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Agilent PD-L1 Assay Receives FDA Approval for Use as a Companion Diagnostic

On May 18, 2020 Agilent Technologies Inc. (NYSE: A) reported that the U.S. Food and Drug Administration has approved the company’s PD-L1 IHC 28-8 pharmDx for expanded use in non-small cell lung cancer (NSCLC) (Press release, Agilent, MAY 18, 2020, View Source [SID1234558249]).

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"The expanded use of PD-L1 IHC 28-8 pharmDx will give physicians in the USA critical information to inform first-line treatment decisions for patients with metastatic non-small cell lung cancer"

Now, physicians will be able to use the PD-L1 IHC 28-8 pharmDx assay as an aid in identifying patients with metastatic NSCLC for treatment with the dual immunotherapy combination of Opdivo (nivolumab) and Yervoy (ipilimumab), manufactured by Bristol Myers Squibb. Based on the results of the Phase 3 CheckMate -227 clinical trial, Opdivo in combination with Yervoy was approved as first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test.

"The expanded use of PD-L1 IHC 28-8 pharmDx will give physicians in the USA critical information to inform first-line treatment decisions for patients with metastatic non-small cell lung cancer," said Sam Raha, president of Agilent’s Diagnostics and Genomics Group.

Agilent developed PD-L1 IHC 28-8 pharmDx in 2016 through a collaboration with Bristol Myers Squibb, and it has been previously approved as a complementary in vitro diagnostic for non-squamous non-small cell lung cancer, as well as other forms of cancer, including, squamous cell carcinoma of the head and neck, and urothelial carcinoma.

Lung cancer is the most commonly diagnosed cancer worldwide across both sexes, causing 18.4% of all cancer deaths, with an estimated two million new cases reported in 2018. NSCLC accounts for 80%–90% of lung cancers, and 75% of NSCLC patients are diagnosed in the advanced stage.

Agilent is a worldwide leader in the development and commercialization of precision medicine diagnostics in collaboration with biopharmaceutical companies.

Opdivo and Yervoy are registered trademarks of Bristol-Myers Squibb Company.

Janssen Announces Phase 1 Results for Bispecific Antibody Amivantamab in the Treatment of Patients with Advanced Non-Small Cell Lung Cancer Harbouring Exon 20 Insertion Mutations

On May 18, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported results from the Phase 1 CHRYSALIS study evaluating amivantamab (JNJ-6372) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 20 insertion mutations (Press release, Janssen Pharmaceuticals, MAY 18, 2020, View Source [SID1234558248]).1 Amivantamab is an EGFR and MET-targeted bispecific antibody, which targets activating and resistance EGFR mutations, and MET pathway activation.2,3 Investigators assessed efficacy using overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), duration of response, as well as the safety profile of amivantamab,1 which were the basis of the U.S. Food and Drug Administration (FDA) Breakthrough Therapy Designation granted earlier this year.4

The Phase 1 CHRYSALIS study is a first-in-human, open-label, multi-cohort, multicentre study evaluating the safety, pharmacokinetics and efficacy of amivantamab as a monotherapy and in combination with lazertinibi, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), in adult patients with advanced NSCLC.5 Fifty patients with EGFR Exon 20 insertion-mutated NSCLC received the recommended Phase 2 dose (RP2D) of amivantamab.1 Among these 50 patients, 39 were evaluable for response with 13 distinct EGFR Exon 20 insertion mutations identified.1 Detailed results will be presented as a poster presentation and discussion at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Programme (Abstract #9512) beginning Friday 29th May.

Patients with NSCLC and EGFR Exon 20 insertion mutations have a form of disease that is generally insensitive to approved EGFR TKI treatments and as a result carries a worse prognosis compared to patients with more common EGFR mutations (Exon 19 deletions/L858R substitution).6 Currently, there are no targeted therapies approved specifically for patients with lung cancer who have EGFR Exon 20 insertion mutations.7 Estimated median overall survival for patients with NSCLC and Exon 20 insertion mutations is 16 months.8

"Lung cancer is the leading cause of cancer deaths worldwide, and genetic factors such as EGFR mutations can have a significant impact on the development and progression of non-small cell lung cancer," said Keunchil Park, M.D., Ph.D., Professor, Division of Haematology-Oncology, Department of Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine in Seoul, South Korea, and lead study investigator. "We look forward to sharing these data that provide initial insights into the potential of amivantamab as a treatment option for patients with non-small cell lung cancer and EGFR Exon 20 insertion mutations who have a high unmet need and often do not respond to the current standard of care."

