On December 11, 2023 Alphamab Oncology (stock code: 9966.HK) reported that the independently developed global first subcutaneous injection HER2 bispecific antibody-conjugated drug (JSKN033) has received approval from the Australian Bellberry Clinical Research Ethics Committee to conduct clinical studies (JSKN033-101) for the treatment of HER2-expressing advanced or metastatic solid tumors.

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!

JSKN033-101 is an open-label, muticenter, phase I/II clinical study. The study consists of dose escalation and dose expansion phases: The Phase I dose escalation stage aims to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of JSKN033 in patients with advanced or metastatic HER2-expressing solid tumors, determining the maximum tolerated dose (MTD) and/or Phase II recommended dose (RP2D); the Phase II dose expansion stage will evaluate the efficacy and safety of JSKN033 in HER2-expressing gastrointestinal tumors at the RP2D dose.

JSKN033 is a subcutaneous injection compound consisting of JSKN003 and envafolimab, independently developed by Alphamab. JSKN033 is expected to provide effective innovative therapy for patients and doctors through IO and ADC combo and have better safety profile and convenience due to the nature of SubC injectables.

About JSKN033

JSKN033 is the global first subcutaneous injection HER2 bispecific antibody-conjugated drug developed by Alphamab, which is composed of JSKN003 and envafolimab. JSKN003 is a HER2 dual-epitope-targeting antibody-conjugated drug composed of three parts: bispecific antibodies targeting two non-overlapping epitopes of the HER2 extracellular domain, a cleavable linker, and a topoisomerase I inhibitor. Envafolimab is a Fc fusion protein consisting of humanized anti-PD-L1 single domain antibody and human IgG1 Fc fragment, which has been approved by China NMPA as the global first subcutaneously administered PD-L1 inhibitor and marketed in China.

(Press release, Alphamab, DEC 11, 2023, View Source [SID1234657029])

On December 11, 2023 Genor Biopharma (Stock code: 6998.HK) reported the company participated at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting held in San Diego, USA on December 9-12, 2023, and shared the poster of the preliminary clinical safety and efficacy results of the phase I/II study of GB261(CD20/CD3) (Press release, Genor Biopharma, DEC 11, 2023, View Source [SID1234656303]).

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!

GB261, an Fc-Function Enabled and CD3 Affinity De-Tuned CD20/CD3 Bispecifc Antibody, Demonstrated a Highly Advantageous Safety/Efficacy Balance in an Ongoing First-in-Human Dose-Escalation Study in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (Poster Number: 1719)

Introduction:
GB261 is a novel and highly differentiated CD20/CD3 bispecific T cell engager antibody computationally designed to maintain Fc effector function, i.e., antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to broaden the mechanisms of action (MOA) for tumor cell killing. Furthermore, the "imbalanced" design of GB261 integrates de-tuned CD3 binding to reduce CRS incidence and improve safety features of the Fc effector function. Extensive pre-clinical studies have shown that GB261 has a highly advantageous safety/efficacy balance. Here, we present the preliminary clinical safety and efficacy results of an ongoing phase I/II study for GB261 (NCT04923048).

Methods:
This is an open-label, multicenter (China and Australia), dose escalation/expansion phase 1/2 study of GB261 to evaluate the safety, tolerability and efficacy in patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma(B-NHL) and Chronic Lymphocytic Leukemia (CLL). Adult patients were eligible when they have CD20+ r/r B-NHL or CLL with no available standard of care treatments, adequate organ function, and no CNS involvement or other CNS disease, infections or other active/serious medical issues that may affect compliance or interpretation of results. GB261 was administered in 21-day cycles, weekly (QW) for the first 6 doses followed by every 3 weeks (Q3W) until disease progression, or other situation defined in protocol. Response assessment was based on Lugano 2014 and LYRIC 2016 criteria.

Results:
As of June 17, 2023, 47 r/r B-NHL patients (DLBCL:76.6%; FL:23.4%) were enrolled at flat or step-up doses of GB261 ranging from 1mg to 300mg. Median age was 60.0 years (range: 28, 81), 55.3% of patients were male. Median prior lines of therapy were 3 (range: 1, 10). 78.7% of patients were refractory to any anti-CD20 therapy, 70.2% refractory to their last systemic therapy. Median time since last prior therapy to first study treatment was 1.9 months.

In efficacy evaluable patients (n=22) from 3mg to 100mg, with at least 75% dose exposure before the first radiographic assessment, the median duration of study follow-up was 4.5 months (95%CI: 4.0, 7.4). The overall response rate (ORR) was 73% (16/22), and complete response rate (CRR) was 45.5% (10/22). ORR and CRR were 100% and 100% in 3mg, 56% and 22% in 10mg, 67% and 33% in 30mg. At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient). Median time to response (TTR) was 1.3 months (95%CI: 1.2, 1.5), the same as median time to CR. Median duration of response (DOR) was not reached.

