On April 16, 2023 Accent Therapeutics, a biopharmaceutical company developing breakthrough, oncology-focused small molecule therapies that target RNA-modifying proteins (RMPs), reported data supporting DHX9 inhibition as a novel cancer treatment approach at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, Florida (Press release, Accent Therapeutics, APR 16, 2023, View Source [SID1234630133]).

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!

DHX9 is a multifunctional DEAH-box RNA helicase which has been reported to play important roles in replication, transcription, translation, and RNA splicing – critical processes that contribute to maintenance of genomic stability. Microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making the helicase an attractive target for oncology drug discovery.

"Accent is advancing the compelling and growing body of evidence linking RMPs to cancer pathobiology and demonstrating their untapped potential for addressing cancers with high unmet clinical need. Our systematic analysis of the RMP landscape has revealed several promising precision oncology targets, including DHX9. The data presented at AACR (Free AACR Whitepaper) illustrate strong proof-of-concept supporting DHX9 inhibition as a promising approach to addressing MSI tumors and validate the overall utility of RMPs as a compelling target class for oncology drug development," said Robert A. Copeland, Ph.D., President, Founder, and Chief Scientific Officer of Accent Therapeutics. "We are pleased with our rapid progress advancing from target identification to promising therapeutic programs and look forward to bringing these therapies closer to patients."

The data presented at the meeting provide compelling support for targeted inhibition of DHX9 as a novel therapeutic modality in MSI colorectal cancer (CRC) and describe the first identification of potent and selective small molecule inhibitors of DHX9 that demonstrate tumor cell killing in both in vitro and in vivo preclinical cancer models.

Informed by a proprietary crystal structure of human DHX9, Accent used structural considerations to design selective small molecule inhibitors of the protein and developed a robust assay suite to characterize inhibitor activity. Data from xenograft models demonstrate that oral administration of one such compound, ATX968, was well tolerated in vivo and induced durable tumor regression during the 28-day treatment period, with minimal tumor regrowth observed within a 28-day post treatment window. Dose dependent changes in biomarkers of DHX9 inhibition, such as circular RNA induction – which can be measured in peripheral blood, indicate a promising pharmacokinetic (PK)/pharmacodynamic (PD) profile and further validate DHX9 as a promising new oncology target.

"Our DHX9 program is one in a portfolio of high impact, RNA-modifying targets that Accent is pursuing with novel, oncology-focused small molecules," said Shakti Narayan, Ph.D., J.D., Chief Executive Officer of Accent. "This progress is a testament to our team’s ability to leverage deep insights into cancer biology and structure-based drug development to deliver new precision oncology therapies with transformative potential."

The abstract is available online as part of the annual meeting’s Proceedings supplement in AACR (Free AACR Whitepaper)’s journal, Cancer Research, and the presentation will be archived on the Accent Therapeutics website, www.accenttx.com.

Presentation details are as follows:

Title: Targeting DHX9 Inhibition as a Novel Therapeutic Modality in Microsatellite Instable Colorectal Cancer
Authors: Jennifer Castro, Matthew H. Daniels, Chuang Lu, David Brennan, Deepali Gotur, Young-Tae Lee, Kevin Knockenhauer, April Case, Jie Wu, Shane M. Buker, Julie Liu, Brian A. Sparling, E. Allen Sickmier, Stephen J. Blakemore, P. Ann Boriack-Sjodin, Kenneth W. Duncan, Scott Ribich, Robert A. Copeland
Accent Therapeutics, Lexington, MA
Abstract Number: 1136
Session Category: Experimental and Molecular Therapeutics
Session Title: Innovative Therapeutic Approaches
Session Date and Time: Sunday, April 16, 2023 3:00 – 5:00 PM ET
Session Location: Room W331, Orange County Convention Center, Orlando, Florida

About DHX9
DHX9 is a multifunctional DEAH-box RNA helicase which has been reported to play important roles in replication, transcription, translation, RNA splicing and RNA processing which contribute to DHX9’s role in maintenance of genomic stability. Overexpression of DHX9 has been observed in multiple cancer types, including colorectal cancer (CRC). In addition, microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery.

