On December 09, 2024 Daiichi Sankyo reported Datopotamab deruxtecan (Dato-DXd) has been granted Breakthrough Therapy Designation (BTD) in the U.S. for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFR-mutated) non-small cell lung cancer (NSCLC) with disease progression on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (Press release, Daiichi Sankyo, DEC 9, 2024, View Source [SID1234648963]).

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Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

The U.S. Food and Drug Administration (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat serious conditions and address significant unmet medical needs. The medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

The FDA granted this BTD based on data from the TROPION-Lung05 phase 2 trial with supporting data from the TROPION-Lung01 phase 3 trial. Results from a pooled analysis of patients with previously treated EGFR-mutated NSCLC in these studies were presented this month at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia 2024 Congress. This is the first BTD for datopotamab deruxtecan and the twelfth BTD across Daiichi Sankyo’s oncology pipeline.

"The Breakthrough Therapy Designation granted by the FDA underscores the significant unmet need for new treatments for patients with previously treated EGFR-mutated non-small cell lung cancer who have experienced disease progression," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Datopotamab deruxtecan has the potential to play an important role in improving outcomes and we look forward to working closely with the FDA to bring this medicine to patients as quickly as possible."

"This Breakthrough Therapy Designation reinforces datopotamab deruxtecan as a promising potential therapy for patients with EGFR-mutated lung cancer who continue to face significant unmet needs following disease progression on or after initial treatments," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "We are proud to have long supported patients with EGFR-mutated lung cancer and look forward to the possibility of bringing another innovative treatment option to this community."

Daiichi Sankyo and AstraZeneca recently announced the submission of a new Biologics License Application for accelerated approval in the U.S. for datopotamab deruxtecan for the treatment of adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior systemic therapies, including an EGFR-directed therapy.

About TROPION-Lung05
TROPION-Lung05 is a global, multicenter, single-arm, open-label phase 2 trial evaluating the efficacy and safety of datopotamab deruxtecan in patients with locally advanced or metastatic NSCLC with actionable genomic alterations who have progressed on at least one TKI (with or without other systemic therapies) and on or after one regimen of platinum-based chemotherapy. Patients receiving up to four prior lines of treatment with tumors with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET or MET were eligible for the trial.

The primary trial endpoint is objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary efficacy endpoints include duration of response (DoR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), time to response (TTR), overall survival (OS) and safety.

TROPION-Lung05 enrolled 137 patients globally in Asia, Europe and North America. For more information visit ClinicalTrials.gov.

About TROPION-Lung01
TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with an approved targeted therapy and platinum-based chemotherapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DoR, TTR, and DCR as assessed by both BICR and investigator, and safety.

TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov.

Primary PFS results and interim OS results from TROPION-Lung01 were presented at the 2023 ESMO (Free ESMO Whitepaper) (#ESMO23) Congress. Final OS results were presented at IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24) and simultaneously published in the Journal of Clinical Oncology in September 2024.

About Advanced Non-Small Cell Lung Cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.1 Lung cancer is broadly split into small or non-small cell lung cancer, the latter accounting for about 80% of cases.2 Approximately 10% to 15% of patients with NSCLC in the U.S. and Europe, and 30% to 40% of patients in Asia have an EGFR mutation.3,4 The majority of EGFR mutations occur in tumors of nonsquamous histology.5

For patients with tumors that have an EGFR mutation, the established first-line treatment in the metastatic setting is an EGFR TKI.6 While EGFR TKIs have improved outcomes in the first-line setting, most patients eventually experience disease progression and receive subsequent therapies, such as chemotherapy.7,8,9,10

TROP2 is a protein broadly expressed in the majority of NSCLC tumors.11 There is currently no TROP2 directed ADC approved for the treatment of lung cancer.6,12

About Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple negative breast cancer and HR positive, HER2 low or negative breast cancer. The program includes seven phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

About the DXd ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.

The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

On December 09, 2024 InnoCare reported latest data of orelabrutinib were presented at the ongoing 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, InnoCare Pharma, DEC 9, 2024, View Source [SID1234648962]).

