On September 10, 2024 BeyondSpring Inc. (NASDAQ: BYSI) ("BeyondSpring" or the "Company"), a clinical-stage global biopharmaceutical company focused on developing innovative cancer therapies, reported Dublin-3 final phase 3 efficacy data of its late clinical-stage agent Plinabulin in combination with docetaxel in second/third line (2L/3L) advanced and metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type (Press release, BeyondSpring Pharmaceuticals, SEP 10, 2024, View Source;utm_medium=rss&utm_campaign=beyondspring-delivers-oral-presentation-at-islac-2024-world-conference-on-lung-cancer-of-its-lead-anti-cancer-asset-plinabulin-showcasing-positive-final-phase-3-data-in-2l-3l-nsclc-egfr-wild-type-with [SID1234646466]). The lead principal investigator, Dr. Trevor Feinstein from Piedmont Cancer Institute, presented the data in an oral presentation (OA08.04) at ISLAC 2024 World Conference on Lung Cancer on September 9th 2024 in San Diego, CA. Concurrently, Dublin-3 study was published in the Lancet Respiratory Medicine (View Source(24)00178-4).

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Docetaxel remains the standard of care for patients with 2L/3L NSCLC without targetable alterations despite severe neutropenia (>40%) that greatly impair patients’ quality of life. Six recent phase 3 studies in patients with EGFR wild-type NSCLC who were previously treated with immune checkpoint inhibitors failed to show overall survival (OS) benefit compared with docetaxel (SAPPHIRE, LEAP-008, CONTACT01, EVOKE-01, CARMEN-LC03, and CANOPY-2). Two phase 3 studies (LUNAR and TROPION-Lung01) showed positive but mixed outcomes compared with docetaxel.

The DUBLIN-3 study was a multicenter, randomized, single-blind, placebo-controlled trial that enrolled patients from 58 medical centers internationally. For the intention-to-treat (ITT) population, 559 patients received either docetaxel plus plinabulin (n=278 [male 199, female 79]) or docetaxel plus placebo (n=281 [male 207, female 74]).

Key findings of Dublin-3 study are summarized below:

Favorable benefit/risk ratio: Significant improvement in OS (Hazard ratio or HR=0.82; same HR in the Western vs. Asian patients), PFS (HR=0.79) and ORR (nearly doubled). Durable anti-cancer benefits in doubling 24-months and 36-months OS rates. And 82% relative reduction in Grade 4 neutropenia in Cycle 1 Day 8 (p<0.0001).
Consistent OS benefit in 24-month follow up after the database lock: OS HR=0.81 in the ITT population, with better OS benefit in the non-squamous subset (OS HR=0.72, p=0.0078). For the non-squamous subset patients, median OS (mOS) in plinabulin/docetaxel arm was 11.4 months vs. 8.8 months in the docetaxel arm, with a mOS benefit of 2.6 months.
Improved OS benefit with more cycles of treatment (≥ 4, 6, 8, 10, or 12 cycles): for patients who used at least 4 cycles of treatment, OS HR=0.64, p=0.0027, with a mOS benefit of 4.8 months (plinabulin/docetaxel arm n=133; docetaxel arm n=127).
Plinabulin/docetaxel combination is well-tolerated: Treatment-emergent adverse-events occurred in 273/274 (99·6%) of patients in the plinabulin group and 276/278 (99·3%) in the control group. Higher incidences of Grade 3/4 gastrointestinal disorders (46 patients [16·8%] vs. 8 [2·9%]) and transient Grade 3 hypertension (50 patients [18·2%] vs. 8 [2·9%]) occurred in the plinabulin vs. control group.
"There is a poor prognosis for NSCLC patients without targetable alterations whose disease has progressed on platinum-based therapies. Unfortunately, multiple high-profile phase 3 studies failed to show overall survival benefit in this hard-to-treat population compared to standard of care docetaxel, a drug approved over 20 years ago. The data from DUBLIN-3 study demonstrates that the addition and proper sequencing of plinabulin to docetaxel has a favorable benefit/risk ratio compared with docetaxel alone and may have broad utility. This combination could be considered as a new treatment option for this population with high unmet medical needs", said Dr. Feinstein, a lead principal investigator of the DUBLIN-3 study at Piedmont Cancer Center, Atlanta.

Citation:

Han B., et al. Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. 2024 Sep 09: S2213-2600(24)00178-4.

About Plinabulin

Plinabulin is a novel first-in-class dendritic cell maturation agent with durable anti-cancer benefit observed across multiple clinical studies. As a reversible binder at a distinct tubulin pocket, plinabulin does not change tubulin dynamics or antagonize tubulin stabilizing agents, such as docetaxel, which contributes to its differentiated activity and tolerability compared to other tubulin binders. In addition, plinabulin significantly reduces chemotherapy induced neutropenia and could thereby increase docetaxel tolerability. Over 700 patients have been treated with plinabulin with good tolerability.