Findings from the study showed an ORR of 36 percent (95 percent CI, 21–53) in all evaluable patients and 41 percent (95 percent CI, 24–61) in the 29 evaluable patients previously treated with platinum-based chemotherapy.1 Additionally, the median duration of response for all evaluable patients was 10 months and seven months for patients previously treated with platinum-based chemotherapy.1 The median progression-free survival was 8.3 months (95 percent CI, 3.0–14.8) for all evaluable patients and 8.6 months (95 percent CI, 3.7–14.8) for patients previously treated with platinum-based chemotherapy.1 The clinical benefit rate (partial response or better or stable disease of at least 12 weeks [two disease assessments]) was 67 percent (95 percent CI, 50–81) for all evaluable patients and 72 percent (95 percent CI, 53–87) for patients previously treated with platinum-based chemotherapy.1 Responses were observed in both treatment-naive patients and those previously treated with platinum-based chemotherapy.1 Tumour responses were most frequently observed at the first disease assessment after starting therapy.1

The most common all-grade adverse events (AE) were rash, infusion-related reaction (IRR), and paronychia.1 IRRs occurred predominantly on the first infusion and did not prevent subsequent treatments.1 No grade ≥3 rash was reported, and one patient reported grade 3 diarrhoea and six percent had diarrhoea of any grade.1 Six percent had treatment-related grade ≥3 AEs of hyperamylasaemia, hypokalaemia, increased lipase and shoulder/chest pain.1 Treatment-related serious AEs of cellulitis, interstitial lung disease and shoulder/chest pain were reported in six percent of patients.1 Additional EGFR-related AEs included stomatitis (sixteen percent), pruritus (fourteen percent), and diarrhoea (six percent).1

"Despite years of research and the availability of more treatment options, lung cancer remains Europe’s biggest cancer death threat," said Dr Joaquín Casariego, M.D., Janssen Therapeutic Area Lead Oncology for Europe, Middle East & Africa, Janssen-Cilag S.A. "It is vital that we develop new, innovative, targeted treatments to improve outcomes for patients with this aggressive cancer. The initial data presented today provides encouraging insights on the potential of amivantamab in non-small cell lung cancer bearing Exon 20 insertion mutations, and we are committed to exploring further the role this innovation may have in addressing the unmet needs for many more patients, their families and the medical community."

#ENDS#

About Amivantamab
Amivantamab (JNJ-6372) is an investigational EGFR-MET bispecific antibody with immune cell-directing activity, which targets activating and resistance EGFR mutations, and MET pathway activation.2,3 The production and development of the antibody followed Janssen Biotech, Inc.’s licensing agreement with Genmab for use of its DuoBody technology platform.9

About Non-Small Cell Lung Cancer (NSCLC)
In Europe, it is estimated that over 470,000 patients were diagnosed with lung cancer in 2018, with around 85 percent diagnosed with NSCLC.10,11 Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined.10 The five-year survival rate for patients with metastatic NSCLC is currently 24 percent.12

The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.13 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase that helps cells grow and divide.13 EGFR mutations are present in 10 to 15 percent of Caucasian patients with NSCLC and occur in 40 to 50 percent of Asian patients who have NSCLC adenocarcinoma.12,14,15 EGFR Exon 20 insertion mutations identify a distinct subset of lung adenocarcinomas, accounting for four to nine percent of all EGFR mutations.16

Janssen Presents First Data from Phase 1 Study of BCMAxCD3 Bispecific Teclistamab in Patients with Heavily Pre-treated Relapsed or Refractory Multiple Myeloma

On May 18, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported results for the first time from a Phase 1 first-in-human dose escalation study (NCT03145181) of teclistamab (JNJ-7957), an investigational bispecific antibody targeting both B-cell maturation antigen (BCMA) and CD3 receptors on T-cells, in the treatment of patients with relapsed or refractory multiple myeloma (Press release, Janssen Pharmaceuticals, MAY 18, 2020, View Source [SID1234558247]). Initial results suggest a manageable safety profile across all teclistamab doses evaluated.1,2 Investigators reported that patients achieved deep responses which persisted, including some minimal residual disease (MRD)-negative complete responses (CR) at 10-6, with one durable beyond 12 months.1 The data will be featured during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Programme as an oral presentation on Saturday, May 30 at 1:00 p.m. ET/6:00 p.m. BST (Abstract #100).