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Poster Presentation

1. Orelabrutinib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) Who Are Intolerant to Prior Bruton Tyrosine Kinase Inhibitors (BTKi): Updated Results from a Phase 2 Study (Abstract No.: 4399)

Orelabrutinib improved outcomes of prior BTKi-intolerant adverse events (AEs), particularly the off-target toxicities. Patients who switched experienced minimal and low levels of intolerance recurrences and all achieved disease control. These updated results show promising efficacy and safety data of orelabrutinib in prior BTKi-intolerant iNHL patients.

As data cutoff (July 9, 2024), 66 patients were enrolled and 64 patients were available for AE and efficacy analysis. At a median follow-up of 6.8 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. Both PFS and OS rates remained 100%.

2. Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (OFCG) for First-Line Treatment of Chronic Lymphocytic Leukemia: A Multicenter, Investigator-Initiated Study (cwCLL-001 Study) (Abstract No.: 3244)

This is a multicenter, open-label, non-randomized phase II study for previously untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without restriction by del(17p)/TP53 aberrations and/or immunoglobulin heavy⁃chain variable region gene (IGHV) mutation status. The Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab regimen leads to a rapid and deep molecular remission with a manageable safety profile in previously untreated CLL patients including those with unfavorable characteristics.

After cycle 6, the rates of peripheral blood (PB) undetectable minimal residual disease (uMRD) and bone marrow (BM) uMRD by flow cytometry (FCM) were 95% and 86%, respectively, and the rate of complete response (CR)/CR with incomplete hematologic recovery (CRi ) was 59%. After cycle 12, the rates of PB-uMRD by FCM, BM-uMRD by FCM, and CR/CRi were 95%, 91% and 77% respectively.

3. A Prospective, Multicenter, Single-Arm Study on the Combination of Orelabrutinib and Rituximab in the Second-Line Treatment of Relapsed/Refractory Marginal Zone Lymphoma (Abstract No.: 4391)

This is a prospective, multicenter, single-arm, phase II clinical trial, aiming to evaluate the efficacy and safety of orelabrutinib in combination with rituximab in patients with relapsed or refractory Marginal Zone Lymphoma (MZL). The preliminary results of this study suggest that the combination therapy of orelabrutinib and rituximab is effective in patients with rrMZL and has manageable safety, with tolerable maintenance therapy.

Of the 12 enrolled patients, 6 have completed the interim efficacy assessment, achieving an overall response rate (ORR) of 100%. 3 patients completed the combination therapy and entered the maintenance phase, keeping the ORR at 100%. All patients chose orelabrutinib for maintenance therapy.

4. Orelabrutinib, Rituximab, and Thiotepa (ORT) in Combination with or without High-Dose Methotrexate in Untreated Primary Central Nervous System Lymphoma (Abstract No.: 4487)

The orelabrutinib, rituximab, and thiotepa (ORT) regimen, with or without high-dose methotrexate (HD-MTX), has shown initial efficacy and a manageable safety profile in treating Primary Central Nervous System Lymphoma (PCNSL), particularly in elderly patients with MCD subtypes. Autologous stem cell transplantation (ASCT) following ORT with or without HD-MTX induction therapy further improves patient response. Patients with complete response (CR) did not relapse and were well-tolerated on orelabrutinib maintenance therapy.

The median follow-up was 8.27 months. The best CR rate was 85.71%, and the longest CR duration was 22.53 months. The objective response rate (ORR) was 85.71%.

5. Preliminary Data of a Single-Arm, Phase II Study of Orelabrutinib with/without Rituximab in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma after BTK Inhibitor Therapy (Abstract No.: 3240)

Despite the currently limited follow-up period, orelabrutinib combined with or without rituximab, demonstrated favorable efficacy in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients with detectable MRD post-BTK inhibitor treatment, and MRD decreased significantly after 9 months. This treatment holds the potential to emerge as a new therapeutic option for CLL/SLL patients.

At 9 months, 66.7% achieved undetectable peripheral blood MRD, with a 9-month complete response rate (CRR) of 77.8% and a 1-year overall survival (OS) of 100%, and no patient has progressed thus far.

6. Preliminary Data on the Efficacy and Safety of Orelabrutinib Combined with Rituximab and Methotrexate (ORM Regimen) As First-Line Treatment for Primary Central Nervous System Lymphoma, and the Exploration of Cerebrospinal Fluid ctDNA Dynamic Monitoring (Abstract No.: 4500)

The Orelabrutinib Combined with Rituximab and Methotrexate regimen demonstrates high overall response rate (ORR) and complete response (CR) in the treatment of Primary Central Nervous System Lymphoma (PCNSL), with acceptable safety. Our results suggest that dynamic monitoring of cerebrospinal fluid circulating tumor DNA (ctDNA) is of significant importance for the early evaluation of therapeutic efficacy and prognosis prediction in PCNSL.

