On October 19, 2023 Akeso (9926. HK) reported the publication of the phase 1a/1b first-in-human study (COMPASSION-01) evaluating cadonilimab (PD-1/CTLA-4 bispecific antibody) in patients with advanced solid tumors in Cell Reports Medicine, a sub-publication of Cell (Press release, Akeso Biopharma, OCT 19, 2023, View Source [SID1234636155]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The study findings revealed that cadonilimab reached a dose of 25 mg/kg every 3 weeks (Q3W) without encountering the maximum tolerated dose (MTD). The occurrence of severe immune-related adverse events (irAE) with a grade of 3 or higher was only 6.7%. These results indicate that cadonilimab exhibits a favorable safety and tolerability profile in the treatment of advanced solid tumors. Based on the study, a recommended dose of 6 mg/kg every 2 weeks (Q2W) was established. Remarkably, tumor response was observed in both PD-L1-positive and PD-L1-negative solid tumor populations, indicating that cadonilimab possesses unique efficacy advantages over PD-1/PD-L1 monoclonal antibodies and may have a broader range of potential indications. In conclusion,cadonilimab was found to have a favorable toxicity profile and promising efficacy for patients with solid tumors that were refractory/relapsed to standard therapies or for which no effective standard therapy was available.

Cadonilimab has been approved by the China National Medical Products Administration (NMPA) for recurrent or metastatic cervical cancer. Currently, Akeso has initiated/conducted a series of more than 60 clinical studies globally for patients with solid tumors that were refractory/relapsed to standard therapies or for which no effective standard therapy was available, covering more than 20 types of malignant tumors, including gastric cancer, hepatocellular carcinoma, lung cancer, cervical cancer, pancreatic cancer, renal cancer, esophageal squamous carcinoma, colorectal cancer, nasopharyngeal carcinoma, pleural mesothelioma, and other malignant tumors.

About Cadonilimab(PD-1/CTLA-4 bispecific antibody)
Cadonilimab is a first-in-class bispecific antibody that targets both PD-1 and CTLA-4 developed by Akeso. It is a symmetric tetravalent bispecific antibody with a crystallizable fragment (Fc)-null design. In addition to demonstrating biological activity similar to that of the combination of CTLA-4 and PD-1 antibodies, cadonilimab possesses higher binding avidity in a high-density PD-1 and CTLA-4 setting than in a low-density PD-1 setting, while a mono-specific anti-PD-1 antibody does not demonstrate this differential activity. With no binding to Fc receptors, cadonilimab shows minimal antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and interleukin-6 (IL-6)/IL-8 release. These features all likely contribute to significantly lower toxicities of cadonilimab observed in the clinic. Higher binding avidity of cadonilimab in a tumor-like setting and Fc-null design may lead to better drug retention in tumors and contribute to better safety while achieving anti-tumor efficacy.

Cadonilimab has been approved by the China National Medical Products Administration for recurrent or metastatic cervical cancer. Cadonilimab has been included and recommended in multiple clinical guidelines such as CSCO. In its first 12 months on the market, cadonilimab generated impressive sales revenue of 1.15 billion RMB. Cadonilimab has been engaged in more than 60 ongoing clinical trials including investigator-initiated studies. Patient enrollment has been completed for the phase 3 study of cadonilimab for first-line treatment of advanced cervical cancer as well as a phase 3 study of cadonilimab in combination with chemotherapy as first-line therapy in gastric cancer. A phase 3 study of cadonilimab as an adjuvant treatment for hepatocellular carcinoma is ongoing. Furthermore, a Phase III study comparing cadonilimab with chemotherapy to tislelizumab Injection with chemotherapy is underway for the first-line treatment of PD-L1 expression-negative non-small cell lung cancer.

