June 2021 – Page 162 – 1stOncology™: Cancer Intelligence Service

Article on CD40 agonistic antibodies published in Expert Opinion on Biological Therapy

On June 7, 2021 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported that the scientific journal Expert Opinion on Biological Therapy has published an article by scientists at Alligator Bioscience, reviewing the field of CD40 agonistic antibodies (Press release, Alligator Bioscience, JUN 7, 2021, View Source [SID1234583634]). The article provides an overview of the CD40 agonistic antibodies in clinical development and the current challenges and opportunities for this important class of immuno-oncology drugs.

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Title: Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

Journal: Expert Opinion on Biological Therapy

Authors: Karin Enell Smith et al

"We’re very pleased to have this peer-reviewed article prepared by Alligator’s scientists published. It highlights the promising role of CD40 agonists in immuno-oncology and explains how Alligator’s CD40 agonist, mitazalimab, has best in class potential," said Søren Bregenholt, CEO of Alligator Bioscience. "We’re now looking forward to initiating the OPTIMIZE-1 Phase II study designed to assess the clinical efficacy of mitazalimab combined with chemotherapy in patients with metastatic pancreatic cancer."

Mitazalimab is an agonistic – or stimulatory – antibody that targets CD40, a receptor on dendritic cells, which are the cells that instruct T cells to kill cancer cells. Mitazalimab activates CD40 enabling dendritic cells to effectively stimulate the immune system directing T cells to selectively attack the tumor. This addresses one of the key mechanistic needs in immuno-oncology and highlights the potential of CD40 as a target to treat patients with metastatic cancer. Mitazalimab’s favorable efficacy-safety profile demonstrated in previous phase I studies, makes it ideal for combination with standard of care treatments such a chemotherapy, check-point inhibitors or cancer vaccines.

Autobahn Labs incubator announces partnership with Cold Spring Harbor Laboratory to advance novel science to the clinic

On June 6, 2021 Autobahn Labs, an early-stage drug discovery incubator, reported a new strategic venture collaboration with Cold Spring Harbor Laboratory (CSHL) (Press release, Evotec, JUN 6, 2021, View Source;announcements/press-releases/p/autobahn-labs-incubator-announces-partnership-with-cold-spring-harbor-laboratory-to-advance-novel-science-to-the-clinic-6068 [SID1234583737]). Together with Autobahn Labs, CSHL will identify promising research programs with therapeutic potential and partner to form promising new drug discovery companies.

"We’re delighted to partner with CSHL, expanding our reach and collaborations with top faculty working on truly compelling science with strong therapeutic potential," said Thomas Novak, PhD, Chief Scientific Officer of Autobahn Labs. "Cold Spring Harbor is a close-knit and collegial campus that also has cultivated one of the premier scientific meeting programs in the world."

"Autobahn has the ability to get involved early and put their resources into CSHL’s drug discovery programs and generate a pipeline of highly investable spin-out companies," said Andrew Whiteley, CSHL Vice President, Business Development and Technology Transfer. "This collaboration will enable us to more quickly advance our basic biology expertise from the lab to the clinic."

Under terms of the agreements with CSHL, Autobahn Labs will invest up to $5M in funding and biopharmaceutical services into specific programs yet to be identified. Since its launch in June 2020, Autobahn Labs has announced partnerships with four leading institutions and has started two new drug discovery programs.

Backed by Samsara BioCapital, Evotec SE, and KCK Ltd, Autobahn Labs invests earlier than traditional venture financing models, providing intellectual, financial and physical capital to efficiently and effectively advance new scientific discoveries from novel concept to preclinical drug candidate. Institutions benefit from Autobahn’s strategy and operational support, as well as the industry-leading drug discovery capabilities of Evotec, a global leader in drug discovery and development. Pre-agreement on many of the economic and intellectual property terms that govern the relationship further facilitates the negotiation and creation of jointly-owned new companies.

