nofazinlimab (CS1003) / CStone Pharma, 3SBio - LARVOL DELTA

Rinatabart sesutecan (PRO1184) in combination with standard-of-care therapy exerted potentiated antitumor activity in preclinical cancer models (AACR 2025) - P1/2 | "Xenograft mouse models inoculated with OC (OVCAR-8 cells) or EC (HEC-1-A cells) received either phosphate-buffered saline (PBS) alone or Rina-S alone, with or without carboplatin (OC), bevacizumab (OC), or olaparib (EC). Syngeneic mouse models of lung cancer or colorectal cancer received either PBS alone or Rina-S alone, with or without an anti-PD1 agent nofazinilmab (CS1003)... These preclinical studies provide evidence for combination therapy with Rina-S and various SOC therapies and suggest that Rina-S may be investigated in different treatment settings in the clinic. A phase 1/2 study (NCT05579366) is currently ongoing to study the efficacy and safety of Rina-S in combination with carboplatin, bevacizumab, or pembrolizumab for the treatment of platinum-sensitive OC, PROC, and EC, respectively."

Combination therapy • IO biomarker • Preclinical • Colorectal Cancer • Endometrial Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • CALR • FOLR1 • HMGB1

CS1002-101: A Study of CS1002 in Subjects with Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=91 | Completed | Sponsor: CStone Pharmaceuticals | Phase classification: P1a/1b ➔ P1

Combination therapy • Metastases • Monotherapy • Phase classification • Oncology • Solid Tumor

CStone Reports 2024 Interim Results and Recent Corporate Updates (PRNewswire) - "Anticipated near-term catalysts include: (i) Sugemalimab: MAA approval for the first-line treatment of Stage IV NSCLC in the U.K. expected in 2024 H2, and more global partnerships expected in 2024; (ii) CS5001: Presentation of the latest clinical safety and efficacy data at international academic conferences (e.g. ASH in 2024 H2), initiation of phase 1b trial with registrational potential in 2024, and global business development (BD) partnerships expected in 2024 or 2025.....(iii) GAVRETO (pralsetinib): Approval for manufacturing localization expected in 2025 H1; (iv) Nofazinlimab: Final OS analysis expected in 2025 H1; seeking ex-China partnership opportunities."

Commercial • Licensing / partnership • MHRA approval • New P1 trial • P1 data • Gastrointestinal Stromal Tumor • Hepatocellular Cancer • Lymphoma • Non Small Cell Lung Cancer

CStone Pharmaceuticals Reports 2023 Annual Results and Business Updates (PRNewswire) - "In March 2024, we completed a prespecified interim analysis for the global phase III trial of nofazinlimab in combination with LENVIMA (lenvatinib) for the first-line treatment of patients with unresectable or metastatic HCC; no new or unexpected safety signals were observed; independent Data Monitoring Committee ('iDMC') recommended a continued follow-up, without protocol modification, until the final assessment of OS....Nofazinlimab: final assessment of OS and ex-China partnership exploration in 2025."

DSMB • P3 data • Hepatocellular Cancer

Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study. (PubMed, Cancer) - "CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the..."

Checkpoint block • Checkpoint inhibition • Journal • Metastases • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Melanoma • Microsatellite Instability • Oncology • Solid Tumor • CTLA4 • MSI

CStone Announces Strategic Partnership and Exclusive Licensing Agreement with 3SBio for Nofazinlimab (Anti-PD-1 Antibody) in Mainland China (CStone Pharma Press Release) - "CStone Pharmaceuticals...announced a strategic partnership and exclusive licensing agreement with Shenyang Sunshine Pharmaceutical Co., Ltd., a subsidiary of 3SBio...for an anti-PD-1 antibody nofazinlimab in mainland China. Under the terms of the agreement, 3SBio will pay CStone an upfront payment of 60 million RMB, near 100 million RMB development and registration milestone payment, and additional payments for future sales based milestones and tiered sales royalties. 3SBio will obtain the exclusive rights for the development, registration, manufacturing, and commercialization of nofazinlimab in mainland China....The topline results...[from]...Phase 3 study CS1003-305, evaluating the efficacy and safety of nofazinlimab in combination with lenvatinib in first-line treatment for advanced HCC patients...are expected to be disclosed in the first quarter of 2024."