On October 19, 2023 Flare Therapeutics Inc., a biotechnology company targeting transcription factors (TF) to discover precision medicines for cancer and other diseases, reported that the first patients have been dosed in the company’s phase 1 study to assess the safety and tolerability of FX-909, a first-in-class small molecule inhibitor of peroxisome proliferator-activated receptor gamma (PPARG), a master regulator of the luminal lineage (Press release, Flare Therapeutics, OCT 19, 2023, View Source [SID1234636154]). FX-909 is a highly potent and selective inhibitor of PPARG and has demonstrated tumor eradication in preclinical animal models of urothelial cancer at low oral doses.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are excited to announce the dosing of patients in the first dose cohort of our Phase 1 clinical study of FX-909, marking a major milestone for Flare Therapeutics as we transition to a clinical stage company," said Michael L. Meyers, M.D., Ph.D., Chief Medical Officer of Flare Therapeutics. "Rooted in innovation and expertise in transcription factors, FX-909 has the potential to become a backbone therapy for advanced urothelial cancer. We believe PPARG’s role as a master regulator of the luminal lineage may represent a differentiated therapeutic option in advanced urothelial cancer, and we are excited to explore this novel mechanism in the clinic."

About FX-909

Flare Therapeutics’ lead investigational compound, FX-909, is a first-in-class novel, highly potent and selective small molecule that inhibits the transcription factor peroxisome proliferator-activated receptor gamma (PPARG) to treat patients with the luminal subtype of advanced urothelial carcinoma (UC) and potentially other solid tumors. Preclinical data for FX-909 has demonstrated robust anti-tumor activity, excellent PK/PD correlation, durable efficacy, and a favorable safety profile in mouse models of UC (PPARG-amp and RXRA-mut) at very low oral doses.

About the FX-909 Phase 1 Study

The ongoing phase 1 study is a first-in-human, dose-escalation and -expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma. The study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of FX-909. FX-909 will be given initially in a dose-escalation phase (Part A) to determine the recommended phase 2 dose. FX-909 will be given initially orally once daily in 28-day cycles. Part B will be a monotherapy expansion phase to further evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of FX-909 in patients with locally advanced (unresectable) or metastatic urothelial carcinoma. Additional information on this clinical trial can be found on www.clinicaltrials.gov (NCT05929235).

About Advanced Urothelial Carcinoma (UC)

In 2020, there were an estimated 725,549 people living with bladder cancer in the United States alone, making it the sixth most common cancer overall, and fourth most common among men (SEER – 2020). Each year, there are more than 83,000 new cases diagnosed among men and women, and about 25% of those cases are classified as muscle-invasive UC (DRG 2020). Advanced UC has high rates of recurrence, where treatment outcomes have remained poor with typical five-year survival rates of 8% in advanced metastatic disease (SEER – 2020). The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is associated with the luminal lineage subtype reflecting approximately 65% of all advanced UC cases (Robertson, Cell 2017). Recurrent genetic alterations in PPARG are characteristic of this molecular subtype.

On October 19, 2023 Qilu Pharmaceutical’s reported that data from clinical trial of its novel bifunctional antibody, QL1706 (iparomlimab and tuvonralimab), will be unveiled during a mini oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2023 (Press release, Qilu Pharmaceutical, OCT 19, 2023, View Source [SID1234636153]). The ESMO (Free ESMO Whitepaper) Congress, the premier global conference in the field of medical oncology, will take place in Madrid, Spain from October 20 to 24, 2023. The presentation will provide updates on a multicenter, single-arm phase II clinical trial of QL1706. This innovative treatment, used in combination with chemotherapy and with or without bevacizumab, is being investigated for its potential as a first-line therapy for recurrent or metastatic cervical cancer (CC).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Additionally, a poster showcasing a multicenter, randomized, double-blind, parallel-controlled Phase III clinical trial conducted by Qilu Pharmaceutical. This study examines the use of a combination of pertuzumab biosimilar (QL1209), trastuzumab and docetaxel as a neoadjuvant therapy for the treatment of early or locally advanced HER2-positive, hormone receptor-negative breast cancer will be featured at the congress.

I. Phase II Clinical Trial of QL1706

Combination immunotherapy has emerged as the first-line treatment approach for recurrent/metastatic CC. Qilu Pharmaceutical’s class 1 novel drug, QL1706, is a bifunctional antibody that simultaneously targets PD-1 and CTLA-4, producing synergistic anti-tumor effects. The phase Ib clinical trial of QL1706 for advanced solid tumors has confirmed the drug’s promising efficacy of monotherapy in patients with advanced cervical cancer (ACC). An objective response rate (ORR) of 28.3% was observed in ACC patients who had not previously undergone immunotherapy[1] . To further investigate the efficacy of dual immunotherapy combined with chemotherapy in patients with recurrent/metastatic CC, a multicenter, single-arm phase II clinical trial was initiated to assess QL1706, administered with chemotherapy and with or without bevacizumab, as a first-line treatment for recurrent or metastatic CC.