Innovent Releases the Phase Ia/Ib Dose-Escalation Trial Results of IBI110 (anti-LAG-3) in Patients with Advanced Solid Tumors at ASCO Annual Meeting 2021

The phase 1 study of IBI110 is a dose-escalation trial evaluating IBI110, an anti-LAG-3 monoclonal antibody, as a single agent and in combination with sintilimab in patients with advanced solid tumors refractory to standard of care therapy. The study is comprised of Phase Ia, an IBI110 single-drug dose-escalation phase, and Phase Ib, the dose-escalation phase of IBI110 in combination with sintilimab (200mg). At disease progression, cross over from IBI110 monotherapy to combo (IBI110+ sintlilimab) was allowed at the investigators’ discretion. At data cutoff (February 9, 2021), 40 patients were enrolled and received treatment. 22 subjects were assigned in dose groups of 7 (0.01mg/kg~20mg/kg) in Phase Ia, the prespecified dose escalation had been completed and no dose-limited toxicity (DLT) was observed. No adverse event (AE) led to discontinuation of IBI110 or sintilimab and no treatment-related death was reported. In terms of efficacy, a subject with advanced ovarian cancer who progressed on multiple prior systemic therapies achieved partial response after IBI110 monotherapy treatment and was still in the study for more than 6 months. 18 subjects were assigned in dose groups of 5 (0.3mg/kg~5mg/kg) in Phase Ib of IBI110 in combination with sintilimab, the prespecified dose escalation had been completed and no dose-limited toxicity (DLT), adverse events leading to discontinuation or death was observed. At data cutoff (April 26, 2021), three subjects had achieved partial response with an objective response rate of 16.7% (3/18) in phase 1b, demonstrating a synergistic anti-tumor activity of IBI110 and sintilimab.

"The efficacy signal and safety profile we see with IBI110 in this study is exciting," said Dr. Hui Zhou, Senior Vice President of Clinical Development, Innovent Biologics. "The single-drug efficacy demonstrated in the trial suggested a huge anti-tumor potential of this target. As we move ahead with the study, we look forward to greater clinical benefits of IBI110 in combination with sintilimab in patients in this trial. We are committed to innovation and relentless pursuit of breakthroughs for cancer patients. Aside from IBI110, we are also initiating phase 1 clinical trial on IBI323, a LAG-3/PD-L1 bispecific antibody, to fully investigate therapeutic value of LAG-3. "

Professor Caicun Zhou from Shanghai Pulmonary Hospital said: "IBI110’s good safety and preliminary efficacy data support the further exploration of this molecule in a variety of tumor types, including non-small cell lung cancer, small cell lung cancer, melanoma, etc. LAG-3 is the third validated immune-related target after PD-1 and CTLA-4. We look forward to seeing more positive results from the upcoming trials of IBI110."

About the Study

This study is a phase Ia/Ib open label, dose escalation and expansion study to evaluate the safety, tolerability and efficacy of IBI110, an anti-LAG-3 monoclonal antibody, as a single agent and in combination with sintilimab in advanced solid tumors. The study follows a classic 3+3 design. Patients received escalating doses of IBI110 once every 3 weeks in phase Ia and escalating doses of IBI110 in combination with TYVYT (sintilimab injection) 200 mg once every 3 weeks in phase Ib until disease progression, unacceptable toxicity, or withdrawal of consent.

Primary objectives of the trial were to evaluate the safety, tolerability and the antitumor activity of IBI110 monotherapy and in combination with sintilimab.

About LAG-3

Lymphocyte activation gene-3 (LAG-3) (CD223) is a novel 498-amino acid type I transmembrane protein identified on activated human NK and T-cell lines. LAG-3 (CD223) is a potential cancer immunotherapeutic target due to its negative regulatory role on T cells and its capacity, in combination with PD-1, to mediate a state of exhaustion.

About TYVYT (sintilimab Injection)

TYVYT (sintilimab injection) is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Lilly. 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. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, TYVYT (sintilimab Injection) has been approved for two indications, including:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of nonsquamous non-small cell lung cancer
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer
Additionally, Innovent currently has regulatory submissions under review in China for TYVYT (sintilimab Injection):

In combination with BYVASDA (bevacizumab injection) for the first-line treatment of hepatocellular carcinoma
The second-line treatment of squamous non-small cell lung cancer
In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

TYVYT (sintilimab Injection) was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

Innovent and AnHeart Release Preliminary Results from the Phase II TRUST Trial of Taletrectinib in ROS1 Fusion Positive NSCLC at the ASCO 2021 Annual Meeting

