FS118 / Sino Biopharm - LARVOL DELTA

The tetravalent, bispecific properties of FS118, an anti-LAG-3/PD-L1 antibody, mediate LAG-3 shedding from CD4+ and CD8+ tumor-infiltrating lymphocytes. (PubMed, Anticancer Drugs) - "We also show that PD-L1, not PD-1, binding drives the LAG-3 reduction on TILs. We hypothesize that the LAG-3 bivalency in the fragment crystallizable region of FS118 allows LAG-3 clustering, which optimizes cleavage by ADAM10/ADAM17 and thus shedding."

IO biomarker • Journal • Tumor-infiltrating lymphocyte • Infectious Disease • Oncology • ADAM10 • ADAM17 • CD4 • CD8 • LAG3

Open-Label Phase 2 Study Results of FS118, a LAG-3/PD-L1 Bispecific Antibody, in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (ASH 2024) - P2 | "Conclusions In this phase 2 study, FS118 was well tolerated in patients with R/R DLBCL with no DLTs reported. FS118 is a new potential immune checkpoint blocker showing meaningful efficacy with durable responses achieved in patients with R/R DLBCL."

Clinical • P2 data • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Cardiovascular • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • LAG3

FS118 Showcases Modest Efficacy in Relapsed/Refractory DLBCL (OncLive) - P2 | N=94 | 2021-003406-47 | Sponsor: invoX Pharma Limited | "Results showed that, of the 10 patients in the cohort with relapsed/refractory DLBCL, the ORR was 20% (n = 2; 95% CI, 2.5%-55.6%), both of which were complete responses (CRs). Of the 2 patients who responded, 1 was previously treated with CAR T-cell therapy and had a duration of response (DOR) longer than 64.9 weeks; the other patient experienced a DOR of 8.1 weeks. Six patients had progressive disease (PD), and 2 patients did not have these data available (NA)...All patients had discontinued study treatment, due to progressive disease (n = 6), confirmed CR (n = 2), or clinical progression (n = 2). Further findings showed that the median PFS was 7.1 weeks (range, 0.0-72.9) and the median OS was 32.9 weeks (range, 6.3-NA). Regarding safety, investigators noted no dose-limiting toxicities, and no patients discontinued treatment due to toxicity or treatment-emergent adverse effects (TEAEs) related to FS118."

P2 data • Diffuse Large B Cell Lymphoma

A Phase 1/2 Study of FS118 in Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=80 | Terminated | Sponsor: invoX Pharma Limited | Active, not recruiting ➔ Terminated; Business Decision

Combination therapy • Metastases • Monotherapy • Trial termination • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • LAG3

Evaluation of Impact Strength and Flexural Strength of Polyether Ether Ketone vs. Computer-Aided Design/Computer-Aided Manufacturing Polymethyl Methacrylate Denture Base Materials: An In-Vitro Study. (PubMed, Cureus) - " PEEK or CAD/CAM PMMA share almost identical and superior mechanical properties, and both can be used as better alternatives for complete denture fabrication rather than using conventional heat cure PMMA."

Journal • Preclinical

A Phase 1/2 Study of FS118 in Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=95 | Active, not recruiting | Sponsor: invoX Pharma Limited | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2022 ➔ Jun 2024 | Trial primary completion date: Dec 2022 ➔ Jun 2024

Enrollment closed • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • LAG3

[VIRTUAL] FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, induces LAG-3 shedding resulting in receptor downregulation by T cells via a novel mechanism of action (SITC 2020) - P1 | "Removing LAG-3 from the surface of TILs via shedding may be an important mechanism by which FS118 overcomes compensatory upregulation of LAG-3 induced by PD-L1 blockade. Soluble LAG-3 may be an important biomarker for monitoring the pharmacodynamic activity of FS118 in patients."

IO biomarker • Oncology • LAG3

LAG-3/PD-L1 mAb2 can overcome PD-L1-mediated compensatory upregulation of LAG-3 induced by single-agent checkpoint blockade (AACR 2019) - P1; "Modulation of sPD-L1 levels in the serum of treated animals was also observed in cynomolgus monkeys treated with FS118. These data provide a strong rationale for investigating both cell surface and soluble LAG-3 and PD-L1 levels as potential pharmacodynamic biomarkers in further clinical development."