The study enrolled recurrent or metastatic CC patients who had not undergone systemic therapy. These patients were treated with either QL1706-chemotherapy (Cohort 1) or QL1706-chemotherapy-bevacizumab (Cohort 2) until disease progression, the occurrence of intolerable toxicity or the patient’s withdrawal of informed consent. The primary endpoint of the study was safety, with secondary endpoints including ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), which were assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

The findings of this study indicated that as of April 24, 2023, out of 58 patients who received at least one post-baseline efficacy evaluation, ORR was 81.0% (95% CI, 68.6-90.1). The results were observed over a median follow-up duration of 14.0 months. Among these patients, eight achieved complete response (CR) and 39 achieved partial response (PR). The DCR was 98.3% (95% CI, 90.8-100.0). The median PFS reached 14.3 months (95% CI, 9.2 months to not estimable), while the median OS has not yet been reached. The data demonstrate the outstanding efficacy of a combination of QL1706 and chemotherapy, with or without bevacizumab, for treating recurrent or metastatic CC. A Phase III clinical trial of the combination therapy is currently ongoing.

Phase III Clinical Trial of QL1209

A multicenter, randomized, double-blind, parallel-controlled Phase III clinical trial was conducted to assess the clinical equivalence of QL1209 and the original drug, both used in conjunction with trastuzumab and docetaxel as a neoadjuvant treatment for early or locally advanced HER2-positive, hormone receptor-negative breast cancer.

The study enrolled patients with early or locally advanced HER2-positive, estrogen receptor (ER) and progesterone receptor (PR) negative breast cancer. These patients were randomly assigned in a 1:1 ratio to either the QL1209 trial group or the control group receiving the original drug. Both groups underwent four cycles of neoadjuvant therapy with QL1209/original drug + trastuzumab + docetaxel (THP), followed by a post-surgical pathological response evaluation. Both groups then received adjuvant chemotherapy with fluorouracil-epirubicin-cyclophosphamide (FEC) for cycles 5-7, and QL1209 + trastuzumab for cycles 8-20. The study’s primary endpoint was the total pathological complete response (tpCR), as assessed by an independent review committee (IRC).

The study enrolled 517 patients, of which 516 received treatment. In terms of efficacy, the IRC-assessed tpCR rates were 42.7% in the trial group, and 45.2% in the control group. The ratio of the tpCR rate between the two groups was 0.946 (90% CI: 0.80-1.11), falling within the equivalence margin (0.76-1.32). Regarding safety, the incidence of treatment-emergent adverse events (TEAEs) was 94.6% in the trial group and 96.1% in the control group; the occurrence of grade 3 or higher TEAEs was 31.9% in the former group and 34.7% in the latter while the incidence of treatment-related adverse events (TRAEs) was 77.4% and 78.0%, respectively. As for immunogenicity, the incidence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) was similar between the two groups (2.3% and 3.1%; 0.8% and 0.8%, respectively). ADA positivity had no impact on efficacy, pharmacokinetics or safety. These findings suggest that the two groups exhibit similar clinical efficacy, with no significant differences observed in safety or immunogenicity. Based on these results, it can be concluded that QL1209 is a biosimilar to pertuzumab.

References:

1. Zhao Y, et al. First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors. J Hematol Oncol. 2023 May 8;16(1):50. doi: 10.1186/s13045-023-01445-1.

On October 19, 2023 Hummingbird Bioscience ("Hummingbird Bio"), a data-driven precision biotherapeutics company discovering and developing transformative biologic medicines for hard-to-treat diseases, and Endeavor BioMedicines ("Endeavor"), a clinical-stage company targeting the drivers of fibrosis and oncology, reported that Endeavor has acquired exclusive worldwide rights to Hummingbird Bio’s antibody-drug conjugate (ADC), HMBD-501 (Press release, Endeavor BioMedicines, OCT 19, 2023, View Source [SID1234636152]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The license agreement provides Endeavor with exclusive rights to HMBD-501, a next-generation HER3-targeted ADC with an exatecan payload that has been optimized for safety and efficacy. Under the terms of the license, Hummingbird Bio will be eligible to receive upfront and milestone payments up to $430 million, plus royalties on net sales.