On April 16, 2023 Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) reported successful preclinical development of radiolabelled olaratumab, an antibody licensed from Eli Lilly and Company (Lilly) (Press release, Telix Pharmaceuticals, APR 16, 2023, View Source [SID1234630132]). Telix has demonstrated proof-of-concept (PoC) of using olaratumab to selectively deliver both diagnostic and therapeutic radiation to tumours as a radiopharmaceutical moiety and has produced a candidate for clinical translation. Telix will now progress to first-in-human clinical studies based on these highly encouraging results.

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!

In April 2022, Telix secured the exclusive worldwide rights to develop and commercialise radiolabelled forms of olaratumab for the diagnosis and treatment of human cancers.[1] Olaratumab was originally developed as a naked (non-radiolabelled) monoclonal antibody targeting Platelet Derived Growth Factor Receptor Alpha (PDGFRα), a target expressed in multiple tumour types. Olaratumab has a well-established clinical safety profile, a favourable toxicology dataset and advanced manufacturing package in relation to Lilly’s development program, which Telix expects to be able to leverage for future development as a radiopharmaceutical drug product.

Telix’s initial development PoC has focused on a rare type of cancer known as Soft Tissue Sarcoma (STS). External beam radiation is a key part of the standard of care for STS, which may therefore be a suitable clinical target for novel radionuclide therapy, particularly for alpha-emitting radionuclides. The ability of olaratumab to target PDGFRα in the STS tumour microenvironment makes it a highly novel and high-potential radiopharmaceutical candidate.

Telix has now completed its preclinical evaluation, with results sufficiently encouraging to advance development toward initial human clinical trials, in line with planned R&D expenditure for 2023/24. The agent has been assigned formal candidate status in Telix’s development pipeline (to be denoted as TLX300-CDx/TLX300 for the diagnostic/patient selection tool and therapeutic, respectively). Specifically, these studies have shown that olaratumab can be bioconjugated with multiple chelators (including Telix’s proprietary DFO-squaramide chelator), radiolabelled with zirconium-89 (89Zr) for imaging by Positron Emission Tomography (PET) and used to demonstrate specific delivery of radiation to STS cancer cells to show proof of concept in xenograft tumour mouse models. Furthermore, olaratumab radiolabelled with therapeutic radionuclide payloads has demonstrated in vivo efficacy with significant reduction in tumour volumes in relevant disease models, even after administration of a single dose. The Company is preparing to publish preliminary findings.

Telix Chief Scientist, Dr Michael Wheatcroft stated, "Building on Telix’s proven track record in acquiring and developing novel radiopharmaceutical assets, it is extremely pleasing to demonstrate the adaptation of this traditional biologic agent for future potential use as a targeted radiopharmaceutical. TLX300 will initially be evaluated in a first-in-human clinical study that is designed to inform both the potential efficacy (dosimetry) and safety profile of this research candidate as a therapeutic, demonstrating the development advantage of a theranostic approach."

About Soft Tissue Sarcoma (STS)

Soft tissue sarcoma is a complex disease that encompasses a diverse group of relatively rare cancers, with more than 50 histological subtypes. In the United States (U.S.), it is estimated that 13,040 new cases and 5,150 deaths were caused by STS in 2019, representing 0.75% of overall cancer incidence and 0.84% of overall cancer mortality.[2] In Europe, nearly 23,600 new STS cases rose annually, and the crude incidence rate was 4.7 per 100,000.[3] Approximately 39,900 new STS cases occurred nationwide in China in 2019, accounting for 1.05% of overall cancer incidence.[4] The crude incidence rate was 2.91/100,000 and generally increased with age. Standard treatment for soft tissue sarcoma includes surgery, radiation therapy and/or chemotherapy. For patients with advanced, unresectable, or metastatic disease, treatment typically involves chemotherapy with single agents (e.g., doxorubicin) or anthracycline-based combination regimens. However, the prognosis for these patients remains poor, with treated patients with metastatic disease having a median overall survival of around 12–18 months.[5]

