On June 2, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, cardiovascular and metabolic, autoimmune, ophthalmology and other major diseases, reported two oral presentations of its first-in-class anti-CLDN18.2/CD3 bispecific antibody (R&D code: IBI389) for the treatment of advanced pancreatic cancer (PDAC) and gastric or gastroesophageal tumors (G/GEJC) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from clinical data of a Phase I study (NCT05164458) (Press release, Innovent Biologics, JUN 2, 2024, View Source [SID1234643942]).

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Dr. Hui Zhou, Senior Vice President of Innovent Biologics, stated, "We are excited to share the latest clinical development progress of IBI389 at ASCO (Free ASCO Whitepaper). Different from monoclonal antibodies, IBI389 redirects T cells to tumor cells by binding both CLDN18.2 expressed on tumor cells and CD3 on T cells, inducing T cell-mediated cell killing. Preclinical results showed that IBI389 could bind to tumor cells and exhibit significant anti-tumor effects even in cell lines with low CLDN18.2 expression. In the presented clinical data, IBI389 has shown promising efficacy in advanced G/GEJ tumors and PDAC, including those subjects with low and moderate CLDN18.2 expression. Notably, IBI389 is the world’s first bispecific antibody targeting CLDN18.2/CD3 to show encouraging efficacy signal in PDAC, representing a breakthrough for innovative treatments in difficult-to-treat cancers. We will continue to advance the clinical development of IBI389 for the benefit of more cancer patients."

Safety and Efficacy of IBI389 in Patients with Advanced Pancreatic Ductal Adenocarcinoma: Preliminary Results from the Phase I Study

Abstract#: 4011

As of March 11, 2024, a total of 72 subjects with advanced unresectable or metastatic pancreatic ductal adenocarcinoma have received IBI389 monotherapy. All subjects had received at least one prior systemic treatment, and 55.6% of the subjects had received two or more prior lines of systemic therapy.

The results showed that:

In subjects with CLDN18.2 IHC 2/3+≥10%, signs of efficacy were observed when treated with 100 μg/kg.
The recommended phase 2 dose (RP2D) 600 μg/kg group shows superior efficacy. 27 subjects have performed at least one post-baseline tumor evaluation, the objective response rate (ORR) was 29.6% (95%CI: 13.8-50.2), the confirmed objective response rate (cORR) was 25.9% (95%CI：11.1-46.3), and the disease control rate (DCR) was 70.4% (95%CI：49.8-86.2). Among the 18 subjects with CLDN18.2 IHC 2/3+≥40%, the cORR was 38.9% (95%CI：17.3-64.3).
As of May 1, 2024, the median progression-free survival (PFS) follow-up time was 4 months, and the median PFS was not yet mature, with a 3-month PFS rate of 57.1%.
Safety was similar to that of the overall population, and no new safety signals were observed.
Professor Jihui Hao, Tianjin Medical University Cancer Institute & Hospital, said, "Pancreatic cancer is one of the most aggressive malignancies with poor prognosis, and the incidence continues to increase. Currently, the standard treatment for most patients with metastatic pancreatic cancer is systemic chemotherapy. In the second-line treatment, the clinical options are very limited and primarily involving a different chemotherapy from the first-line regimen. The response rate to second-line chemotherapy is only 6%~16%, and the median survival time is only about 3~6 months [1,2]. Therefore, there is a great unmet clinical need for patients who have failed standard treatment. Studies have shown that the expression of CLDN18.2 in pancreatic cancer patients is up to 50%~70% [3], making it a potential novel target for therapy. IBI389 is the first bispecific antibody targeting CLDN18.2/CD3 that reported clinical data, and showed positive efficacy signals in patients with advanced pancreatic cancer. I hope the clinical exploration of this innovative drug could drive the progress in pancreatic cancer treatment."

Safety and Preliminary Efficacy Outcomes of IBI389 in Patients with Advanced Solid Tumors and Gastric or Gastroesophageal Tumors: A Phase I Dose Escalation and Expansion Study

Abstract#: 2519

This Phase I study is designed to evaluate the safety, tolerability, and preliminary efficacy of IBI389 in subjects with advanced solid tumors and G/GEJ tumors.

