis: Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1719), 2.9% of XALKORI-treated patients had any grade ILD, 1.0% had Grade 3/4, and 0.5% had fatal ILD. ILD generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.

QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1616), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5% of 1582 patients had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECGs. Avoid use in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at next lower dosage.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 13% of patients treated with XALKORI (n=1719). Avoid use in combination with other medications known to cause bradycardia. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% of 1719 patients. Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.

Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.

Embryo-Fetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.

ROS1-positive Metastatic NSCLC: Safety was evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC. Vision disorders occurred in 92% of patients in the ROS1 study; 90% of patients had Grade 1 vision disorders and 2% had Grade 2.

Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), esophagitis (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%), decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.

Drug Interactions: Use caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. If concomitant use of XALKORI is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling.

Lactation: Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with XALKORI and for 45 days after the final dose.

Hepatic Impairment: Crizotinib concentrations increased in patients with pre-existing moderate (any AST and total bilirubin >1.5x ULN and ≤3x ULN) or severe (any AST and total bilirubin >3x ULN) hepatic impairment. Reduce XALKORI dosage in patients with moderate or severe hepatic impairment. The recommended dose of XALKORI in patients with pre-existing moderate hepatic impairment is 200 mg orally twice daily or with pre-existing severe hepatic impairment is 250 mg orally once daily.

Renal Impairment: Decreases in estimated glomerular filtration rate occurred in patients treated with XALKORI. Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis.

About Pfizer Oncology

At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 23 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma.

Pfizer Inc.: Breakthroughs that change patients’ lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

On November 19, 2020 Affimed N.V. (Nasdaq: AFMD), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported that the Phase 1b study of AFM13, a CD30/CD16A innate cell engager (ICE), in combination with KEYTRUDA was published in Blood, the renowned Journal of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Affimed, NOV 19, 2020, View Source [SID1234571436]). The results demonstrate promising signs of efficacy including an objective response rate (ORR) of 88% at the highest treatment dose, as well as a complete CR of 46%. As a monotherapy, KEYTRUDA demonstrated an ORR of 69% and a CR of 22.4% in the KEYNOTE-087 trial.

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"We showed for the first time that the combination of an ICE with a PD-1 checkpoint inhibitor can be safely administered with manageable side effects," said Dr. Andreas Harstrick, Chief Medical Officer at Affimed. "The high objective response rate and complete response rate seen in this proof-of-concept study of AFM13 combined with KEYTRUDA are very encouraging and indicate that the activation of innate immunity could improve upon current therapies."

The study assessed the safety and efficacy of AFM13 in combination with KEYTRUDA in 30 heavily pre-treated patients with R/R Hodgkin lymphoma. The safety profile for the combination was described as well-tolerated and similar to the known profiles for each agent alone. Most adverse events were low grade and remained manageable with standard-of-care therapies.

AFM13 presents a novel approach of activating innate immunity through CD16A-directed tumor-cell killing by NK cells and macrophages. The phase 1b study supports the notion that in combination with an established therapy such as an immune checkpoint inhibitor, that releases the brakes on adaptive immune responses, the ICE AFM13 complements the PD-1 checkpoint inhibitor, thereby triggering both arms of the immune system against tumors.

Dr. Nancy Bartlett, a medical oncologist and Koman Chair in Medical Oncology at Washington University School of Medicine in St. Louis and lead author on the publication, said, "There is an unmet need for patients with Hodgkin lymphoma who have relapsed or are refractory to current therapies. For these patients, there are no therapies that show durable efficacy. The combination of AFM13 with KEYTRUDA was well tolerated and showed an 88% response rate with a very encouraging 46% complete metabolic response rate in a heavily pretreated patient population. This exciting data shows that there are potential treatments on the horizon for patients with limited options."

"Engagement of the innate immune system to kill tumors is novel. The studies of AFM13 and KEYTRUDA in Hodgkin lymphoma, as well as AFM13 in patients with T-cell lymphoma, present exciting approaches to controlling blood cancers that could significantly benefit patients," said Lee Greenberger, Ph.D., Chief Scientific Officer of The Leukemia & Lymphoma Society (LLS), which supported Affimed’s clinical study of AFM13 through its Therapy Acceleration Program (TAP), LLS’s strategic venture philanthropy funding initiative.

More details about the Phase 1b of AFM13 in combination with KEYTRUDA study can be found at www.clinicaltrials.gov using the identifier NCT02665650. The article published in Blood, Volume 136, Number 21 can be found here https://bit.ly/2KiL293 .

About AFM13
AFM13 is a first-in-class innate cell engager that induces specific and selective killing of CD30-positive tumor cells by engaging and activating natural killer (NK) cells and macrophages, thereby leveraging the power of the innate immune system. AFM13 is Affimed’s most advanced ICE clinical program, and it is currently being evaluated as a monotherapy in a registration-directed trial in patients with relapsed/refractory peripheral T-cell lymphoma or transformed mycosis fungoides (REDIRECT). The study is actively recruiting and can be found at www.clinicaltrials.gov using the identifier NCT04101331. Affimed is currently studying AFM13 in combination with cord blood-derived allogeneic natural killer cells in cooperation with the MD Anderson Cancer Center in Houston. The investigator-sponsored Phase 1 study is preparing to administer a stable complex of AFM13 pre-mixed with cord blood-derived allogeneic NK cells, the study can be found at www.clinicaltrials.gov using the identifier NCT04074746.