In safety evaluable patients (n=47), the median duration of study follow-up was 4.1 months (95%CI: 2.9, 5.3). Treatment-emergent adverse events (TEAEs) were 95.7%, treatment-related adverse events were 85.1%. The most common TEAEs were COVID-19 infection (40.4%; grade 1 or 2: 27.6%; grade >=3: 12.8%) and neutropenia (31.9%; grade 1or 2: 14.9%; grade >=3: 17.0%). AE related treatment discontinuation and death were reported in 2 patients, which were all due to COVID-19 pneumonia. CRS occurred in 12.8% (6/47) patients, was mild and transient. CRS in 100mg were 14.3% (2/14). All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab. The median duration of CRS was 7 hours. No ICANS were reported.

The PK profile of GB261 appeared to be linear across dose ranges tested (1mg -100mg). Effective half-life appeared to be 2-3 weeks which supports every 3-4 weeks dosing.

Conclusion:
GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. At the 100mg dose level, 80% of patients achieved CR and with favorable safety. Additionally, clinical benefit seen in other CD20/CD3 bispecific antibody failed patients provides clinical support to the unique and differentiated MOA of GB261.

On December 11, 2023 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported that the United States Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to naporafenib in combination with trametinib (MEKINIST) for the treatment of adult patients with unresectable or metastatic melanoma who have progressed on, or are intolerant to, an anti‑programmed death-1 (ligand 1) (PD‑(L)1)-based regimen, and whose tumors contain an NRAS mutation (NRASm) (Press release, Erasca, DEC 11, 2023, View Source [SID1234639350]). Naporafenib is an orally available, Phase 3-ready pan-RAF inhibitor with a potential first-in-class and best-in-class profile in NRASm melanoma and other RAS/MAPK pathway-altered solid tumors.

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!

FTD is designed to help drugs reach patients faster by facilitating the development and expediting the review of drugs with the potential to fill an unmet medical need by treating a serious or life-threatening condition. Programs that receive FTD benefit from early and frequent interactions with the FDA during the clinical development process and, if relevant criteria are met, the FDA may consider reviewing portions of a marketing application before the sponsor submits the complete application.

"The outcomes for patients with NRASm melanoma after frontline immunotherapy (IO) treatment are dismal with low response rates and short median progression free survival (mPFS). By contrast, as previously presented by Novartis at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 and as published in March 2023 by de Braud et al. in the Journal of Clinical Oncology, naporafenib in combination with trametinib has demonstrated strong and durable anti-tumor activity," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "We are now rapidly advancing clinical development of naporafenib in combination with trametinib in the post-IO setting in patients with NRASm melanoma with initiation of our pivotal Phase 3 SEACRAFT-2 trial expected in the first half of 2024. Receiving FTD further strengthens our ability to work closely with the FDA toward our goal of bringing this new therapy for difficult-to-treat melanoma to patients as soon as possible."

NRASm melanoma comprises 20-30% of all melanomas and is associated with a worse prognosis compared to other alterations. Effective treatment options are needed for patients following progression on frontline IO with anti-CTLA-4 and/or anti-PD-(L)1 antibodies. Currently, chemotherapy is the approved post-IO standard of care with a 7% objective response rate (ORR) and 1.5 months mPFS (historical Phase 3 data generated when the drug was administered in the front-line/second-line setting). While not approved in this indication in the United States, the MEK inhibitor binimetinib is used off label and demonstrated a 15% ORR and 2.8 months mPFS (historical Phase 3 data generated when the drug was administered in the front-line/second-line setting). There are currently no approved therapies that target NRAS mutations. Erasca recently reported that End of Phase 2 meetings with the FDA and European health authorities confirmed the SEACRAFT-2 Phase 3 trial design and provided clarity on the registrational pathway.

About SEACRAFT-2
SEACRAFT-2 is a randomized, pivotal Phase 3 trial that will evaluate the clinical efficacy of naporafenib in combination with trametinib (MEKINIST) compared to physician’s choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy) in the post-immunotherapy setting in patients with NRAS-mutated metastatic melanoma. Initiation of the SEACRAFT-2 trial is expected in H1 2024.

About Naporafenib
Naporafenib (formerly LXH254) is a potent and selective pan-RAF inhibitor, with a potential first-in-class and best-in-class profile. Naporafenib has been dosed in over 500 patients to date, whereby safety, tolerability, pharmacokinetics, and pharmacodynamics have been established in both monotherapy and select combinations. Clinical proof-of-concept (PoC) has been established for the combination with trametinib for patients with NRAS-mutant (NRASm) melanoma, which includes NRAS Q61X melanoma, and preliminary clinical PoC has been established for the combination with trametinib for patients with RAS Q61X in non-small cell lung cancer (NSCLC). Erasca plans to focus initially on advancing and securing regulatory approval for naporafenib plus trametinib in NRASm melanoma as part of the planned pivotal Phase 3 SEACRAFT-2 trial and in RAS Q61X tissue agnostic solid tumors as part of the Phase 1b SEACRAFT-1 trial, respectively. Erasca is also exploring additional combinations of naporafenib with other proprietary therapeutic agents in our pipeline. Naporafenib has received FDA Fast Track Designation for patients with advanced NRASm melanoma.