On June 6, 2021 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 and other major diseases, together with AnHeart Therapeutics Co., Ltd ("AnHeart"), a clinical stage oncology company focused on underserved patients in global markets, reported a presentation of a scientific poster entitled "Preliminary results from TRUST: A phase II clinical study to investigate Taletrectinib in treating patients with ROS1 fusion positive non-small cell lung cancer (NSCLC)" which summarizes initial data from its ongoing trial of taletrectinib (NCT04395677) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting (Press release, Innovent Biologics, JUN 6, 2021, View Source [SID1234583621]).

As of the data cut-off date of April 8, 2021, there were 15 crizotinib treatment-naïve patients and 5 crizotinib pre-treated patients, who had been confirmed to be ROS1 fusion positive and assessed at least twice by investigators. The results were as follows:

In the crizotinib treatment-naïve patients (n=15), the overall response rate (ORR) was 93% (14/15) and the disease control rate (DCR) was 93% (14/15);
In the crizotinib pre-treated patients (n=5), the ORR was 60% (3/5); and the DCR was 100% (5/5). ROS1 G2032R resistant mutations were identified in three of the five patients and all three patients experienced tumor regressions; and
Taletrectinib has shown a manageable safety profile characterized primarily by gastrointestinal adverse events, with reversible increases of aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
"These safety and efficacy data for taletrectinib are very promising for ROS1 fusion positive lung cancer patients," said Dr. Caicun Zhou, director of the Department of Oncology, Shanghai Pulmonary Hospital. "Responses appear particularly impressive in crizotinib treatment-naïve patients, and while the number of crizotinib pre-treated patients is limited, thus far all five patients continue to benefit from the drug."

"We are glad to see the study result of Taletrectinib can be presented at ASCO (Free ASCO Whitepaper) meeting, the most authoritative clinical oncology conference", said Dr. Hui Zhou, Senior Vice President of Clinical Development, Innovent Biologics, "In China, ROS1 positive fusion patients have limited treatment choices at present. More new drugs are needed to develop for clinical application. Taletrectinib has shown good efficacy and safety results, which offers hope to patients with ROS1 fusion positive non-small cell lung cancer."

"Our team is highly focused on completing patient enrollment for this phase II TRUST trial in Q3 2021," said Bing Yan, MD, co-founder and chief medical officer of AnHeart. "These data from the TRUST trial have built a solid foundation for our upcoming global trials of taletrectinib and will support us in seeking regulatory approvals of talectrectinib in China and globally. We sincerely thank the patients, their families and investigators in the TRUST trial and look forward to bringing taletrectinib to all ROS1 fusion positive patients in the near future upon approval."

About Taletrectinib

Taletrectinib is an investigational next-generation tyrosine kinase inhibitor (TKI) designed to effectively target ROS1 and NTRK fusion mutations with potential to treat TKI-naïve or pre-treated patients. ROS1 rearrangement is estimated to be an oncogenic driver in approximately 2 to 3 percent of patients with advanced NSCLC, and NTRK rearrangement is estimated to be an oncogenic driver in approximately 0.5 percent of patients with other advanced solid tumors. More information about the ongoing TRUST (Taletrectinib ROS1 LUng STudy) trial and the basket trial in NTRK fusion positive solid tumors of taletrectinib may be found by searching clinical trial identifiers NCT04395677 and NCT04617054, respectively at View Source

On 1 June 2021, Innovent and Anheart announced an exclusive license agreement for the co-development and commercialization of AnHeart’s lead drug candidate, taletrectinib – a next-generation tyrosine kinase inhibitor (TKI) designed to effectively target ROS1 and NTRK – in Greater China, including mainland China, Hong Kong, Macau and Taiwan.