Licensing / partnership • P3 data: top line • Hepatocellular Cancer

CStone Announces Publication of First-in-Human Study Results of Anti-PD-1 Antibody Nofazinlimab in British Journal of Cancer and Update of Global Phase III Trial of Nofazinlimab in HCC (CStone Pharma Press Release) - P1 | N=108 | NCT03475251 | Sponsor: CStone Pharmaceuticals | "The research data show that nofazinlimab monotherapy demonstrates good safety and tolerability, with no observed dose-limiting toxicities. Preliminary anti-tumor activity was also observed in multiple tumor types. The study explored different dosing frequencies and found that the safety and efficacy of nofazinlimab at doses of 200 mg every three weeks and 400 mg every six weeks are essentially equivalent. Furthermore, the trial investigated the use of nofazinlimab in combination with regorafenib, and the data reveal a manageable safety profile for patients with heavily pre-treated metastatic colorectal cancer....The topline results are expected to be disclosed in the first quarter of 2024 and will be used to support the new drug applications of nofazinlimab globally."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer (Nature, Br J Cancer) - P1a/1b | N=108 | NCT03475251 | Sponsor: CStone Pharmaceuticals | "In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study....ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer (Nature, Br J Cancer) - P1a/1b | N=108 | NCT03475251 | Sponsor: CStone Pharmaceuticals | "In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study....ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

CStone Pharmaceuticals Reports 2023 Interim Results and Updates (PRNewswire-Asia) - "Topline readouts expected: (i) Sugemalimab: topline readout of the pre-specified OS final analysis in the GEMSTONE-303 study of sugemalimab in combination with chemotherapy for the first-line treatment of patients with advanced GC/GEJ in the third quarter of 2023; (ii) Nofazinlimab: topline readout of the global phase III trial of nofazinlimab in combination with LENVIMA® (lenvatinib) for the first-line treatment of patients with advanced HCC in the first quarter of 2024. Early clinical programs: (i) CS5001: update on clinical safety and efficacy by the end of 2023 and conference presentation in the first half of 2024."

P1 data • P3 data: top line • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

A Study of Nofazinlimab (CS1003) in Subjects With Advanced Hepatocellular Carcinoma (clinicaltrials.gov) - P3 | N=534 | Active, not recruiting | Sponsor: CStone Pharmaceuticals | Trial completion date: Jun 2023 ➔ Jun 2025 | Trial primary completion date: Jun 2023 ➔ Jun 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

CStone to Regain Development and Commercialization Rights to Sugemalimab and Nofazinlimab Outside of Greater China (CStone Pharma Press Release) - "CStone Pharmaceuticals...announced that CStone will regain rights for the development and commercialization of sugemalimab (anti-PD-L1 monoclonal antibody) and nofazinlimab (anti-PD-1 monoclonal antibody) outside of Greater China, upon the termination of the License Agreement for sugemalimab and nofazinlimab between CStone and EQRx. Both parties are committed to ensuring a smooth transition. The termination of this License Agreement will not affect the upfront and milestone payments previously received from EQRx....Upon transition completion, CStone will lead the regulatory process for sugemalimab MAA reviews by the EMA and the U.K. MHRA....In the meantime, CStone will actively explore partnership for the development and commercialization of sugemalimab and nofazinlimab outside of Greater China."

Licensing / partnership • Hematological Malignancies • Oncology • Solid Tumor

CStone Pharmaceuticals Reports 2022 Annual Results and Business Updates (PRNewswire-Asia) - "Topline readouts expected: Nofazinlimab: topline readout of the global phase III trial of nofazinlimab in combination with LENVIMA® (lenvatinib) in first-line treatment of patients with advanced HCC in Q4 2023 or Q1 2024."

P3 data: top line • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Updated efficacy and safety results from a phase 1b study of the PD-1 antagonist CS1003 combined with lenvatinib (LEN) as first-line (1L) treatment in Chinese patients (pts) with unresectable hepatocellular carcinoma (uHCC). (ASCO 2022) - P1a/1b, P3 | "The antitumor activity of CS1003 + LEN combination as 1L treatment in Chinese pts with uHCC remains encouraging and durable through a longer follow-up period, and the safety profile is well tolerated and manageable. The PFS is longer and the ORR is higher compared to the data previously reported, which support further development as a combination treatment for improving outcomes in uHCC pts. The ongoing multi-regional, double-blinded, randomized, placebo-controlled, phase 3 trial (CS1003-305, NCT04194775) is currently recruiting and will further evaluate adding CS1003 to LEN as a 1L treatment in uHCC."