The results showed that:

As of May 1, 2024, 26 G/GEJC subjects with CLDN18.2 IHC 2/3+≥10% received ≥ 10 μg /kg IBI389 monotherapy and performed at least one post-baseline tumor evaluation, of which 8 subjects achieved partial response (PR); the objective response rate (ORR) and disease control rate (DCR) were 30.8% and 73.1%, respectively.
In terms of safety, as of March 11, 2024, a total of 120 subjects with advanced solid tumor malignancies who had previously failed or were intolerant to standard therapy were enrolled. IBI389 was generally well tolerated, and no dose-limiting toxicity (DLT) events were observed in each dose group. Cytokine release syndrome (CRS) occurred in 60% of subjects, and only one case developed grade 3. No grade 4 or 5 CRS happened. 58.3% subjects occurred ≥ grade 3 treatment-related adverse events (TRAEs). The most common ≥ grade 3 TRAEs were increased gamma-glutamyl transferase (21.7%), decreased lymphocyte count (13.3%) and decreased appetite (5. 0%）.
Professor Feng Bi, West China Hospital of Sichuan University, said, "Gastric cancer is one of the most common malignant tumors in the world, ranking the 5th most common malignant tumors, and the 4th leading cause of cancer death worldwide [4]. Single-agent chemotherapy is the main second-line treatment for advanced gastric cancer. Multiple studies have shown that the PFS of second-line single-agent chemotherapy is 2.0~4.1 months, and the OS was only 5.3~9.5 months, with limited clinical benefit [5]. In recent years, CLDN18.2 has gained the most attention as a therapeutic target in the field of gastrointestinal tumors, and studies have shown that the expression rate of CLDN18.2 in gastric cancer patients is 40%-87% [6]. Preliminary efficacy results from several studies show that this target has high druggability potential. In this study, IBI389 has demonstrated encouraging preliminary efficacy and tolerable safety in patients with advanced gastric tumors, suggesting the possibility of further exploration in this indication."

About IBI389 (anti-CLDN18.2/CD3 bispecific antibody)

IBI389 is an anti-CLDN18.2 T cell-engaging bispecific antibodies developed by Innovent Biologics. It induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the surfaces of tumor cells. Therefore, IBI389 stimulates T-cell activation, resulting in cytolytic protein production, inflammatory cytokine release and further T-cell proliferation, which eventually leads to durable anti-tumor effects. Based on urgent clinical needs, Innovent has conducted clinical studies to explore the efficacy and safety of IBI389 as a monotherapy or in combination with various advanced malignancies.

On June 2, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, metabolic, autoimmune, ophthalmology and other major diseases, reported that the clinical data of a randomized controlled Phase 1b study evaluating IBI310 (anti-CTLA-4 monoclonal antibody) in combination with sintilimab as neoadjuvant treatment of colon cancer was orally presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ClinicalTrials.gov, NCT05890742) (Press release, Innovent Biologics, JUN 2, 2024, View Source [SID1234643941]). The abstract was selected for ASCO (Free ASCO Whitepaper) Daily News coverage.

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Based on the promising Phase 1b results, Innovent has opened the Phase 3 trial (Neoshot) evaluating IBI310 in combination with sintilimab as neoadjuvant treatment of colon cancer. The Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has also granted Breakthrough Therapy Designation (BTD) for IBI310.

Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: results from a randomized, open-labeled, Phase 1b study

Abstract #: 3505

In this Phase 1b study, the efficacy and safety of IBI310 in combination with sintilimab versus sintilimab as neoadjuvant therapy for resectable stage IIB-III MSI-H/dMMR colon cancer was evaluated.

As of February 4, 2024, 101 pts were enrolled and randomized to receive IBI310 plus sintilimab (n=52) or sintilimab alone (n=49). For per-protocol set, the pathologic complete response (pCR) rates in IBI310 plus sintilimab arm were significantly improved than sintilimab alone arm（80.0% vs 47.7%, p=0.0007）.
Treatment related adverse events (TRAEs) leading to surgery delay occurred in 2 pts (3.8%) in IBI310 plus sintilimab arm and 0 pt in sintilimab alone arm. Grade ≥3 immune-related adverse events (irAEs) occurred in 3 pts (5.8%) and in 4 pts (8.2%), respectively. IBI310 plus sintilimab did not increase safety risk compared to sintilimab alone, and did not affect the subsequent surgery.
The Principal Investigator of the study, Prof. Ruihua Xu from Sun Yat-sen University Cancer Center, stated, "At present, complete (R0) resection for some stage IIB-III colon cancer patients remain a significant challenge, along with risks of extensive trauma and poor prognosis. In particular, neoadjuvant chemotherapy is not effective in MSI-H/dMMR colon cancer, and the pCR rate is only about 5%[1]. This Phase 1b study was the first randomized study to demonstrate the significant higher pCR rate of the dual immunotherapy in MSI-H/dMMR colon cancer. Neoadjuvant treatment of IBI310 in combination with sintilimab is potentially practice-changing that could reduce the preoperative staging, narrow the scope of radical resection, increase the complete resection rate, reduce the requirement of adjuvant chemotherapy and decrease the incidence of relapse, so as to improve the long-term prognosis and potentially cure the patients. The Phase 3 clinical study (Neoshot) is ongoing in China, and we look forward to positive results from this study to provide a more effective treatment option for patients with MSI-H/dMMR colon cancer."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "There is a huge unmet clinical need for neoadjuvant therapy of resectable MSI-H/dMMR colon cancer in China. In this randomized, controlled Phase 1b study, IBI310 in combination with sintilimab significantly improved pCR rate than sintilimab alone in MSI-H/dMMR CRC with manageable safety profile. Based on the strong results of this study, we moved IBI310 in combination with sintilimab into Phase 3 trial (Neoshot) earlier this year, and we are looking forward to the positive results."

About IBI310
IBI310 is a fully human monoclonal antibody injection independently developed by Innovent. IBI310 can specifically bind cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), thereby blocking CTLA-4 mediated T cell inhibition, promoting T cell activation and proliferation, improving tumor immune response, and achieving anti-tumor effects.

About Sintilimab
Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody co-developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells[2].

In China, sintilimab has been approved and included in the National Reimbursement Drug List (NRDL) for seven indications. The updated NRDL reimbursement scope for TYVYT (sintilimab injection) includes:

For the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy;
For the first-line treatment of unresectable locally advanced or metastatic non-squamous non-small cell lung cancer lacking EGFR or ALK driver gene mutations;
For the treatment of patients with EGFR-mutated locally advanced or metastatic non-squamous non-small cell lung cancer who progressed after EGFR-TKI therapy;
For the first-line treatment of unresectable locally advanced or metastatic squamous non-small cell lung cancer;
For the first-line treatment of unresectable or metastatic hepatocellular carcinoma with no prior systematic treatment;
For the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma;
For the first-line treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma.
Besides, the New Drug Application ("NDA") for the combination of sintilimab and fruquintinib for the treatment of patients with advanced endometrial cancer with pMMR or non-MSI-H tumors that have failed prior systemic therapy but are not candidates for curative surgery or radiation has been accepted and granted priority review by the NMPA.

In addition, two clinical studies of sintilimab have met their primary endpoints:

Phase 2 study of sintilimab monotherapy as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study of sintilimab monotherapy as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.
Statement: Innovent does not recommend the use of any unapproved drug (s)/indication (s).

On June 2, 2024 Nanjing leads Biolab reported that after rigorous evaluation by Scientific Program Committee and ASCO (Free ASCO Whitepaper) Leadership, LBL-024, a bispecific antibody independently developed by Leads Biolabs with global intellectual property rights, was selected for an oral presentation (Press release, Nanjing Leads Biolabs, JUN 2, 2024, View Source [SID1234643940]). Today, Dr. Panpan Zhang, the investigator of LBL-024, presented the outstanding clinical data during the Clinical Science Symposium-Building Novel Antibody-Based Approaches in Gastrointestinal Cancers.

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This is a phase I/II first in human, open-label, multicenter, dose escalation/expansion study that evaluates the safety and efficacy of LBL-024 monotherapy in patients with advanced malignant tumors and neuroendocrine carcinoma. The study results demonstrated good safety profile and very promising antitumor effects as a monotherapy in patients with advanced malignant tumors, particularly extrapulmonary neuroendocrine carcinomas (EP-NEC) patients who failed at least one line of chemotherapy.

EP-NEC is a rare disease that typically occurs in the stomach, intestines, and pancreas. Most patients are diagnosed at a later stage when the cancer has already metastasized to other areas in the body. By then, the disease has progressed rapidly and the prognosis is extremely poor. No drug has been approved by the Regulatory Agencies for this lethal malignancy so far and the recommended treatment options for the advanced EP-NEC are very limited, especially for those who progress beyond first-line platinum-based chemotherapy. These underscore the urgency to develop novel therapeutic approaches.

According to results in the oral presentation, LBL-024 monotherapy showed good safety profile, especially mild liver toxicity in advanced solid tumors. The severity of AEs was mostly grade 1-2, no unexpected AEs were observed. At the dose of 15 mg/kg, ORR was 37.5% and DCR was 50.0% in 2nd line EP-NEC, and robust anti-tumor activities were observed in wide therapeutic dose range (0.8-15mg/kg) in EP-NEC. Median follow-up was 8.5 months, Median DoR was 5.3 months, mOS was not reached, 6-months OS rate of the overall, 2nd line, and ≥3rd line were 61.7%, 72.7% and 52.0%，respectively. 54.5% ORR in 22 patients with PD-L1 negative expression (CPS<1) were observed, which indicate patients can benefit from treatment with LBL-024 regardless of PD-L1 expression in tumor tissue.

The promising efficacy data of the LBL-024 monotherapy support continued development of LBL-024 in patients with EP-NEC. A single-arm pivotal study of LBL-024 monotherapy in EP-NEC was approved on April 30, 2024, which will help accelerate the listing process of LBL-024 (Click to view details). Currently, there are no 4-1BB-targeting drugs available both domestically and internationally. LBL-024 has First-in-Class potential and is expected to become the first approved standard treatment for EP-NEC after progression on second-line therapy, offering a more effective treatment option and providing hope for survival to patients with advanced EP-NEC.

Dr. Charles Cai, Chief Medical Officer of Leads Biolabs, said "ASCO has very strict selection criteria, and abstracts selected for oral presentation must be among the most representative studies in the field of cancer that are significant for patient treatment. Leads Biolabs adopted a differentiated, innovative, and efficient development strategy in the clinical development of LBL-024. In patients with advanced malignant tumors, particularly EP-NEC patients who failed at least one line of chemotherapy, LBL-024 has demonstrated good safety and strong efficacy signals and was recently approved to conduct an accelerated development of single-arm pivotal clinical study by China Regulatory Authority, CDE."

Dr. Xiaoqiang Kang, founder, chairman and CEO of Leads Biolabs, said" Leads Biolabs has always been committed to differentiated innovation, encompassing the development of new targets, the design of drug molecules, and clinical development strategies. From the very beginning of the project, we evaluate whether our technology and products are scientifically sound, whether they can overcome obstacles and challenges of current products, and whether they can bring better therapeutic benefits. It is this persistence that ensures our products have potential advantages, enabling them to stand out from numerous competitors. These innovative achievements, in turn, have verified the feasibility of our R&D strategy. In the future, Leads Biolabs will continue to focus on unmet medical need, persist in innovation, and look forward to innovative drugs with clinical value bringing benefits to patients as soon as possible."

About LBL-024

LBL-024 is a uniquely designed bispecific antibody composed of an anti-Programmed Cell Death Ligand-1 (PD-L1) and an anti-4-1BB (CD137) antibody. It binds to PD-L1 with high affinity, blocks the immunosuppressive pathway of tumor cells by targeting PD-L1 and effectively localizes 4-1BB co-stimulation to the tumor microenvironment. This activation of T cells exerts a powerful immune response, resulting in a potentially stronger antitumor effect than anti-PD-1/PD-L1 monoclonal antibodies alone.

On June 2, 2024 Gilead Sciences, Inc. (Nasdaq: GILD) and Arcus Biosciences, Inc. (NYSE: RCUS) reported longer-term efficacy and safety results from Arm A1 of the Phase 2 EDGE-Gastric study. These updated data show consistent objective response rate (ORR) and provide mature progression-free survival (PFS) in patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma (upper GI cancers) (Press release, Gilead Sciences, JUN 2, 2024, View Source [SID1234643936]). The ongoing, multi-arm, global Phase 2 EDGE-Gastric study is evaluating the safety and efficacy of various combinations of the Fc-silent anti-TIGIT antibody domvanalimab plus the anti-PD-1 monoclonal antibody zimberelimab and chemotherapy in this patient population. These results will be presented today during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series: Rapid Abstract Updates session by Yelena Y. Janjigian, M.D., Chief, Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, and a principal investigator for the EDGE-Gastric study (Abstract 433248).

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"I am encouraged to see that patients treated with domvanalimab plus zimberelimab and chemotherapy had a median progression-free survival beyond one year, which exceeds the historical benchmarks for anti-PD-1 plus chemotherapy alone," said Dr. Janjigian. "Notably, nearly 60% of patients in the EDGE-Gastric study achieved progression-free survival at 12 months. These promising results reinforce our confidence in the ongoing Phase 3 STAR-221 study, which evaluates the same regimen in the same patient population and has the potential to address a high unmet need for people with these cancers."

At data cutoff (DCO, March 12, 2024), safety and efficacy were evaluated in all patients enrolled and treated (n=41). With a median time on treatment of 49.4 weeks (range: 0.4 – 79.4 weeks), the domvanalimab plus zimberelimab and chemotherapy regimen demonstrated sustained improvement across efficacy measures, including in those patients who have low PD-L1 expression.

Summary of efficacy results:

Endpoint

Overall*

PD-L1-high

PD-L1-low

n=41

(TAP ≥5%)

(TAP <5%)

n=16

n=24

Progression-Free Survival (PFS)

Median in Months (95% CI)

12.9 mos (9.8, 13.8)

13.8 mos (11.3, NE)

11.3 mos (5.5, 13.8)

12-month PFS Rate (95% CI)

57.6% (41.7,73.5)

68.8% (46.0, 91.5)

46.8% (24.7, 68.9)

Objective Response Rate (ORR)

per RECIST v1.1

Confirmed ORR (95% CI)

58.5% (42.1, 73.7)

68.8% (41.3, 89.0)

50.0% (29.1, 70.9)

Complete Response

3 (7.3%)

1 (6.3%)

1 (4.2%)

Partial Response

21 (51.2%)

10 (62.5%)

11 (45.8%)

Stable Disease

14 (34.1%)

5 (31.3%)

9 (37.5%)

Progressive Disease Confirmed

2 (4.9%)

0

2 (8.3%)

Not Evaluable**

1 (2.4%)

0

1 (4.2%)

Median Duration of Response (DOR) in Months

12.4 mos (9.9, NE)

NE (11.5, NE)

10.2 mos (4.0, 12.4)

*One subject with no tissue available for central PD-L1 testing. From local lab results, the subject is PD-L1 low via 22-C3 assay. This subject achieved confirmed complete response.

** One subject has no post baseline scans.

CI: confidence interval

NE: not evaluable

TAP: tumor area positivity

No unexpected safety signals were observed at the time of DCO. The domvanalimab plus zimberelimab and chemotherapy regimen was generally well tolerated and showed an overall safety profile consistent with the known safety profiles of each individual molecule to date. Infusion-related reactions were observed in 19.5% of the total subjects, and the majority were related to chemotherapy.

The updated data from Arm A1 of the Phase 2 EDGE-Gastric study support the ongoing Phase 3 STAR-221 study, in unresectable or metastatic upper GI cancers, which is expected to complete enrollment mid-year 2024.

Domvanalimab and zimberelimab are investigational molecules. Neither Gilead nor Arcus has received approval from any regulatory authority for any use of these molecules, and their safety and efficacy for the treatment of gastrointestinal cancers have not been established.

About the EDGE-Gastric Study

The ongoing, multi-arm, multi-cohort global Phase 2 EDGE-Gastric trial (NCT05329766) is evaluating the safety and efficacy of various combinations of the Fc-silent anti-TIGIT antibody domvanalimab and the anti-PD-1 monoclonal antibody zimberelimab in patients with locally advanced unresectable or metastatic gastric (G), gastroesophageal junction (GEJ) or esophageal (E) adenocarcinoma. Patients in Arm A1, with previously untreated G/GEJ/E adenocarcinoma, received 1600 mg of domvanalimab intravenously (IV) every four weeks (Q4W) plus 480 mg of zimberelimab IV Q4W + FOLFOX (oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, fluorouracil 400 mg/m2 IV bolus + 2400 mg/m2 continuous 46-48-hour IV infusion) every two weeks.

About Domvanalimab

Domvanalimab is the first and most clinically advanced Fc-silent investigational monoclonal antibody that is specifically designed with Fc-silent properties to block and bind to the T-cell immunoreceptor with Ig and ITIM domains (TIGIT), a checkpoint receptor on immune cells that acts as a brake on the anticancer immune response. By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting the peripheral regulatory T cells important in avoiding immune-related toxicity.

Combined inhibition of both TIGIT and programmed cell death protein-1 (PD-1) is believed to significantly enhance immune cell activation, as these checkpoint receptors play distinct, complementary roles in anti-tumor activity. Domvanalimab is being evaluated in combination with anti-PD-1 monoclonal antibodies, including zimberelimab, as well as other investigational cancer immunotherapies and A2a/A2b adenosine receptor antagonist etrumadenant, in multiple ongoing and planned early and late-stage clinical studies in various tumor types.

About Zimberelimab

Zimberelimab is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody that binds PD-1, with the goal of restoring the antitumor activity of T cells. Zimberelimab has demonstrated high affinity, selectivity and potency in various tumor types.

Zimberelimab is being evaluated in the U.S. and globally as a foundational anti-PD-1 treatment option in multiple ongoing and planned early and late-stage clinical studies in combination with other immunotherapies, including investigational Fc-silent anti-TIGIT monoclonal antibody domvanalimab and A2a/A2b adenosine receptor antagonist etrumadenant.

Guangzhou Gloria Biosciences Co. Ltd., which holds commercialization rights for zimberelimab in greater China, has obtained approval for zimberelimab for the treatment of recurrent or metastatic cervical cancer and for relapsed or refractory classical Hodgkin’s lymphoma. Zimberelimab is not approved for any use in the U.S. or other regions outside of China. Gloria conducts its development and commercialization activities independent of Arcus and Gilead.

On June 2, 2024 Gilead Sciences, Inc. (Nasdaq: GILD) and Arcus Biosciences, Inc. (NYSE: RCUS) reported new data from Cohort B of ARC-9, a Phase 1b/2 study evaluating the safety and efficacy of etrumadenant, a dual A2a/b adenosine receptor antagonist, plus anti-PD-1 monoclonal antibody zimberelimab, FOLFOX chemotherapy and bevacizumab (EZFB) in third-line metastatic colorectal cancer (mCRC) (Press release, Gilead Sciences, JUN 2, 2024, View Source [SID1234643935]). These results will be presented today during an oral session at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting by Zev A. Wainberg, M.D., MSc, Co-Director of the GI Oncology Program at University of California Los Angeles and a principal investigator of the ARC-9 trial (Abstract 3508).

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"ARC-9 is the first randomized Phase 2 study to show that combining an adenosine receptor blocker with anti-PD-1, anti-VEGF and chemotherapy can meaningfully improve clinical outcomes for people with metastatic colorectal cancer who have progressed on at least two prior therapies," said Dr. Wainberg. "19.7 months is the longest median overall survival reported in third-line mCRC and warrants further investigation of an etrumadenant-based regimen as a potential treatment option in CRC1."

Cohort B of ARC-9 randomized 112 patients with comparable baseline characteristics between two arms: EZFB or regorafenib. At the time of data cut-off (November 13, 2023) median follow-up was 20.4 months. Patient baseline characteristics were similar to those of third-line patients who have progressed on oxaliplatin- and irinotecan-based regimens in mCRC1. OS and PFS were consistently longer in the EZFB arm versus regorafenib, in all sub-groups analyzed, including in patients with liver metastases.

Summary of efficacy results:

EZFB*

n=75

regorafenib

n=37

Median OS, months

19.7

9.5

Hazard Ratio (95% CI), P-value

HR 0.37

95% CI 0.22-0.63

p=0.0003

Median PFS, months

6.2

2.1

Hazard Ratio (95% CI), P-value

HR 0.27

95% CI 0.17-0.43

p<0.0001

Confirmed ORR

13 (17.3%)

1 (2.7%)

Median DOR, months

11.5

NE

CI: confidence interval

OS: overall survival

PFS: progression-free survival

ORR: objective response rate

DOR: duration of response

NE: not evaluable; only one patient with response

*bevacizumab was included for all patients in whom it is not contraindicated

The EZFB regimen had a safety profile consistent with the known safety profiles of each individual molecule to date, without unexpected toxicities. A higher percentage of patients treated with regorafenib (17%) had a treatment emergent adverse event (TEAE) leading to discontinuation of all study drugs than those treated with EZFB (5%). A lower percentage of patients experienced Grade ≥3 TEAEs attributed to etrumadenant or zimberelimab versus regorafenib (23.0% vs 25.7%).

Etrumadenant and zimberelimab are investigational molecules. Neither Gilead nor Arcus has received approval from any regulatory authority for any use of these molecules, and their safety and efficacy for the treatment of colorectal cancer have not been established.

About the ARC-9 Study

ARC-9 (NCT04660812) is a Phase 1b/2 trial evaluating the safety and efficacy of etrumadenant (E), a dual A2a/A2b adenosine receptor antagonist, plus anti-PD-1 antibody zimberelimab (Z), FOLFOX and bevacizumab (if not contraindicated) in three cohorts of patients with mCRC. The primary endpoint is PFS per RECIST 1.1, and OS is a key secondary endpoint. Cohort B enrolled patients who previously progressed on both oxaliplatin- and irinotecan-containing chemotherapy in combination with anti-VEGF (R) therapy or anti-EGFR. Patients were randomized 2:1 to the etrumadenant plus zimberelimab regimen: E (150 mg orally [PO] once daily [QD]) + Z (240 mg intravenous [IV] once every 2 weeks [Q2W]) + mFOLFOX-6 + bevacizumab (5 mg/kg IV Q2W), or regorafenib (administered at a starting dose of 80 mg/day for the first week, followed by a dose escalation of 40 mg every week to 120 mg/day for the second week and 160 mg/day for the third week during Cycle 1 followed by 160 mg/day on Days 1-21 of each subsequent 28-day cycle). Patients who progressed on regorafenib were allowed to crossover to the etrumadenant plus zimberelimab regimen.

ARC-9 is a multi-cohort study in mCRC including Cohort A, which enrolled patients who previously progressed on FOLFOX/FOLFIRI in combination with anti-VEGF(R) or anti-EGFR. Patients were randomized 2:1 to the etrumadenant plus zimberelimab regimen, or FOLFOX-6 + bevacizumab. Data from Cohort A will be presented when they are mature.

About Etrumadenant

Etrumadenant is an investigational small molecule, selective dual antagonist of the A2a and A2b receptors designed to prevent adenosine-mediated immunosuppression. Adenosine elicits its immunosuppressive effects within the tumor microenvironment by binding and activating adenosine-specific receptors expressed on the surface of tumor-infiltrating immune cells, which can help cancer cells evade host antitumor immunity. Once etrumadenant binds to the A2a and A2b receptors and blocks the immunosuppressive effects of adenosine, activation of antitumor immune cells may be restored, which could result in tumor cell death.

Etrumadenant is being evaluated in combination with other cancer immunotherapies, including the investigational Fc-silent anti-TIGIT monoclonal antibody domvanalimab and anti-PD-1 monoclonal antibody zimberelimab, in certain types of non-small cell lung and colorectal cancers.

About Zimberelimab

Zimberelimab is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody that binds PD-1, with the goal of restoring the antitumor activity of T cells. Zimberelimab has demonstrated high affinity, selectivity and potency in various tumor types.

Zimberelimab is being evaluated in the U.S. and globally as a foundational anti-PD-1 treatment option in multiple ongoing and planned early and late-stage clinical studies in combination with other immunotherapies, including investigational Fc-silent anti-TIGIT monoclonal antibody domvanalimab and A2a/A2b adenosine receptor antagonist etrumadenant.

Guangzhou Gloria Biosciences Co. Ltd., which holds commercialization rights for zimberelimab in greater China, has obtained approval for zimberelimab for the treatment of recurrent or metastatic cervical cancer and for relapsed or refractory classical Hodgkin’s lymphoma. Zimberelimab is not approved for any use in the U.S. or other regions outside of China. Gloria conducts its development and commercialization activities independent of Arcus and Gilead.