During treatment the best response evaluation showed an ORR of 86.4% and a disease control rate (DCR) of 100%; Among the 21 patients who completed all induction therapies, the ORR was 85.71% with a CR rate of 76.19%.

Among 19 patients with detectable ctDNA in baseline CSF, 13 patients had undetectable ctDNA in C5D1 CSF, of which 12 patients achieved CR. Patients with undetectable CSF ctDNA at C5D1 showed longer progression-free survival (PFS), indicating that early clearance of CSF ctDNA can predict favorable prognosis.

7. Preliminary Efficacy of Orelabrutinib Targeted Therapy in Induction Therapy of Primary Central Nervous System Diffuse B-Cell Lymphoma (Abstract No.: 4496)

The Orelabrutinib, Rituximab and High-dose MTX regimen is an effective and safe induction therapy for primary central nervous system diffuse B-cell lymphoma, with a total response rate of 83.3% and a median onset time of 1 course for partial response (PR) and 2 courses for complete response (CR). It is a promising induction therapy for primary central nervous system diffuse B-cell lymphoma.

8. The Primary Results of R-MTO Regimen (Rituximab, Methotrexate, Thiotepa, and Orelabrutinib) As the First-Line Induction Therapy Followed By Autologous Stem Cell Transplantation in Newly Diagnosed Primary Central Nervous System Lymphoma (Abstract No.: 1742)

This is a prospective designed, ongoing, single-center, single-arm, open-label study. The Rituximab, Methotrexate, Thiotepa, and Orelabrutinib induction treatment has demonstrated notable efficacy in achieving higher response rates among patients with newly diagnosed Primary Central Nervous System Lymphoma (PCNSL), and a tolerable safety profile.

A total of 26 patients with newly diagnosed PCNSL were enrolled in this study. The overall response rate (ORR) was 96.15%, and the complete response (CR) rate was 92.30% after 4 cycles of treatment. Among ten patients who underwent autologous hematopoietic stem cell transplantation (HSCT), all of them (100%) remained in CR. The progression-free survival (PFS) and overall survival (OS) rate at 12 months were 82.24%, and 87.00% respectively.

9. Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Idiopathic Multicentric Castleman Disease: A Single-Center, Retrospective Study (Abstract No.: 1656)

Orelabrutinib, with its high response rate, durable response time, and improved safety profile can be a viable alternative for the treatment of patients with relapsed/refractory (r/r) idiopathic multicentric Castleman disease (iMCD).

Ten patients with r/r iMCD were included in the study, Seven patients (70%) were assessed as responders, two of whom achieved complete response. The median time to remission for responders was 9.8 months (range: 5.9–20.5 months). In the non-responder group, despite not achieving response criteria, these patients still showed a continuous improvement in median hemoglobin, albumin, C-reactive protein (CRP) and creatine levels with treatment at month 12. No grade 3 or above adverse reactions occurred.

Except poster presentation, more than 10 studies were also selected as online publications at the meeting. For more detailed clinical data, please refer to ASH (Free ASH Whitepaper) website.

On December 09, 2024 AngioDynamics, Inc. (NASDAQ: ANGO), a leading and transformative medical technology company focused on restoring healthy blood flow in the body’s vascular system, expanding cancer treatment options and improving patient quality of life, reported it received U.S. Food and Drug Administration (FDA) 510(k) clearance for the NanoKnife System for prostate tissue ablation (Press release, AngioDynamics, DEC 9, 2024, View Source [SID1234648961]).

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"These efforts are designed to accelerate the adoption of the NanoKnife System, redefine the standard of care for prostate health, and deliver treatment outcomes that patients and physicians need. AngioDynamics is committed to driving meaningful impact through this revolutionary technology, providing new hope to patients and improved quality of life."

The Company received clearance for the NanoKnife System for prostate tissue ablation following the completion of the pivotal PRESERVE clinical study and submission of results to the FDA in September. The study evaluated the safety and effectiveness of the system for ablating prostate tissue in patients with intermediate-risk prostate cancer (PCa). Conducted in collaboration with the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC), PRESERVE enrolled 121 patients across 17 clinical sites.