About olaratumab

Olaratumab (previously marketed under the brand name, Lartruvo) was originally developed as a monoclonal antibody targeting PDGFRα. Olaratumab was granted "Accelerated Approval" in the U.S. and "Conditional Approval" in the EU based on Phase II trial data which showed a 1-year survival benefit in patients with STS, when given in combination with standard chemotherapy. Olaratumab was voluntarily withdrawn from the market by Lilly following the failure of the Phase III ANNOUNCE clinical trial, in which olaratumab did not improve survival for patients.

On April 16, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that the final analysis results of ORIENT-15, the Phase 3 study evaluating sintilimab in combination with chemotherapy for the first-line treatment of esophageal squamous cell carcinoma (ESCC) were released in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Abstract CT075) (Press release, Innovent Biologics, APR 16, 2023, View Source [SID1234630131]).

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!

As of data cutoff date (August 28, 2022), a total of 690 patients were randomly assigned and received treatment, and the median follow-up was 32.2 months.

Sintilimab plus chemotherapy significantly improved the median overall survival (mOS) over placebo plus chemotherapy with a 33.9% reduction in risk of death (HR 0.661; P<0.0001) and a 4.6-month improvement in mOS (17.4 vs 12.8 months) in all randomized patients (the ITT population); and 36.5% reduction in risk of death (HR 0.635; P=0.0001) and a 3.9-month improvement in mOS (18.4 vs 14.5 months) in PD-L1 positive patients (defined as combined positive score [CPS] ≥10).

Estimated OS rates at 12 and 24 months for sintilimab plus chemotherapy versus chemotherapy alone in all randomized patients were 64.0% vs 53.5% and 41.4% vs 22.9%, respectively.

The safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy with approximate 16 months of extended follow-up.

The principal investigator of the ORIENT-15 study, Prof. Shen Lin from Peking University Cancer Hospital and Institute, stated, "More than half of new and fatal cases of esophageal cancer in the world occur in China every year. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, and squamous cell carcinoma is the predominant histologic type[i]. The interim analysis of ORIENT-15 met all endpoints, and sintilimab in combination with chemotherapy has been approved by the NMPA to be a first-line treatment option for patients with advanced ESCC. In addition, this new indication of sintilimab has been included in the updated China National Reimbursement Drug List (NRDL), benefiting broader patient groups. In this final analysis, sintilimab in combination with chemotherapy demonstrated continued significant OS benefits, further supporting the use of sintilimab plus chemotherapy as a standard of care for first-line treatment in these patients."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "The approval of immunotherapy has significantly improved the clinical benefits of standard treatments in patients with advanced esophageal squamous cell carcinoma. According to the results of interim analysis, sintilimab plus chemotherapy has been approved by NMPA. We are also pleased that this indication of sintilimab has been included in the NRDL, making sintilimab the only PD-1 inhibitor for the first-line treatment of five high-incidence cancer types included in the NRDL. In this final analysis, the continued significant OS benefits have been verified in advanced ESCC patients with an acceptable safety profile over time, and further demonstrated that sintilimab as a first-line treatment option will benefit ESCC patients in China."

About the ORIENT-15 Study

ORIENT-15 is a global randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab in combination with chemotherapy, compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ClinicalTrials.gov, NCT03748134). At the time of interim analysis, a total of 659 eligible patients (of the planned 676 estimated participants) were enrolled and randomly assigned into the experimental group or control group in a 1:1 ratio. The primary endpoints were overall survival (OS) in all randomized patients and OS in PD-L1 positive (defined as CPS ≥10) patients[ii].