Checkpoint inhibition • IO biomarker • PD(L)-1 Biomarker • Oncology

[VIRTUAL] A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy (SITC 2020) - P1 | "Conclusions Weekly treatment with FS118 was well tolerated up to 20 mg/kg and was associated with pharmacodynamic markers of FS118 activity. Encouraging signs of clinical activity were observed in highly pre-treated patients who had acquired resistance to prior PD-(L)1 therapy."

Clinical • IO biomarker • P1 data • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • LAG3

[VIRTUAL] FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, induces LAG-3 shedding resulting in receptor downregulation by T cells via a novel mechanism of action (SITC 2020) - P1 | "Removing LAG-3 from the surface of TILs via shedding may be an important mechanism by which FS118 overcomes compensatory upregulation of LAG-3 induced by PD-L1 blockade. Soluble LAG-3 may be an important biomarker for monitoring the pharmacodynamic activity of FS118 in patients."

IO biomarker • Oncology • LAG3

A first-in-human phase I study of FS118, an anti-LAG-3/PD-L1 bispecific antibody in patients with solid tumors that have progressed on prior PD-1/PD-L1 therapy. (ASCO 2019) - P1; "Cohorts 1 through 6 have been completed, enrollment in cohort 7 began December 2018. Clinical trial information: NCT03440437"

Clinical • IO biomarker • P1 data • PD(L)-1 Biomarker • Oncology • Solid Tumor

Interferon biology and LAG3 shedding in PD-(L)1 plus LAG3 immunotherapy. (PubMed, Clin Cancer Res) - "The bispecific LAG-3 and PD-L1 blocking antibody FS118, potentially through LAG-3 shedding, represents a promising strategy to improve immune-checkpoint blockade. Soluble LAG-3 is an intriguing biomarker for LAG-3 drug activity."

IO biomarker • Journal • Immune Modulation • Inflammation • Oncology • IFNG • LAG3

A Phase 1 first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1 in patients with advanced cancer and PD-L1 resistance. (PubMed, Clin Cancer Res) - P1/2 | "FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti-PD-(L)1 therapy."

Journal • P1 data • Oncology • Solid Tumor • LAG3

A Phase 1 first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1 in patients with advanced cancer and PD-L1 resistance (Clin Cancer Res) - P1/2 | N=80 | NCT03440437 | Sponsor: F-star Therapeutics Limited | "Forty-three patients, with a median of three prior regimens in the locally advanced/metastatic setting including at least one anti-PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLTs) were observed, and a maximum tolerated dose (MTD) was not reached. The recommended Phase 2 dose of FS118 was established as 10 mg/kg weekly....The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1-targeted therapy."

P1 data • Oncology • Solid Tumor

F-star Therapeutics Announces Publication of Phase 1 Dose-Escalation Trial of FS118 in Patients with Advanced Cancer and PD-L1 Resistance in Clinical Cancer Research (GlobeNewswire) - P1/2 | N=80 | NCT03440437 | Sponsor: F-star Therapeutics Limited | "F-star Therapeutics, Inc...announced the publication of safety and efficacy results from Phase 1 trial of FS118 in patients with advanced cancer and PD-L1 resistance in Clinical Cancer Research, a journal of the American Association for Cancer Research...'We are pleased to see that FS118 was well-tolerated, and in this population of heavily pre-treated patients with PD-L1 acquired resistance achieved one partial response and 54.8% disease control rate.'...Weekly administration was well tolerated, with no dose-limiting toxicities (DLTs), and no serious adverse events (SEAs) relating to FS118. The recommended Phase 2 dose of FS118 was established at 10 mg/kg weekly."

P1/2 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Durable response of anaplastic thyroid carcinoma to FS118, a bispecific LAG-3/PD-L1 antibody, after checkpoint inhibitor progression: a case report. (PubMed, J Immunother Cancer) - "Simultaneously, expanded use should be considered for those with refractory disease, especially if PD-L1 positive. Insights Dual PD-L1/LAG-3 blockade may be an effective treatment strategy for refractory metastatic tumors, including anaplastic thyroid cancer."

Checkpoint inhibition • IO biomarker • Journal • Endocrine Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • LAG3

The tetravalent structure of FS118, a bispecific antibody targeting LAG-3 and PD-L1, is required for its novel mechanism of LAG-3 shedding (AACR 2022) - "Bivalent LAG-3 and PD-L1 binding is required for enhanced shedding of cell surface LAG-3 in vitro. Removing LAG-3 from the surface of exhausted TILs is a novel mechanism attributed to the tetravalent structure of FS118, which may be important to overcome compensatory upregulation of LAG-3 induced by blockade of PD-L1 in patients."