"This exclusive license with Hummingbird Bio provides Endeavor with a potential best-in-class HER3-ADC, with the opportunity to treat a large number of patients in multiple tumor types," said John Hood, Ph.D., Co-Founder, CEO and Chairman of Endeavor. "HER3 is more broadly expressed on tumors than HER2 and is expressed on tumors that do not express HER2. This next generation ADC has the potential to address significant unmet clinical needs in areas left behind by HER2 agents."

HMBD-501 is a differentiated ADC generated by Hummingbird Bio’s proprietary antibody discovery and engineering platform and key state-of-the-art ADC technologies, enabling a potentially enhanced efficacy and safety profile compared to previous generation ADCs. HMBD-501 binds a novel epitope on the HER3 receptor, such that binding is unaffected by NRG1 (HER3 ligand) levels, allowing binding to HER3-expressing tumors even in high ligand contexts.

"Hummingbird Bio has designed HMBD-501 to have a wider therapeutic index than current HER3 ADCs, maximizing the potential clinical benefit for patients, and we are delighted that Endeavor has recognized the potential of this ADC built with our proprietary antibody technology," said Piers Ingram, Ph.D., Co-Founder and CEO of Hummingbird Bio. "We are pleased to license HMBD-501 to the experienced Endeavor team to bring the molecule into the clinic and a step closer to benefiting patients."

About HMBD-501

Multiple HER3-positive tumor settings have demonstrated response to HER3-ADC therapeutic approaches. HMBD-501 has been generated by combining Hummingbird Bioscience’s antibody discovery and engineering platform and state-of-the-art ADC technologies to enable a potentially enhanced efficacy and safety profile compared to previous generation ADCs. With key proprietary technologies enabling a differentiated molecule, HMBD-501 is poised to become a best-in-class HER3 ADC.

On October 19, 2023 The European Organisation for Research and Treatment of Cancer (EORTC) and the Menarini Group (Menarini), a leading international pharmaceutical and diagnostics company, reported they have launched a new study for breast cancer patients: EORTC 2129-BCG TREAT ctDNA, a clinical trial supported by the EORTC Breast Cancer Group. Menarini and its subsidiary, Stemline, will provide elacestrant. A molecular residual disease (MRD) test for the detection of circulating tumour DNA (ctDNA) will also be used. The study was submitted under the new Clinical Trial Regulation, and it is expected to start the activation process in the fourth quarter of 2023.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

ORSERDU (elacestrant) was approved by the European Commission in September 2023 as a monotherapy for the treatment of postmenopausal women, and men, with estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer (mBC) with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK4/6 inhibitor.

"We are excited to offer to our high-risk, ctDNA positive, ER+/HER2- early-stage breast cancer patients the possibility to participate in the Treat ctDNA trial. ctDNA positive patients will be identified using a personalised assay. We aim to study the value of the new selective estrogen receptor degrader (SERD), elacestrant, in reducing the rate of late distant relapses for these patients," said Prof. Michail Ignatiadis, chair of the EORTC Breast Cancer Group and Director of the Breast Medical Oncology Clinic and Program at the Jules Bordet Institut.

This intergroup trial, managed by the EORTC Breast Cancer Group, will be jointly conducted with several national and international cancer clinical research groups, including the German SUCCESS group under the umbrella of BIG (Breast International Group). Twelve countries have been selected to participate in the trial (Italy, France, Belgium, Spain, Ireland, Cyprus, Germany, Greece, the Netherlands, Portugal, Sweden and Switzerland) with more than 120 sites expected to screen approximately 1960 patients. The randomised, open label, superiority phase III trial will evaluate whether elacestrant can delay the occurrence of metastasis or death compared to standard adjuvant endocrine therapy in patients with early-stage ER+/HER2- breast cancer and molecular relapse.