About Esophageal Squamous Cell Carcinoma (ESCC)

Esophageal cancer (EC) is one of the most common malignant tumors worldwide that begins in the inner layer (mucosa) of the esophagus, which connects the throat to the stomach. Based on GLOBOCAN 2020 estimates, approximately 600,000 new cases of esophageal cancer are diagnosed and approximately 540,000 deaths result from the disease worldwide each year[iii]. Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwideiii. More than half of new and fatal cases of esophageal cancer in the world occur in Chinai. In China, it is estimated there were approximately 320,000 new cases of esophageal cancer diagnosed and approximately 300,000 deaths resulting from the disease in 2020i. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, where it has a five-year survival rate of only 30%i.

The two main types of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. In China, SCC is the predominant histologic type, accounting for more than 90% of all esophageal cancer[iv]. In the past, first-line standard systemic therapy was chemotherapy based on platinum drugs for unresectable locally advanced, recurrent or metastatic ESCC, which calls for more effective first-line treatment options. Several PD-1 inhibitors have been approved as first-line treatment in combination with chemotherapy[v]，[vi].

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody co-developed by Innovent and Eli Lilly and Company. 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[vii]. 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, sintilimab has been approved and included in the National Reimbursement Drug List (NRDL) for all six indications. The updated NRDL reimbursement scope of TYVYT (sintilimab injection) include:

For the treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma;
For the treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma;
For the treatment of unresectable locally advanced or metastatic non-squamous non-small cell lung cancer lacking EGFR or ALK driver gene mutations;
For the treatment of unresectable locally advanced or metastatic squamous non-small cell lung cancer;
For the treatment of unresectable or metastatic hepatocellular carcinoma with no prior systematic treatment;
For the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy.
Innovent currently has the regulatory submission for sintilimab in combination with bevacizumab biosimilar and chemotherapy for EGFR-TKI failed EGFR-mutated non-squamous NSCLC under review in the China’s NMPA.

Additionally, two clinical studies of sintilimab have met their primary endpoints:

Phase 2 study of sintilimab monotherapy as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study of sintilimab monotherapy as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.

On April 16, 2023 Abbisko (Stock Code: 2256.HK) reported the results of five latest preclinical studies at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting (Press release, Abbisko Therapeutics, APR 16, 2023, View Source [SID1234630130]).

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!

These include its self-developed CSF-1R inhibitor Pimicotinib (ABSK021), which has been recognized as a breakthrough therapy in China and the United States, and ABSK112, a next-generation of EGFR Exon20 inhibitor that may become the best-in-class to overcome resistance mutations, and a next-generation of the latest preclinical and translational research progress of the FGFR4 inhibitor ABSK012 and FGFR inhibitor ABSK121 that overcome drug-resistant mutations, and the next-generation KRAS inhibitor ABSK071.

Abbisko presented the following posters at the AACR (Free AACR Whitepaper) Annual Meeting:

Medicine

Title

Abstract Number

ABSK021

A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma

LB329

ABSK112

Discovery and characterization of ABSK112, a next-generation and potential best-in-class EGFR Exon20 mutant inhibitor with superior selectivity and brain penetration ability

LB327

ABSK012

Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations

LB328

ABSK121

Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations

LB317

ABSK071

A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models

LB316

Title: A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma
Abstract Number: LB329
Research Background：
Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgery combined with multimodal chemotherapy remains as the standard treatment for osteosarcoma patients. However, patients with osteosarcoma metastasis have a five-year survival rate of less than 30%, and their long-term outcomes have not improved over the last 30 years, representing a high unmet medical need. CSF-1/CSF-1R signaling is crucial for the survival, function, proliferation and differentiation of myeloid lineage cells, including osteoclasts and monocytes/macrophages. Targeting CSF-1R either on tumor cells or tumor-associated macrophages has been reported to limit osteosarcoma progression in preclinical models. ABSK021, an oral, highly potent and selective small molecule inhibitor of CSF-1R, showed significant anti-tumor activity and favorable safety profile in patients with advanced tenosynovial giant cell tumor in phase 1b trial. We demonstrated the treatment potential of ABSK021 for osteosarcoma patients through a series of preclinical in vitro and in vivo experiments, as well as human osteosarcoma profiling.
Result：
ABSK021 has strong inhibition of CSF-1R activity and corresponding anti-tumor activity in preclinical osteosarcoma models. High prevalence of CSF-1R expression was also found in osteosarcoma patients, suggesting great potential of utilizing ABSK021 as a novel therapy to treat osteosarcoma patients in clinic.

Title: ABSK112, a potential best-in-class EGFR exon 20 mutant Inhibitor with excellent selectivity and brain penetration
Abstract Number: LB327
Research Background：
EGFR Exon20 mutations are clinically validated oncogenic alterations including a wide spectrum of mutations occurring in lung cancer and various other cancer types. Although several EGFR Exon20 inhibitors have reached clinical stage or received approval, there still leave large room for improvement in safety and efficacy, likely due to their limited selectivity against wild-type EGFR or other kinases, suboptimal mutation coverage, and lack brain penetrating ability. Herein, we have discovered a novel and next-generation EGFR Exon20 mutation inhibitor, ABSK112. It showed high selectivity over wild-type EGFR and other kinases, as well as a more comprehensive coverage over majority of EGFR Exon20 mutations in comparison with other EGFR Exon20 inhibitors.
Result：
ABSK112 is a leading next-generation EGFR Exon20ins inhibitor with improved selectivity over wild-type EGFR and strong brain penetrating ability. It shows superior in vivo efficacy in various EGFR Exon20ins xenograft models, and broader spectrum of mutation coverage than clinical stage competitors.

Title: Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations
Abstract Number: LB328
Research Background：
Aberrant activation of FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of Hepatocellular carcinoma (HCC) and FGFR4 inhibitors have shown preliminary efficacy in recent clinical trials for patients with FGF19 overexpression. However, the observed responses only lasted a few months before tumors relapse. Acquired FGFR4 resistant mutations were found in ~30% of FGFR4 inhibitor responsive patients. Similar FGFR4 mutations haven also been found de novo in about 7-10% of Rhabdomyosarcoma (RMS) and ER-treated invasive lobular carcinoma patients. First generation FGFR4 inhibitors have minimal activity against these de novo or acquired resistant mutations. Therefore, next-generation of FGFR4 inhibitors are needed to overcome these resistant FGFR4 mutations to provide better treatment options for patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a next-generation small molecule FGFR4 inhibitor, ABSK012, and demonstrated its strong activities against de novo and acquired resistant FGFR4 mutations while retaining inhibition for wild-type FGFR4.
Result：
ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic.

Title: Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations
Abstract Number: LB317
Research Background：
FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations.
Result：
ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development.

Title: A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models
Abstract Number: LB316
Research Background：
KRAS is frequently mutated in human cancers, including pancreatic (~90%), colorectal (~35%), and lung cancer (~25%). The KRASG12C mutation (single amino acid substitution of cysteine for glycine at position 12) accounts for ~14% of lung cancer, ~4% of colorectal cancer, and ~2% of pancreatic cancer. Currently, two covalent KRASG12C inhibitors, namely sotorasib (AMG-510) and adagrasib (MRTX-849), have been approved as monotherapy to treat locally advanced or metastatic NSCLC with KRASG12C mutation through accelerated approval process.
Despite the beneficial effects of KRASG12C inhibitors in clinic for certain patients, the limited antitumor efficacy in most patients and potential drug resistance are major concerns. A next-generation inhibitor with better inhibitory activity may improve anti-tumor efficacy. Combination with other therapeutic agents may also improve the single-agent activity of KRASG12C inhibitors. These approaches could both overcome the limitations of sotorasib and adagrasib and provide additional benefits to patients.
Result：
ABSK071 is a next-generation KRASG12C inhibitor with greater activity and anti-tumor efficacy in vitro and in vivo. It also demonstrated broad synergistic effects with a large set of targeted agents and immuno-oncology agents, indicating its strong potential in combinatory therapy in treating a wider range of KRASG12C-dependent cancers.