Oncology • ADAM10 • ADAM17 • CD4 • LAG3

F-star Therapeutics Presents a Novel LAG-3 Reduction and Shedding Mechanism with FS118 at AACR 2022 (GlobeNewswire) - "The presentation demonstrates that bivalent LAG-3 binding by FS118 was required for maximal LAG-3 shedding and a reduction in cell surface LAG-3 expression by TILs in mouse models. By contrast, a reduction in LAG-3 cell surface expression by TILs was not observed with a LAG-3/PD-1 bispecific. These data demonstrate the importance of tetravalent binding by FS118 which may be crucial to overcoming compensatory upregulation of LAG-3 induced by blockade of PD-L1 in patients with cancer."

Preclinical • Oncology

F-star Therapeutics Reports Full-Year 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - "Anticipated Program Milestones: In 2022: A clinical efficacy readout of FS118 in PD-1 acquired resistance head and neck cancer patients who have failed checkpoint therapies. Clinical update on FS222 Phase 1 trial. Program update on the Phase 1 trial of FS120. FS120 trial part B initiation, in combination with Merck’s pembrolizumab...R&D expense was $28.8M for the year ended December 31, 2021, compared to $14.1M for the 2020 year-end. The increase in R&D expense was due primarily to the expansion of our FS118 clinical trial into acquired resistance head & neck patients, as well as our CPI naïve trial in NSCLC and DLBCL, a full year of spend on the mono and combo SB11285 clinical trial, and continued progression of our FS120 and FS222 clinical programs."

Clinical • Clinical data • Commercial • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

F-star Announces Issuance of U.S. Patent Protecting FS118, a Bispecific Antibody Targeting PD-L1 and LAG-3 (GlobeNewswire) - "F-star Therapeutics...announced that the United States Patent and Trademark Office (USPTO) has granted a patent protecting the composition of matter of FS118, F-star’s tetravalent bispecific antibody which blocks PD-L1 and LAG-3 receptors. U.S. Patent No. 11,214,620 is entitled 'Binding Molecules Binding PD-L1 and LAG-3' and is expected to provide F-star with exclusivity for FS118 out to at least August 2038."

Patent • Oncology

F-star Therapeutics to Host Virtual R&D Day on December 6, 2021 (GlobeNewswire) - "Following a discussion of F-star’s R&D platform, Louis Kayitalire, M.D., Chief Medical Officer, will present on the vast potential of the company's clinical pipeline of tetravalent mAb2 bispecifics, each of which is directed against some of the most exciting targets in immuno-oncology drug development, including LAG-3 and CD137 (4-1BB)."

Clinical • Breast Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

FS118: Expiry of patents related to composition-of-matter in 2037 (F-star therapeutics) - Q3 2021 Results

Patent • Oncology

F-star Therapeutics to Present at The Society for Immunotherapy of Cancer (SITC) 2021 Conference (GlobeNewswire) - "In her presentation, Dr. Morrow explains how bispecific antibodies can unlock new biology via mechanisms that combination approaches cannot. F-star’s FS118 is a dual checkpoint inhibitor targeting PD-L1 and LAG-3 that drives LAG-3 shedding and receptor down-regulation, via bispecific activity....FS120 in combination with anti-PD-1 (pembrolizumab) was shown to enhance T cell activity in multiple human primary immune assays. In combination with an anti-PD-1, FS120 surrogate increased antitumor efficacy in a mouse tumor model with pharmacodynamic changes related specifically to T cell activation, when compared to monotherapies, either alone or in combination."

Preclinical • Oncology

F-star Therapeutics Reports Third Quarter 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - "FS118 development expanded following external clinical validation of the LAG-3 target....This adds to the already ongoing checkpoint inhibitor relapsed head and neck cancer study that is anticipated to report data in mid-2022."

Clinical • P1/2 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck

[VIRTUAL] A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy (SITC 2020) - P1 | "Conclusions Weekly treatment with FS118 was well tolerated up to 20 mg/kg and was associated with pharmacodynamic markers of FS118 activity. Encouraging signs of clinical activity were observed in highly pre-treated patients who had acquired resistance to prior PD-(L)1 therapy."

Clinical • IO biomarker • P1 data • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • LAG3