On December 11, 2023 Kirilys Therapeutics, Inc., a multi-asset biotechnology company founded by investment firm Catalys Pacific and supported by Lightspeed Venture Partners, reported to present a detailed preclinical profile for KRLS-017 at AACR (Free AACR Whitepaper) 2024 in San Diego, CA (Press release, Kirilys Therapeutics, DEC 11, 2023, View Source [SID1234638566]).

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!

KRLS-017 is a potent, selective, and reversible inhibitor of Cyclin Dependent Kinase 7 (CDK7) and is being developed for the treatment of patients with advanced solid tumor malignancies. CDK7 function in control of both cell cycle and gene transcription, and overexpression of CDK7 is a poor prognostic indicator in breast, ovarian, gastric, and other tumor types.

The preclinical presentation titled "Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies" will include pharmacology, toxicology, and efficacy across several dosing schedules using in vivo tumor models. A Phase 1 clinical program for KRLS-017 is planned as a monotherapy dose escalation study in refractory solid tumors followed by an indication-specific cohort expansion that will include breast, ovarian and potentially other transcriptionally active tumor types to evaluate anti-tumor activity.

On December 11, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported that results of its two Phase 2 Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) studies were published in Annals of Oncology, the peer-reviewed journal of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) and the Japanese Society of Medical Oncology (Press release, Sermonix Pharmaceuticals, DEC 11, 2023, View Source [SID1234638500]).

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 articles, published online and with open access in the December edition of the journal, are as follows:

Lasofoxifene versus fulvestrant for ER+/HER2- advanced breast cancer with an ESR1 mutation: Results from the randomized, phase 2 ELAINE 1 trial
Open-label, phase 2, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after progression on prior therapies: ELAINE 2
"These Phase 2 ELAINE studies ideally position Sermonix for the initiated global registrational ELAINE-3, Phase 3 study comparing lasofoxifene in combination with abemaciclib versus fulvestrant plus abemaciclib," said Dr. David Portman, Sermonix founder and chief executive officer. "We are excited to share the results of our recent studies in this prestigious journal and to continue our path toward potential approval and commercial development of our novel targeted endocrine therapy."

Top-line data for ELAINE-1, a study of postmenopausal women with locally advanced or metastatic estrogen receptor-positive (ER+)/HER2- breast cancer with an ESR1 mutation, were shared as an oral presentation at the 2022 ESMO (Free ESMO Whitepaper) Congress. The study demonstrated that lasofoxifene, a novel targeted and tissue-selective oral endocrine therapy that acts as an ER antagonist at the breast, numerically prolonged median progression-free survival (PFS) compared with fulvestrant (5.6 months vs. 3.7 months; P=0.138) in metastatic breast cancer patients with ESR1 mutations who had progressed taking a prior aromatase inhibitor (AI) and CDK4/6i, with a favorable safety profile. Also, 30.7% of patients on lasofoxifene achieved a PFS of 12 months compared to 14.1% on fulvestrant.

ELAINE-1 also demonstrated an objective response rate (ORR) of 13.3% for lasofoxifene compared to 2.9% for fulvestrant (P=0.124), and saw on lasofoxifene the first-ever known finding of a durable complete response – ongoing at 2.5 years – that could be characterized as complete clinical remission in a metastatic ER+/HER2- breast cancer patient with an ESR1 mutation after prior CDK4/6 inhibitor treatment and subsequent treatment with a single-agent hormonal therapy.

An exploratory ELAINE-1 analysis, shared in March 2023 at the International Society for the Study of Women’s Sexual Health (ISSWSH) Annual Meeting, found in patients presenting at baseline with moderate to severe vaginal and vulvar dryness/pain on a validated measurement scale that lasofoxifene numerically improved these symptoms compared to fulvestrant.

ELAINE-2 (NCT04432454), an open-label study of lasofoxifene in combination with Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib, evaluated 29 heavily pre-treated women with ER+/HER2- locally advanced or metastatic breast cancer and an ESR1 mutation. Results were initially shared at a poster discussion session during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and updated in June at ASCO (Free ASCO Whitepaper) 2023.

The primary endpoint for ELAINE-2 was safety/tolerability, with secondary endpoints including PFS and ORR. With patient follow-up through Jan. 31, 2023, the combination of lasofoxifene and abemaciclib continued to be well-tolerated, with clinically meaningful efficacy in women with ER+/HER2- metastatic breast cancer and an ESR1 mutation. The PFS, a median of 13 months, and ORR of 56% were promising.

"Lasofoxifene has demonstrated compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations, and potential benefit on quality of life with respect to vaginal and sexual health," said Paul Plourde, M.D., vice president of oncology clinical development for Sermonix. "We look forward to the results of ELAINE-3, and a greater understanding of lasofoxifene’s potential."

An accompanying invited (closed-access) editorial by Dr. Seth Wander of Massachusetts General Hospital addresses the context of these two seminal trials in the current and future treatment landscape of ER+/HER2- advanced breast cancer.

Annals of Oncology provides rapid and efficient peer-review publications on innovative cancer treatments or translational work related to oncology and precision medicine.

To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit SermonixPharma.com. To learn more about the ELAINE studies, visit elainestudy.com.

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.