"We are incredibly proud to receive FDA clearance for the NanoKnife System’s use in prostate tissue," said Jim Clemmer, President and Chief Executive Officer of AngioDynamics. "This milestone is the first step in recognizing our vision to become the standard, function-preserving treatment for men with prostate tumors. The NanoKnife System minimizes the life-altering complications often associated with traditional treatments by selectively targeting prostate tissue while preserving critical functions. As we expand our global footprint and increase access to our technology, we are launching comprehensive education and awareness campaigns to empower physicians with hands-on training and clinical support while engaging patients through innovative outreach initiatives."

Mr. Clemmer added, "These efforts are designed to accelerate the adoption of the NanoKnife System, redefine the standard of care for prostate health, and deliver treatment outcomes that patients and physicians need. AngioDynamics is committed to driving meaningful impact through this revolutionary technology, providing new hope to patients and improved quality of life."

The PRESERVE clinical study met its primary effectiveness endpoint demonstrating the performance of the NanoKnife System for the ablation of prostate tissue in patients with intermediate-risk PCa. At 12-months post-procedure, 84.0% of men were free from in-field, clinically significant disease. In addition, the study demonstrated strong quality of life outcomes with short-term urinary continence being preserved (96.6% at baseline, 95.4% at 12-months) and the ability to maintain erections sufficient for intercourse only decreasing 9% compared to baseline (80.7% to 71.7%).1

The study’s results validated the robust safety and clinical efficacy profile of the NanoKnife System, reinforcing findings from more than 32 clinical studies performed around the world involving over 2,600 patients.1

Prostate cancer is the second most common cancer in men worldwide, with approximately 1.5 million new cases diagnosed annually.2 Many of these patients seek alternatives to radical procedures that can lead to significant, long-term urological side effects.3 The NanoKnife System is the first and only non-thermal, radiation-free, ablation technology designed to treat prostate tissue by using IRE technology, offering patients a minimally invasive option for prostate treatment.

The NanoKnife System delivers an innovative alternative to conventional radical surgery or radiotherapy, which often results in significant dysfunction in urinary continence and erectile potency.4 With its non-thermal approach, the system is engineered to preserve vital structures inside and outside the prostate, offering patients improved outcomes, reduced recovery times, and enhanced quality of life.5

For important risk information, visit View Source

About the NanoKnife System

The NanoKnife System utilizes Irreversible Electroporation (IRE) technology to effectively destroy targeted cells without the use of thermal energy by delivering high-voltage pulses, creating permanent nanopores within the cell membrane. This stimulus induces an apoptotic-like cellular death in the targeted tissue, resulting in a complete ablation of the targeted tissue.6 Visit nanoknife.com for full product information.

United States: The NanoKnife System with six outputs is indicated for surgical ablation of soft tissue, including prostate tissue.

Canada: The NanoKnife System is a medical device for cell membrane electroporation. Electroporation is a phenomenon that occurs in cell membranes as cells are exposed to an electrical field of sufficiently high intensity. The electric field acts as a physical stimulus, bringing about alterations in cell membranes that result in increased permeability.

European Union: The NanoKnife System is indicated for the ablation of prostate tissue in patients with intermediate risk prostate cancer.

On December 09, 2024 Molecular Targeting Technologies, Inc. (MTTI) reported preclinical study results for their proprietary 225Ac-EBTATE against SSTR2 NET cancers online in the European Journal of Nuclear Medicine. ("Long acting 225Ac-EBTATE is highly efficacious against somatostatin receptor-2-positive neuroendocrine tumors" (View Source) (Press release, Molecular Targeting Technologies, DEC 9, 2024, View Source [SID1234648960]).

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Professor Humphrey Fonge of the Université de Laval and lead author commented, "At just 40% of the administered dose reported for 225Ac-DOTATATE, 225Ac-EBTATE produces enhanced anti-tumor efficacy in Small Cell lung cancer (SCLC) and Pan-neuroendocrine tumor (NET) models as shown with complete tumor remissions. At a therapeutic dose of 2x 34 kBq, 225Ac-EBTATE showed general safety for 28 days after blood biochemistry analysis, CBC, and histopathological examination of major organs and tissues. We demonstrated that 225Ac-EBTATE was effective against human small-cell lung cancer (SCLC) with 80% complete remission and 100% survival in preclinical models."