About Dublin-3 Study
DUBLIN-3 is a multicenter, single-blinded (patient) and randomized, phase 3 trial in 58 medical centers (US, China, and Australia). Only patients with EGFR wild-type NSCLC who had progressed after first-line platinum-based therapy were enrolled. Patients were randomized (1:1) to receive docetaxel (75 mg/m2) on Day 1 and either plinabulin (30 mg/m2) or placebo on Days 1 and 8 in 21-day cycles until progression, unacceptable toxicity, withdrawal, or death. Treated patients were included in the safety analysis and ITT population in the primary efficacy analyses (NCT02504489). The primary endpoint for the study was OS, and secondary endpoints were PFS, ORR, Duration of Response (DoR), Grade 4 neutropenia and Quality of Life.

On September 10, 2024 I-Mab (NASDAQ: IMAB) (the "Company"), a U.S.-based, global biotech company exclusively focused on the development of highly differentiated immunotherapies for the treatment of cancer, reported a poster presentation of PK/PD modeling data for uliledlimab at the International Association for the Study of Lung Disease (IASLD)’s 2024 World Conference on Lung Cancer (WCLC 2024) held September 7-10, 2024 in San Diego, CA (Press release, I-Mab Biopharma, SEP 10, 2024, View Source [SID1234646482]).

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Uliledlimab (TJ004309) is an antibody designed to target CD73, the rate-limiting enzyme critical for adenosine-driven immunosuppression in the tumor microenvironment. Blocking CD73 allows anti-tumor immunity to proceed without the presence of an adenosine-induced "immunological fog". The WCLC 2024 presentation includes data from uliledlimab PK/PD analyses from three Phase 1 studies including patients with treatment naïve metastatic non-small cell lung cancer (mNSCLC).

"The PK/PD analysis presented at WCLC underscores our view that uliledlimab has the potential to be a differentiated, best-in-class, CD73 inhibitor. The data support our dose selection work and upcoming combination studies, with a study of uliledlimab plus pembrolizumab plus chemotherapy expected to begin in the first half of 2025," said Phillip Dennis, MD, PhD, Chief Medical Officer of I-Mab. "We are particularly encouraged by the E-R analysis, which showed a positive relationship between uliledlimab exposure and the probability of an overall response in patients with NSCLC, as well as positive target engagement data and dose proportional PK results. These data, plus a previously presented favorable safety profile and clinical efficacy, fortify our view that uliledlimab has the potential to meaningfully improve the care of patients with mNSCLC."

Poster Title: Integrated PK/PD Modeling for Uliledlimab, an Anti-CD73 Monoclonal
Antibody, in Non-Small Cell Lung Cancer Patients (Poster #2979)

Data are based on analysis of three Phase 1 studies conducted in China evaluating uliledlimab, as a monotherapy and in combination studies with the checkpoint inhibitors, toripalimab or atezolizumab, in patients with advanced cancers, including mNSCLC.

Key Findings Include:

Most of the simulated population (95%) could achieve the target threshold with 30 mg/kg of uliledlimab
Integrated PK/PD modeling and pharmacometrics analyses indicate there is a positive relationship between the probability of overall response and uliledlimab trough concentration in NSCLC patients
CD73 receptor occupancy (RO) in peripheral B cells achieved 90% or above and maintained at high levels until the end of treatment
The 30 mg/kg dose with a single boost dose on C1D8 provided uliledlimab concentrations that achieved the target concentration of 80 μg/mL immediately after the first dose and maintained this threshold afterward
A Ctrough target threshold of 80 μg/mL may be clinically meaningful, associated with PFS benefit and is achievable by a 30 mg/kg initial dose followed by a booster dose on Cycle 1, Day 8 (C1D8)
A full copy of the poster is available on the I-Mab website, on the "Innovation, Publications & Presentations" tab.

On September 10, 2024 BriaCell Therapeutics Corp. (NASDAQ: BCTX, BCTXW) (TSX: BCT) ("BriaCell" or the "Company"), a clinical-stage biotechnology company that develops novel immunotherapies to transform cancer care, reported that it has received positive feedback from its Pre-IND meeting with the U.S. Food and Drug Administration (FDA), which is a step forward to opening an IND to conduct a Phase 1/2 study of its personalized off-the-shelf immunotherapy, Bria-PROS+, in advanced prostate cancer (Press release, BriaCell Therapeutics, SEP 10, 2024, View Source [SID1234646467]).

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"We were truly impressed by the FDA team of experts’ keen interest in Bria-PROS+ as a potential novel personalized approach for advanced prostate cancer," stated Dr. William V. Williams, BriaCell’s President and CEO. "Despite numerous approved drugs, prostate cancer remains the second-leading cause of cancer death in American men. We view the FDA’s positive feedback as a major step forward in the clinical development of our Bria-PROS+ and in our efforts to bring hope to patients and families suffering from this deadly disease."