"The Menarini Group is glad to partner with EORTC on this important study, to expand our understanding of how elacestrant may potentially benefit ER+/HER2- patients with early-stage breast cancer," said Elcin Barker Ergun, CEO of the Menarini Group. "Evaluating new treatments with a manageable safety profile, such as elacestrant, is important as we seek new options for this population."

After verification that patients meet the eligibility criteria, they will enter the ctDNA screening phase of the study, in which plasma samples will be collected and tested the to detect the presence of ctDNA. The test will be performed every six months from study entry until the end of accrual. Patients with a positive ctDNA test, who do not have metastasis and who fulfill the eligibility criteria, will be randomised to either the standard endocrine treatment arm (the same treatment they were receiving before detection of ctDNA) or to the elacestrant arm. Patients will be randomised to one of the two treatment arms within four weeks of receiving their test results, with the goal of randomising 110 patients in each arm. Patients in both the control and experimental
arms will benefit from timely detection of macroscopic disease relapse.

About elacestrant (ORSERDU)

European Union Indication: ORSERDU (elacestrant) monotherapy is indicated for the treatment of postmenopausal women, and men, with estrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK4/6 inhibitor.

Important Safety Information from the ORSERDU SmPC

Hepatic Impairment: Administration of ORSERDU should be undertaken with caution at a dose of 258 mg once daily in patients with moderate hepatic impairment (Child-Pugh B). In the absence of clinical data, ORSERDU is not recommended in patients with severe hepatic impairment (Child-Pugh C).

Concomitant use with CYP3A4 Inducers and/or inhibitors: Concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU should be avoided. Concomitant use of strong or moderate CYP3A4 inducers with ORSERDU should be avoided.

Thromboembolic events: Thromboembolic events are commonly observed in patients with advanced breast cancer and have been observed in clinical studies with ORSERDU. This should be taken into consideration when prescribing ORSERDU to patients at risk.

Adverse Reactions:

Serious adverse reactions reported in ≥ 1% of patients included nausea, dyspnoea, and thromboembolism (venous).

The most common (≥ 10%) adverse reactions with ORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia, potassium decreased, and alanine aminotransferase increased.

The most common Grade ≥3 (≥2%) adverse reactions of elacestrant were nausea (2.7%), AST increased (2.7%), ALT increased (2.3%), anaemia (2%), back pain (2%), and bone pain (2%).

Nausea: Nausea was reported in 35% of patients. Grade 3-4 nausea events were reported in 2.5% of patients. Nausea occurred more frequently in the first cycle and from Cycle 2 onward, the incidence of nausea was generally lower in subsequent cycles (i.e., over time).

Elderly: Gastrointestinal disorders were reported more frequently in patients aged ≥ 75 years.

Fertility, pregnancy, and lactation:

ORSERDU should not be used during pregnancy or in women of childbearing potential not using contraception. Based on the mechanism of action of elacestrant and findings from reproductive toxicity studies in animals, ORSERDU can cause foetal harm when administered to pregnant women. Females of reproductive potential should be advised to use effective contraception during treatment with ORSERDU and for one week after the last dose.

It is recommended that lactating women should not breast-feed during treatment with ORSERDU and one week after the last dose of ORSERDU.

Based on findings from animal studies and its mechanism of action, ORSERDU may impair fertility in females and males of reproductive potential.

Effects on ability to drive and use machines: Fatigue, asthenia, and insomnia have been reported in some patients taking ORSERDU. Caution should be observed by patients who experience those adverse reactions when driving or operating machinery.

The safety and efficacy of ORSERDU in children from birth to 18 years of age has not been established.

To report SUSPECTED ADVERSE REACTIONS: [email protected]
To Report a Product Complaint: [email protected]
To Request Medical Information: [email protected]

Elacestrant is also being investigated in several clinical trials in metastatic breast cancer disease, alone or in combination with other therapies: ELEVATE (NCT05563220); ELECTRA (NCT05386108); and ELCIN (NCT05596409). Elacestrant is also planned to be evaluated in early breast cancer disease.

The Menarini Group obtained global licensing rights for elacestrant in July 2020 from Radius Health, Inc. The Menarini Group is now fully responsible for global registration, commercialization, and further development activities for elacestrant.