On April 16, 2023 MorphoSys U.S. Inc., a fully owned subsidiary of MorphoSys AG (FSE: MOR; NASDAQ: MOR), and Incyte (Nasdaq: INCY) reported final five-year follow-up data from the Phase 2 L-MIND study showing that Monjuvi (tafasitamab-cxix) plus lenalidomide followed by Monjuvi monotherapy provided prolonged, durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (Press release, MorphoSys, APR 16, 2023, View Source [SID1234630127]). These data were featured as a late-breaking oral presentation (Abstract # CT022) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, Florida.

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!

"Five-year data demonstrating durability of response is meaningful for oncologists as they consider the most appropriate treatment option for a patient," said Johannes Duell, M.D., University Hospital Würzburg Medical Clinic and Polyclinic. "The prolonged and durable responses seen at five years among relapsed or refractory DLBCL patients in the L-MIND study show that the Monjuvi treatment regimen may have curative potential, which I look forward to seeing explored in future studies."

At the data cut-off (Nov. 14, 2022) for the full analysis set (80 patients), the overall response rate (ORR) was 57.5% (95% CI = 45.9, 68.5), and a complete response (CR) was observed in 41.2% of patients (95% CI = 30.4, 51.6; n = 33). A partial response (PR) was observed in 16.2% of patients (95% CI = 8.9, 26.2; n =13). Additional results include:

Median duration of response was not reached after a median follow up of 44.0 months (95% CI = 29.9, 57.0).
The median overall survival was 33.5 months (95% CI = 18.3, NR) and median progression-free survival was 11.6 months (95% CI = 5.7, 45.7).
Of the 21 patients with >60 months of follow-up, 14 had received one prior line of therapy (pLoT), and seven patients had received ≥2 pLoT.
Patients with one pLoT (n = 40) had a higher ORR of 67.5% (CR = 52.5% and PR = 15%) compared to 47.5% of patients with two or more pLoT (n = 40; CR = 30% and PR = 17.5%)
No new safety signals were identified. The majority of adverse events (AEs) were grade 1 or grade 2 during both combination and monotherapy treatment. Patients experienced a lower frequency of all-grade and grade 3 or higher adverse events during monotherapy. The most common adverse events with combination therapy were neutropenia (incidence per person per year, all-grade/grade ≥3: 3.79/2.09) and thrombocytopenia (1.52/0.52), which declined after patients switched to monotherapy (all-grade/grade ≥3: 1.09/0.70 and 0.17/0.06, respectively, in the first two years of monotherapy). Neutropenia and diarrhea were the most common adverse events in the first two years of monotherapy.

"The totality of the long-term L-MIND data presented at AACR (Free AACR Whitepaper) further reinforce our confidence that the Monjuvi plus lenalidomide combination remains the in-practice, outpatient, targeted immunotherapy option that can provide sustained remissions for patients with relapsed or refractory DLBCL who are not eligible for autologous stem cell transplant," said Tim Demuth, M.D., Ph.D., Chief Research and Development Officer, MorphoSys. "The durable responses and consistent safety profile observed in the five-year analysis are encouraging and further support the use of the Monjuvi regimen as a potentially curative option for appropriate patients."

"The new five-year L-MIND data build on prior analyses that detail the potential for Monjuvi plus lenalidomide to provide long-term, meaningful responses for certain patients with relapsed or refractory DLBCL, a historically difficult-to-treat form of the disease," said Steven Stein, M.D., Chief Medical Officer, Incyte. "We look forward to continuing to explore the potential of Monjuvi to help patients with newly diagnosed DLBCL, as well as other CD19-expressing lymphomas."