Clinical • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGFR1 • FLT1 • PD-1 • PDGFRA

[VIRTUAL] CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance (AACR-II 2020) - P1 | "Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib have been approved by US FDA as single agent or in combination with endocrine therapy to treat patients with HR+/Her2- breast cancer...Furthermore, CS3002 showed excellent in vivo activity as a single agent, and in combinations with either endocrine therapy (fulvestrant) or PD-1 blockade (CS1003) in a set of tumor models, together with desirable ADME/PK and safety profile...Across a panel of 19 AML cell lines, CS3002 demonstrated a similar sensitivity profile to gilteritinib (an approved FLT-3 inhibitor), but overall higher sensitivity compared to palbociclib. Interestingly, when MCF-7 breast cancer cell line was treated continuously with CS3002 in vitro, the emergence of drug-resistance was much delayed compared to treatment with palbociclib or abemaciclib. Given the encouraging preclinical properties as well as the unique potential in allowing indication expansion and delaying drug..."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • CDKN2A • FLT3 • HER-2 • NTRK • NTRK1

Preclinical characterization of CS1003, a novel clinical-stage PD-1 monoclonal antibody (AACR 2019) - P1a/1b; "CS1003 bound PD-1-expressing cell lines and chronically-activated T cells, blocked PD-1 interactions with PD-L1/PD-L2, resulting in inhibition of PD-1 signaling, and enhanced T cell cytokine secretion and proliferation to levels comparable to those observed with nivolumab or pembrolizumab reference molecules. CS1003 is a novel anti-PD-1 mAb with favorable preclinical characteristics and safety profile in cynomolgus monkeys. The unique feature of CS1003 is its cross-reactivity with both human and murine PD-1. This should greatly facilitate further evaluation its potential for combination therapy in various syngeneic mouse tumor models."

Oncology

CS1002-101: A Study of CS1002 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1a/1b | N=91 | Completed | Sponsor: CStone Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Jun 2023 ➔ Jan 2022 | Trial primary completion date: Jun 2023 ➔ Jan 2022

Combination therapy • Metastases • Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A Study of CS1003 in Subjects With Advanced Solid Tumors or Lymphomas (clinicaltrials.gov) - P1a/1b | N=107 | Completed | Sponsor: CStone Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Sep 2022 ➔ Jun 2022

Trial completion • Trial completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Preliminary safety and efficacy results from phase Ib study of the anti-CTLA-4 monoclonal antibody (mAb) CS1002 in combination with anti-PD-1 mAb CS1003 in patients with advanced solid tumors (ESMO-IO 2021) - P1a/1b | "Funding CStone Pharmaceuticals (Su Zhou) Co. Ltd."

Clinical • Combination therapy • P1 data • Oncology • Solid Tumor • CTLA4 • MSI

[VIRTUAL] Preliminary safety and efficacy results from phase Ib study of the anti-CTLA-4 monoclonal antibody (mAb) CS1002 in combination with anti-PD-1 mAb CS1003 in patients with advanced solid tumors (ESMO 2021) - P1a/1b | "The combination of CS1002 and CS1003 demonstrated an acceptable safety profile and showed promising preliminary anti-tumor activity in pts with MSI-H/dMMR tumors and anti-PD-(L)1 refractory melanoma at two dose levels. One dose regimen will be chosen to support further exploration."

Clinical • Combination therapy • P1 data • Melanoma • Oncology • Solid Tumor • CTLA4 • MSI

A Study of CS1003 in Subjects With Advanced Hepatocellular Carcinoma (clinicaltrials.gov) - P3 | N=534 | Active, not recruiting | Sponsor: CStone Pharmaceuticals | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

CS1002-101: A Study of CS1002 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1a/1b | N=91 | Active, not recruiting | Sponsor: CStone Pharmaceuticals | Trial completion date: Jan 2022 ➔ Jun 2023 | Trial primary completion date: Dec 2021 ➔ Jun 2023

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

CStone Pharmaceuticals Reports 2022 Interim Results and Business Updates (PRNewswire-Asia) - "Topline readouts expected: (i) Nofazinlimab: topline readout of the global phase III trial of nofazinlimab in combination with LENVIMA® (lenvatinib) in first-line treatment of patients with advanced HCC in the first half of 2023."

P3 data: top line • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

CStone presents updated results of anti-PD-1 antibody nofazinlimab in combination with lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC) at ASCO 2022 (PRNewswire-Asia) - P1 | N=107 | NCT03809767 | Sponsor: CStone Pharmaceuticals | "CStone Pharmaceuticals...announced that the company has published updated results from the phase 1b study of anti-PD-1 antibody nofazinlimab (CS1003)...at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting....A total of 20 patients with uHCC in Arm 5 of phase Ib study for CS1003-102 received nofazinlimab 200 mg, intravenously once every three weeks in combination with lenvatinib....Nofazinlimab in combination with lenvatinib as first-line treatment for unresectable hepatocellular carcinoma demonstrated an objective response rate of 45.0%. The median duration of response was not yet reached as of the data cutoff date (4.2 to 18.7+ months). The median progression free survival was 10.4 months."

P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

A Study of CS1003 in Subjects With Advanced Solid Tumors or Lymphomas (clinicaltrials.gov) - P1a/1b | N=107 | Active, not recruiting | Sponsor: CStone Pharmaceuticals | Trial completion date: Mar 2022 ➔ Sep 2022

Trial completion date • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor