On December 6, 2023 Qilu Pharmaceutical reported the latest results of the single-arm, phase II pivotal clinical study for iparomlimab (QL1604), an innovative Class 1 antibody monotherapy used to treat unresectable or metastatic dMMR/MSI-H solid tumors through a poster presentation at the European Society for Medical Oncology Asia Congress 2023 (ESMO Asia) taken place from December 1-3 (Press release, Qilu Pharmaceutical, DEC 6, 2023, View Source [SID1234638201]). Professor Weijian Guo from the Fudan University Shanghai Cancer Center and Professor Feng Bi from the West China Hospital, Sichuan University led the study.

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QL1604 is a highly selective humanized monoclonal antibody that targets PD-1. The study demonstrated that iparomlimab was effective in treating unresectable or metastatic dMMR/MSI-H solid tumors, with an objective response rate (ORR) of 45.8% (95% CI, 36.7-55.2) in total population as assessed by the Independent Imaging Review Committee (IRRC), exceeding the prespecified primary study endpoint.

I. Background

The presence of defective DNA mismatch repair (dMMR) or high microsatellite instability (MSI-H) signifies a unique phenotype in solid tumors [1]. Microsatellite sequences are most susceptible to mismatches during DNA replication and require mismatch repair, and dMMR can lead to code-shifting mutations causing microsatellite instability (MSI). Immune checkpoint inhibitors have proven to be effective in treating dMMR/MSI-H solid tumors. Treatment of dMMR/MSI-H solid tumors with programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibitors results in a high objective response rate (ORR) and a long duration of response [2-3].

Phase I study showed that iparomlimab has demonstrated good safety and anti-tumor activity when treating advanced solid tumors, with an ORR of 20% in all patients who received iparomlimab (0.3-3 mg/kg Q3W) [4]. The objectives of this pivotal study were to evaluate the efficacy and safety of iparomlimab in the treatment of unresectable or metastatic dMMR/MSI-H solid tumors.

II.Study Design and Methods

This single-arm, phase II pivotal clinical study enrolled patients with unresectable or metastatic histopathologically or cytologically confirmed dMMR/MSI-H solid tumors. Iparomlimab was administered intravenously at a fixed dose of 200mg (or 3mg/kg for patients under 40kg) every three weeks. Treatment continued until disease progression, intolerable toxicities, initiation of new anti-tumor treatment, death, withdrawal of informed consent, or other reasons, with a maximum treatment duration of 2 years. At the end of treatment, patients were followed up for survival. The primary endpoint of the study was ORR as assessed by IRRC according to the Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1).

III. Results

From June 2020 to January 2023, 120 patients with dMMR/MSI-H solid tumors were enrolled, including 80 (66.7%) with colorectal cancer, 18 (15.0%) with gastric cancer, and 22 (18.3%) with other solid tumors. The majority (97.5%) were stage IV at enrollment. The median number of treatment lines was 2.0 (range 0-6).

As of 20 July 2023, after a median follow-up of 13.6 months, 11 patients achieved complete response (CR) and 44 patients achieved partial response (PR), resulting in an ORR of 45.8% (95% CI: 36.7%-55.2%) and a disease control rate (DCR) of 77.5% (95% CI. 69.0%-84.6%). In patients with colorectal cancer, the ORR and DCR were 42.5% (95% CI: 31.5%-54.1%) and 77.5% (95% CI: 31.5%-54.1%), respectively. Median duration of response (DoR) was not yet reached, with 6- and 12-month DoR rates of 100% and 97.4%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were yet to be reached.

IV. Summary

Iparomlimab monotherapy showed good efficacy and safety in treating unresectable or metastatic dMMR/MSI-H solid tumors. The new drug application of iparomlimab was accepted by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) in September 2023.

On December 6, 2023 Antengene Corporation Limited ("Antengene" SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class therapeutics in hematology and oncology, reported that the Pharmaceutical Administration Bureau of Macau has approved a New Drug Application (NDA) for XPOVIO (selinexor), applicable in combination with dexamethasone (Xd), for the treatment of adult patients with relapsed and/or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (PIs), two immunomodulatory agents (IMiDs), an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy (Press release, Antengene, DEC 6, 2023, View Source [SID1234638200]).

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XPOVIO is the world’s first oral selective inhibitor of the nuclear export protein XPO1, with regulatory approvals in 42 countries and regions including Mainland of China, Taiwan China, Hong Kong China, Macau China, South Korea, Singapore and Australia. The approved indications for each market can be reviewed below. In addition, multiple XPOVIO regimens have been added to the clinical practice guidelines of major cancer societies in the U.S., the EU, and APAC, including the National Cancer Care Network (NCCN) Guidelines, the Chinese Society of Clinical Oncology (CSCO) Guidelines, the Guidelines for the Diagnosis and Management of Multiple Myeloma in China, the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Guidelines, and the International Myeloma Working Group (IMWG) Guidelines.

"Antengene is excited to receive approval of XPOVIO in Macau, first in the next wave of expected approvals in the APAC." said Dr. Jay Mei, Antengene’s Founder, Chairman and CEO. "In recent years, the APAC region has witnessed a rapid growth in the population of patients with R/R MM, adding to the huge unmet clinical need of this patient population. I am glad that XPOVIO has become the first and only XPO1 inhibitor approved for the treatment of patients with R/R MM in Macau China. To date, XPOVIO has been approved in seven markets across APAC. While expanding the geographical presence of XPOVIO, we are also striving to expand the indications of the drug in the region in order to bring renewed hope to more patients and families."

About Multiple Myeloma
Multiple myeloma (MM) is caused by the dysregulated proliferation of plasma cells. It is the second most common hematologic malignancy in many countries. Despite availability of a number of treatments for relapsed patients, MM is prone to relapse and most patients still succumb to their disease. MM is the second most common hematologic malignancy in China, with an estimated 15,000 to 20,000 new MM patients and 10,300 deaths per year.1

About XPOVIO (selinexor)
XPOVIO is the world’s first approved orally-available, selective inhibitor of the nuclear export protein XPO1. It offers a novel mechanism of action, synergistic effects in combination regimens, fast onset of action, and durable responses.

By blocking the nuclear export protein XPO1, XPOVIO can promote the intranuclear accumulation and activation of tumor suppressor proteins and growth regulating proteins, and down-regulate the levels of multiple oncogenic proteins. XPOVIO delivers its antitumor effects through three mechanistic pathways: 1) exerting antitumor effects by inducing the intranuclear accumulation of tumor suppressor proteins; 2) reducing the level of oncogenic proteins in the cytoplasm by inducing the intranuclear accumulation of oncogenic mRNAs; 3) restoring hormone sensitivity by activating the glucocorticoid receptors (GR) pathway. To utilize its unique mechanism of actions, XPOVIO is being evaluated for use in multiple combination regimens in a range of indications. At present, Antengene is conducting 8 clinical studies of XPOVIO in mainland of China for the treatment of relapsed/refractory hematologic malignancies and solid tumors (3 of these studies are being jointly conducted by Antengene and Karyopharm Therapeutics Inc. [Nasdaq:KPTI]).

XPOVIO is approved in South Korea for the following two indications:

In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
As a monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.
XPOVIO is approved in mainland of China for the following indication:

In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory agent, and an anti-CD38 monoclonal antibody.
XPOVIO is approved in Taiwan China for the following three indications:

In combination with dexamethasone (Xd) for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (PIs), at least two immunomodulatory agents (IMiDs), and an anti-CD38 monoclonal antibody.
In combination with bortezomib and dexamethasone (XVd) for the treatment of adult patients with MM who have received at least one prior therapy.
As a monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) , not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.
XPOVIO is approved in Hong Kong China, for the following indication:

In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (PIs), two immunomodulatory agents (IMiDs), an anti-CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy.
XPOVIO is approved in Macau China, for the following indication:

In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (PIs), two immunomodulatory agents (IMiDs), an anti-CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy.
XPOVIO is approved in Australia for the following two indications:

In combination with bortezomib and dexamethasone (XVd) for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.
In combination with dexamethasone (Xd) for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor (PI), at least one immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody (mAb).
XPOVIO is approved in Singapore for the following three indications:

In combination with bortezomib and dexamethasone for treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
As a monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy who are not eligible for haematopoietic cell transplant.

On December 6, 2023 Imugene Limited (ASX:IMU), a clinical stage immuno-oncology company, reported that it has signed a letter of intent with the University of Southampton in collaboration with Cancer Research UK Southampton Clinical Trials Unit at the Royal Surrey Hospital NHS Foundation Trust and The Australasian Gastro-Intestinal Trials Group (AGITG) to open a Phase 2 clinical trial, "Neo-POLEM", in which PD1-Vaxx vaccine will be evaluated for patients diagnosed with operable CRC cancer (Press release, Imugene, DEC 6, 2023, https://mcusercontent.com/e38c43331936a9627acb6427c/files/c775a9b4-092f-5f07-cd7b-52899fee7961/New_PD1_Vaxx_Phase_2_CRC_Cancer_Trial_to_Open_in_UK_and_AUS.pdf [SID1234638199]).

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The Chief Investigator is Dr Tony Dhillon based at the Royal Surrey Hospital NHS Foundation Trust in Surrey in collaboration with the University of Southampton, UK and Co-Chief Investigator Prof Timothy Price from the Queen Elizabeth Hospital in Adelaide, SA.

Dr Tony Dhillon said, "We are very excited to open this potentially groundbreaking trial using a vaccine to PD-1 in MSI High early colorectal cancer. Prof Tim Price, Imugene and I have been working on the trial design and are thrilled to finally see sites set up in the UK and Australia. We are grateful to the University of Southampton Clinical trials Unit (CTU) who are running the trial and the Australasian Gastro-Intestinal Trials Group (AGTIG) who have been involved from the beginning".

The title of the study is "A phase 2 trial of neoadjuvant PD-1 vaccine IMU-201 (PD1-Vaxx) in operable dMMR/MSI-H Colorectal Cancer" (see below for further explanation and definition). The primary objective of the study is to determine the pathological response rates and the secondary objectives are to assess the safety of PD1-Vaxx, evaluate biomarkers, and evaluate the objective response rates and overall survival.

Imugene MD & CEO, Ms Leslie Chong said, "We are excited to commence this important Phase 2 trial with PD1-Vaxx after being approached by the leading colorectal cancer oncologists from both Australia and the UK. The study costs are partially funded being Investigator Sponsored studies, and fall within current cash flow forecasts, she added."

Colorectal cancer (CRC), also known as bowel cancer, is the third most common cancer, with a worldwide annual incidence of over 1.2 million cases and a mortality rate of approximately 50%. About 80% of patients with colon cancer have localised and resectable disease at diagnosis. In 2018, there were 15,610 new cases of bowel cancer diagnosed in Australia (8,490 males and 7,120 females). In 2022, an estimated 15,713 new cases of bowel cancer were diagnosed in Australia (8,300 males and 7,413 females). It is estimated that a person has a 1 in 19 (or 5.2%) risk of being diagnosed with bowel cancer by the age of 85 (1 in 18 or 5.6% for males and 1 in 21 or 4.8% for females)1.

Neoadjuvant (before surgery) chemotherapy and surgical resection of the colon or rectum is the standard of care treatment for locally advanced colorectal cancer. A subset of colorectal cancer is caused by a deficiency in "mismatch repair" (dMMR), a phenomenon known as microsatellite instability (MSI), which results in a higher mutation of the cancer cells and more rapid tumour growth. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it is hypothesized that checkpoint blockade with PD1-Vaxx could be effective in patients with mismatch repair–deficient, locally advanced colorectal cancer.

On December 6, 2023 Ten63 Therapeutics, a biotechnology company unlocking previously undruggable targets by leveraging proprietary algorithms combining interpretable generative AI and physics-based models, reported a multi-target drug discovery collaboration with Boehringer Ingelheim (Press release, Ten63 Therapeutics, DEC 6, 2023, View Source [SID1234638198]). The new partnership is aiming to enable the discovery of novel therapeutic molecules, to address diseases that are out of reach of conventional drug discovery, i.e. diseases with high unmet patient needs.

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Hundreds of millions of people are living with diseases that to date cannot be cured or are inadequately treated and which limit the daily activities or life expectancy of affected individuals. New technologies are needed to accelerate the discovery of medicines addressing molecular targets, which have so far eluded attempts to create effective treatment approaches.

The collaboration will apply Ten63’s computational drug discovery engine, BEYOND, to discover novel molecules for multiple Boehringer Ingelheim targets in diverse indications, and leverage Boehringer Ingelheim’s expertise in pre-clinical discovery and drug development.

Ten63’s CEO Dr. Marcel Frenkel said: "Ten63 is proud to partner with Boehringer Ingelheim on finding new molecules addressing challenging Boehringer targets that could have a tremendous impact on human lives. We believe the combination of Ten63’s BEYOND platform with Boehringer’s leading discovery and development capabilities will be a powerful combination to bring groundbreaking therapeutics to patients."

The BEYOND platform is composed of a suite of proprietary algorithms designed to enable drug discovery for targets that are difficult for conventional drug discovery technologies. BEYOND combines cryptic pocket discovery with a data-independent and interpretable generative chemistry engine to find potent drug candidates by completely exploring the conformational and chemical space of over 100 trillion synthetically feasible drug-like molecules to provably find the best solutions given Ten63’s state-of-the-art models. Furthermore, BEYOND learns from every iteration of chemistry, combining target specific data generated by the platform with models based on large external data sets to quickly allow it to transfer prediction of multiple absorption, distribution, metabolism and excretion (ADME) properties accurately to new chemical space.

Financial terms of the collaboration are not disclosed.

On December 6, 2023 Syros pharmaceuticals presented its corporate presentation (Presentation, Syros Pharmaceuticals, DEC 6, 2023, View Source [SID1234638197]).

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