The study enrolled patients with multiple myeloma who had relapsed or were refractory to established therapies and had previously been treated with a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).1,2 Patients had received a median of six prior lines of treatment (range, 2-14) before starting the study; 92 percent were triple-class exposed, 86 percent were refractory to the last line of therapy, 80 percent were triple-class refractory, and 41 percent were penta-drug refractory, meaning their cancer did not respond to treatment or had relapsed within 60 days with two or more immunomodulatory agents, two or more PIs, and an anti-CD38 therapy.1 Patients with triple-class refractory and penta-drug refractory multiple myeloma face poorer survival outcomes as treatment options are limited.3

"While the treatment of multiple myeloma has significantly advanced over recent years, finding additional treatment options for patients who relapse and become resistant to existing therapies remains critical," said Saad Usmani, M.D., FACP, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, and lead study investigator. "Initial findings for teclistamab in this heavily pre-treated population support further study of this investigational dual-targeting immunotherapeutic."

The study will be conducted in two parts: dose escalation (part 1) and dose expansion (part 2).1,2 Results from the Phase 1 portion of the study showed deep responses among patients (n=78) who were treated with teclistamab across dose groups, ranging from 0.3 µg/kg-720 µg/kg. At the 270 µg/kg dose (n=12), the overall response rate (ORR) was 67 percent (8/12); 50 percent (6/12) of patients achieved a very good partial response (VGPR) or better, and three patients achieved CR.1 Responses were deep and persisted. At the time of data cut-off, 76 percent (16/21) of patients who achieved a response across all doses remained in the study with an ongoing response, and 80 percent (4/5) who were evaluable for MRD analysis were MRD-negative, with two patients having a MRD-negative CR. Maintained MRD-negativity was confirmed for both patients who could be evaluated.1 Additional dose escalation and expansion of the study is ongoing.1

"We are continuing to pursue scientific advances in cancer types that we know best, like multiple myeloma, where we can achieve the optimal impact," said Patrick Laroche, M.D., Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. "With teclistamab we aim to make a difference to the lives of the most vulnerable patients."

"We are committed to a multiplatform approach in our scientific strategy to address patients’ needs and provide treatment options for all patients with multiple myeloma," said Yusri Elsayed, M.D., M.H.Sc., Ph.D. Vice President, Global Head, Hematologic Malignancies, Janssen Research & Development, LLC. "Teclistamab is an example of one of our bispecific antibodies where we look to harness our immunotherapy expertise to advance potentially new options for patients whose disease has sadly progressed."

In the Phase 1 study, the most common adverse events (AEs) (all grade) were anaemia (58 percent); cytokine release syndrome (CRS) (56 percent); neutropenia (45 percent); thrombocytopenia (40 percent); and pyrexia (31 percent). In patients who experienced Grade 3 and above AEs (≥20 percent), the most common were neutropenia (38 percent); anaemia (36 percent); and thrombocytopenia (24 percent).1 One Grade 5 AE, respiratory failure in the setting of pneumonia, was reported but deemed by the investigator to be unrelated to the treatment.1 CRS events were all mild or moderate (Grade 1–2) and generally confined to first step-up and full doses, which may support the use of step-up dosing to mitigate CRS.1

About Teclistamab

Teclistamab (JNJ-7957) is an investigational bispecific antibody targeting both BCMA and CD3.1 CD3 is involved in activating the immune system’s response to fight infection, and BCMA is expressed at significantly higher levels in people with multiple myeloma.4,5,6 Teclistamab redirects CD3 T-cells to BCMA-expressing myeloma cells to induce cytotoxicity of the targeted cells.4,5 Results from preclinical studies demonstrate that teclistamab kills myeloma cell lines and myeloma bone marrow cells from heavily pre-treated patients.4

Teclistamab is currently being evaluated in a Phase 1 clinical study for the treatment of relapsed or refractory multiple myeloma and is also being explored in combination studies. The production and development of the antibody followed Janssen Biotech, Inc.’s licensing agreement with Genmab for use of its DuoBody technology platform.*

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.7 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.8 Around 50 percent of newly diagnosed patients do not reach five-year survival,7,9 and almost 29 percent of patients with multiple myeloma will die within one year of diagnosis.10

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.11 Relapsed and refractory myeloma is defined as disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course.12 While some patients with MM have no symptoms at all, others are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.13 Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and require new therapies for continued disease control.14