As a result of the Pre-IND meeting, FDA waived the animal toxicology and animal pharmacokinetic (PK) studies requirement for opening the IND, greatly simplifying the development pathway for Bria-PROS+. Other areas of discussion included BriaCell’s plan to initiate the Phase 1/2 study pending completion of standard manufacturing and testing requirements. These interactions also inform the further development of the proprietary Bria-OTS+ platform as the company pursues the development of Bria-BRES+, Bria-LUNG+ and Bria-MEL+, for breast cancer, lung cancer and melanoma, respectively.

BriaCell is currently evaluating its personalized immunotherapy Bria-BRES in a phase 1/2a study in metastatic breast cancer (ClinicalTrials.gov NCT06471673).

On September 10, 2024 Qilu Pharmaceutical reported that during the World Conference on Lung Cancer (WCLC) held from September 7-10, 2024, in San Diego, California, updated findings from the Phase II clinical trial (INTELLECT study) were presented (Press release, Qilu Pharmaceutical, SEP 10, 2024, View Source [SID1234646483]). The study assessed the efficacy and safety of Qilu Pharmaceutical’s iruplinalkib tablets (Qixinke) in treating patients with anaplastic lymphoma kinase (ALK)-positive crizotinib-resistant non-small-cell lung cancer (NSCLC). The highlights were showcased in a poster presentation.

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Iruplinalkib, a next-generation ALK/ROS1 kinase inhibitor formulated by Qilu Pharmaceutical, was approved by NMPA in June 2023 for the treatment of patients with ALK-positive locally advanced or metastatic NSCLC who had disease progression after treatment with crizotinib or who were intolerable to crizotinib. In January of this year, iruplinalkib was approved for the first-line treatment of patients with ALK-positive NSCLC.

The trial is led by principal investigator, Prof. Yuankai Shi from the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College. The results of the study were published in BMC Medicine in 2023. Updated data with an extended two-year follow-up were presented during the WCLC.

A total of 146 subjects were enrolled in this study. As of December 29, 2023, the median follow-up time was 42.41 months, revealing a median overall survival (OS) of 41.79 months. The investigator-evaluated objective response rate (ORR) was 63.7%, while the disease control rate (DCR) reached 94.5%. Additionally, the median duration of response (DoR) and median progression-free survival (PFS) were reported to be 14.06 months and 14.55 months, respectively.

According to the RECIST v1.1 evaluation criteria, the ORR and DCR in the subgroup with CNS metastasis at baseline (90 patients) were 55.6% and 93.3%, respectively. Both the median DoR and median PFS were 17.25 months, while the median OS stood at 43.01 months.

Based on RANO-BM criteria, intracranial complete response (CR) was achieved in 17 (18.9%) of the 90 patients with CNS metastasis at baseline. Among the 42 subjects with measurable intracranial lesions at baseline, the intracranial objective response rate (iORR) was 64.3% while the intracranial disease control rate (iDCR) reached 95.2%.

The safety profile was characterized by a 93.8% (137 cases) incidence of treatment-related adverse events (TRAEs), with 30.8% (45 cases) being grade 3 or 4. The most common TRAEs included elevated aspartate aminotransferase (45.2%), hypercholesterolemia (37.7%), and increased alanine aminotransferase (37.0%). No new safety signals were identified.

Long-term follow-up results from the INTELLECT study demonstrated that iruplinalkib provided an OS benefit with no new safety signal in patients with ALK-positive crizotinib-resistant advanced NSCLC.

On September 10, 2024 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported it has successfully delivered a second development candidate to Biogen and earned an $8 million milestone payment (Press release, C4 Therapeutics, SEP 10, 2024, View Source [SID1234646468]). This marks the final development candidate under this strategic collaboration.

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"We are thrilled to deliver a highly catalytic, brain penetrant orally bioavailable BiDAC degrader development candidate to Biogen in their pursuit of discovering, developing and delivering innovative therapies that improve the lives of patients," said Andrew Hirsch, president and chief executive officer. "It is rare that discovery collaborations deliver one, much less two, development candidates to the partner. This result is a testament to the dedication of the Biogen and C4T teams and the productivity of our TORPEDO platform, which has demonstrated its potential to design innovative degraders against a broad range of target classes. Since our founding in 2015, we have discovered and advanced four development candidates for our clinical pipeline and delivered two development candidates to Biogen, an impressive feat for a company of our size. We are proud to continue advancing the exciting field of targeted protein degradation and bring new medicines to patients."

Under the terms of the strategic collaboration established in 2018, C4T provided expertise and research services in targeted protein degradation and Biogen provided scientific and drug development capabilities. Biogen is responsible for all future clinical development and commercialization for development candidates delivered under the collaboration. Previously, C4T earned an $8 million payment in April 2024 after Biogen accepted delivery of a first development candidate in an undisclosed indication as part of this collaboration.