Innovent and HUTCHMED Release Phase 1b preliminary Results of TYVYT (Sintilimab Injection) plus Fruquintinib as a Third Line Treatment for Advanced Colorectal Cancer at ASCO Annual Meeting 2021

This is a Phase 1b dose escalation and dose expansion study to evaluate the tolerability, safety and preliminary efficacy of sintilimab plus fruquintinib, and to determine the recommended phase 2 dose (RP2D). 44 CRC patients that had failed at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan were enrolled. They received either 5mg-intermittent or 3mg-continous dosage (n=22, each). The objective response rate (ORR) was 22.7% (10/44, 95% CI: 11.5-37.8%) with 27.3% (6/22, 95% CI: 10.7-50.2%) in the 5mg-intermittent group and 18.2% (4/22, 95% CI: 5.2-40.3%) in the 3mg-continuous group. With a median follow-up time of 11.3 (range: 9.8-11.7) months, the Kaplan-Meier estimated median progression free survival (PFS) was 5.6 (95% CI:4.3-7.5) months among all 44 patients, with 6.9 (95% CI:5.4-8.3) months for the 5mg-intermittent group and 4.2 (95% CI:2.9-9.5) months for the 3mg-continuous group. The safety for this combination therapy was controllable.

Dr. Hui Zhou, Senior Vice President of Clinical Development, Innovent Biologics, said, "The preliminary results were very encouraging, which have given us a very promising efficacy signal that TYVYT (sintilimab injection) in combination with ELUNATE (fruquintinib) could be used as a third-line treatment for advanced CRC with microsatellite stability. These results would warrant further investigation in a larger population. This study also underscores our commitment to provide innovative treatment options to patients with cancer."

Dr. Weiguo Su, Chief Scientific Officer of HUTCHMED, said, "Fruquintinib’s clean profile led us to evaluate this sintilimab combination in many different tumor types, with this favorable safety profile further highlighted by the combination’s RP2Ds similarity to their monotherapy RP2D. This CRC data at RP2D is promising, showing median PFS at nearly double what was demonstrated under monotherapy. We are exploring next steps in bringing this novel therapy to cancer patients."

About Colorectal Cancer

Colorectal cancer is one of the most common malignancies in the world with relatively high morbidity and mortality. With the improvement of living conditions, the incidence of CRC in China has been increasing in recent years. Surgery is the major treatment for early stage CRC, but a large proportion of patients who have received surgery would develop relapse or distant metastasis, and die from disease progression. More than 95% of advanced CRCs are microsatellite stable, with very limited efficacy of immunotherapy and large unmet clinical needs.

About TYVYT (Sintilimab Injection)

In China, TYVYT (sintilimab Injection) has been approved for two indications, including:

TYVYT (sintilimab Injection) was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year..

About ELUNATE (fruquintinib)

Fruquintinib is a highly selective and potent oral inhibitor of VEGFRs –1, –2 and –3. VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. Fruquintinib was designed to improve kinase selectivity to minimize off-target toxicities, improve tolerability and provide more consistent target coverage. The generally good tolerability in patients to date, along with fruquintinib’s low potential for drug-drug interaction based on preclinical assessment, suggests that it may also be highly suitable for combinations with other anti-cancer therapies.

Fruquintinib was approved for marketing by the NMPA in September 2018 and is marketed under the brand name ELUNATE in China. ELUNATE is for the treatment of patients with metastatic CRC that have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan, including those who have previously received anti-VEGF therapy and/or anti-EGFR therapy (RAS wild type).

HUTCHMED retains all rights to fruquintinib outside of China. In China, HUTCHMED is partnered with Eli Lilly and Company and is responsible for development and execution of all on-the-ground medical detailing, promotion and local and regional marketing.

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Month: June 2021

Article on CD40 agonistic antibodies published in Expert Opinion on Biological Therapy

Autobahn Labs incubator announces partnership with Cold Spring Harbor Laboratory to advance novel science to the clinic

Innovent Releases the Phase Ia/Ib Dose-Escalation Trial Results of IBI110 (anti-LAG-3) in Patients with Advanced Solid Tumors at ASCO Annual Meeting 2021

Innovent and AnHeart Release Preliminary Results from the Phase II TRUST Trial of Taletrectinib in ROS1 Fusion Positive NSCLC at the ASCO 2021 Annual Meeting

Innovent and HUTCHMED Release Phase 1b preliminary Results of TYVYT (Sintilimab Injection) plus Fruquintinib as a Third Line Treatment for Advanced Colorectal Cancer at ASCO Annual Meeting 2021