ALX Oncology to Present ALX148 Phase 1 Clinical Data at the Virtual 25th Congress of the European Hematology Association (EHA)

On May 18, 2020 ALX Oncology Holdings Inc., a clinical-stage immuno-oncology company developing therapies that block the CD47 checkpoint pathway, reported that the Phase 1 study of ALX148 in patients with relapsed/refractory Non-Hodgkin Lymphoma has been selected for an e-Poster presentation at the Virtual 25th Annual Congress of EHA (Free EHA Whitepaper), June 11 – 14, 2020 (Press release, ALX Oncology, MAY 18, 2020, View Source [SID1234558246]).

Virtual 25th Congress of EHA (Free EHA Whitepaper) Presentation Information
Title: ALX148, a CD47 blocker, in combination with rituximab in patients with relapsed/refractory (R/R) Non-Hodgkin Lymphoma (NHL) (Abstract #EP1247).
Session Title: Aggressive Non-Hodgkin Lymphoma – Clinical
Date: Friday, June 12

Provectus Announces PV-10® STING Agonist Abstract at American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting II

On May 18, 2020 Provectus (OTCQB: PVCT) reported the publication of an abstract about and data from ongoing preclinical study of investigational autolytic cancer immunotherapy PV-10 (rose bengal disodium) for the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II, to be held June 22-24, 2020 (Press release, Provectus Biopharmaceuticals, MAY 18, 2020, View Source [SID1234558244]). The abstract was posted online by AACR (Free AACR Whitepaper) on May 15 in advance of the virtual meeting.

Small molecule-based PV-10 is administered either by cutaneous intratumoral (IT) injection to superficial melanoma and non-melanoma skin cancer tumors (such as basal cell carcinoma, Merkel cell carcinoma, and squamous cell carcinoma) or by percutaneous IT injection to visceral primary and metastatic tumors of the liver (such as hepatocellular carcinoma, metastatic colorectal cancer, metastatic neuroendocrine tumors, and metastatic uveal melanoma). By targeting tumor cell lysosomes, PV-10 treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-4

Abstract:

Title: Association of heat shock proteins as chaperone for STING: A potential link in a key immune activation mechanism revealed by the novel anti-cancer agent PV-10
Session Category: Clinical Research
Track(s): Clinical Research Excluding Trials, Immunology
Session Title: Inflammation, Immunity, and Cancer/Modifiers of the Tumor Microenvironment 1
Abstract number: 5393
This work was led by Aru Narendran, MD, PhD and his team of researchers at the Alberta Children’s Hospital Research Institute and the University of Calgary (Calgary, Alberta, Canada), who previously showed that PV-10 treatment mediates another immune system signaling pathway (poly-ADP ribose polymerase [PARP] cleavage)5.

About PV-10

PV-10 is an investigational new drug undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and metastatic uveal melanoma). PV-10 is also undergoing preclinical study for pediatric solid tumor cancers (like neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma) and pediatric blood cancers (like leukemia).5,6

Tumor Cell Lysosomes as the Seminal Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.7 Cancer progression and metastasis are associated with lysosomal compartment changes8,9, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance10.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,11, external collaborators6, and other researchers13,14,16 have independently shown that PV-10 (RB) triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via PV-10: PV-10 induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine HCC cells can be viewed in this Provectus video of the event (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames; the event has a duration of approximately one hour). Exposure to PV-10 triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video; this event has a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators from POETIC using relapsed and refractory human pediatric neuroblastoma cells to show that lysosomes are disrupted upon exposure to PV-10.5

Immune Signaling Pathways: PV-10 causes acute autolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways studied to date, such as the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Other mediated immune signaling pathways that have been identified include PARP cleavage5 and, now, stimulator of interferon genes (STING), which plays an important role in innate immunity15. PV-10 is the first cancer drug that may facilitate multiple, complementary, immune system signaling pathways.16

Orphan Drug Designations (ODDs)

ODD status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Drug Product

Rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt) is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. PV-10 drug product is a formulation of 10% w/v RB in 0.9% saline, supplied in single-use glass vials containing 5 mL (to deliver) of solution, and administered without dilution to solid tumors via IT injection.

Intellectual Property (IP)

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which pharmaceutical grade RB and related halogenated xanthenes are produced, reducing the formation of previously unknown impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of PV-10 and systemic immunomodulatory therapy (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035.