In July 2020, the U.S. Food and Drug Administration (FDA) approved Monjuvi in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for ASCT. This indication is approved under accelerated approval based on ORR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). The U.S. approval is based on an efficacy subgroup of 71 patients confirmed by central lab. The FDA decision represented the first approval of a second-line treatment for adult patients with DLBCL who progressed during or after first-line therapy. Monjuvi, in combination with lenalidomide, was granted accelerated approval based on the one-year primary analysis of the L-MIND study. The data for the five-year analysis of the L-MIND study have not yet been submitted to, or reviewed by, the FDA.

About Diffuse Large B-cell Lymphoma (DLBCL)

DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide1, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about 40% of patients not responding to initial therapy or relapsing thereafter2, leading to a high medical need for new, effective therapies2, especially for patients who are not eligible for an autologous stem cell transplant in this setting.

About L-MIND

The L-MIND trial was a single arm, open-label Phase 2 study (NCT02399085) investigating the combination of tafasitamab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma who had at least one, but no more than three, prior lines of therapy, including an anti-CD20 targeting therapy (e.g., rituximab), who were not eligible for high-dose chemotherapy or refused subsequent autologous stem cell transplant. The study’s primary endpoint was overall response rate. Secondary outcome measures included duration of response, progression-free survival and overall survival. In May 2019, the study reached its primary completion. For more information about L-MIND, visit View Source

About Monjuvi (tafasitamab-cxix)

Tafasitamab is a humanized Fc-modified CD19 targeting immunotherapy. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the United States, Monjuvi (tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi (tafasitamab) received conditional marketing authorization in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Monjuvi and Minjuvi are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi in the U.S., and marketed by Incyte under the brand name Minjuvi in Europe and Canada.

XmAb is a registered trademark of Xencor, Inc.

Important Safety Information

What are the possible side effects of MONJUVI?

MONJUVI may cause serious side effects, including:

Infusion-related reactions. Your healthcare provider will monitor you for infusion reactions during your infusion of MONJUVI. Tell your healthcare provider right away if you get fever, chills, rash, flushing, headache, or shortness of breath during an infusion of MONJUVI.
Low blood cell counts (platelets, red blood cells, and white blood cells). Low blood cell counts are common with MONJUVI, but can also be serious or severe. Your healthcare provider will monitor your blood counts during treatment with MONJUVI. Tell your healthcare provider right away if you get a fever of 100.4°F (38°C) or above, or any bruising or bleeding.
Infections. Serious infections, including infections that can cause death, have happened in people during treatments with MONJUVI and after the last dose. Tell your healthcare provider right away if you get a fever of 100.4°F (38°C) or above, or develop any signs and symptoms of an infection
The most common side effects of MONJUVI include:

Feeling tired or weak
Diarrhea
Cough
Fever
Swelling of lower legs or hands
Respiratory tract infection
Decreased appetite
These are not all the possible side effects of MONJUVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Before you receive MONJUVI, tell your healthcare provider about all your medical conditions, including if you:

Have an active infection or have had one recently.
Are pregnant or plan to become pregnant. MONJUVI may harm your unborn baby. You should not become pregnant during treatment with MONJUVI. Do not receive treatment with MONJUVI in combination with lenalidomide if you are pregnant because lenalidomide can cause birth defects and death of your unborn baby.
You should use an effective method of birth control (contraception) during treatment and for at least 3 months after your final dose of MONJUVI.
Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with MONJUVI.
Are breastfeeding or plan to breastfeed. It is not known if MONJUVI passes into your breastmilk. Do not breastfeed during treatment for at least 3 months after your last dose of MONJUVI.
You should also read the lenalidomide Medication Guide for important information about pregnancy, contraception, and blood and sperm donation.

Tell your healthcare provider about all the medications you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Please see the full Prescribing Information for Monjuvi, including Patient Information, for additional Important Safety Information.