MTTI has licensed commercial use rights for the patented Evans blue (EB) technology from the National Institute of Biomedical Imaging and Bioengineering ("NIBIB"), part of the National Institutes of Health ("NIH"). This platform is the basis for the best-in-class, new generation, collection of targeted radiopharmaceuticals (TRP). EB binds to serum albumin, extending in vivo circulatory half-life and tumor residence time, enhancing up to 30-fold uptake at a tumor and enabling good efficacy with significantly lower radiopharmaceutical activity and fewer dosing cycles vs. the current standard of care. Our 3-year follow up of 177Lu-EBTATE in patients* (N=30) with metastatic neuroendocrine tumors, demonstrated good safety with no nephro- or hepatoxicity and 86% disease control rate using only 40% of the administered dose of 177Lu-DOTATATE.

Dr. Jean-Mathieu Beauregard, MD, Associate Professor of Department of Radiology of Université Laval, said, "I am encouraged to see the positive results of 225Ac-EBTATE in treating small cell lung cancer and Pan-neuroendocrine tumor (NET) in preclinical studies. I look forward to working with MTTI and Professor Fonge to translate this into the clinic."

Dr. Chris Pak, President & CEO of MTTI commented "225Ac-EBTATE effectiveness was encouraging, paralleling the clinical superiority of 177Lu-EBTATE. We look forward to collaborating with Professors Beauregard and Fonge to drive 225Ac-EBTATE into clinical trials in 2025."

On December 09, 2024 TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics ("BBOT" or the "Company"), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, reported the publication of preclinical data supporting the hypothesis that targeting both "ON" and "OFF" forms of KRASG12C results in greater potency, deeper responses, and slowed development of resistance leading to significant benefits over "OFF" only KRASG12C inhibitors approved in non-small cell lung cancer (NSCLC) (Press release, BridgeBio, DEC 9, 2024, View Source [SID1234648959]). The publication, titled "Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C" was published in the peer-reviewed journal Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Current KRASG12C inhibitors work by binding to the inactive guanosine diphosphate (GDP)-bound "OFF" form of the protein, preventing its oncogenic activation. However, they do not directly target or inhibit the active guanosine triphosphate (GTP)-bound "ON" form. This limitation leaves KRASG12C "ON" unaddressed, leading to adaptive resistance characterized by increased expression and activity of the active KRASG12C "ON" state. The data in this manuscript demonstrate that BBO-8520, a first-in-class direct dual inhibitor, directly binds to both the "ON" and "OFF" states of KRASG12C in the Switch-II/Helix3 pocket. There, it covalently modifies the target cysteine to disable effector binding to the "ON" state of KRASG12C. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of downstream signaling, resulting in durable tumor regression in multiple tumor models, including those resistant to KRASG12C "OFF" only inhibitors.

"The aspiration to design a first-in-class, direct, dual inhibitor of the GTP-bound ‘ON’ and GDP-bound ‘OFF’ forms of KRASG12C has been achieved," said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. "BBO-8520 is a dual inhibitor of KRASG12C that provides optimal target coverage with exquisite potency, overcoming key deficiencies of ‘OFF’ only inhibitors, and represents a novel mechanism of action because it is the only direct inhibitor that actually blocks effector binding. Preclinical data shows that this novel mechanism delays the emergence of adaptive resistance seen with ‘OFF’ only inhibitors in the clinic. The potential of this approach holds significant promise for delivering enhanced clinical outcomes in patients with NSCLC."

"Using nuclear magnetic resonance (NMR) and X-ray crystallography, as well as biochemical and cell-based assays, we’ve been able to decipher the mechanism of action of this potent dual inhibitor," said lead author Anna Maciag, PhD, Principal Scientist at Frederick National Laboratory for Cancer Research (FNLCR). "Our ability to apply the multitude of high throughput screens and assays available at FNLCR allowed for quick structure activity relationship (SAR) determination and progress."

Resistance to KRASG12C "OFF" inhibitors primarily arises from increased KRASG12C activity in its "ON" state. This can occur through mutant allele amplification or activation of receptor tyrosine kinases (RTKs) by growth factors. Newly synthesized KRAS is likely to bind GTP, as intracellular GTP concentrations are roughly ten times higher than GDP. As a result, upregulating the mutant protein’s transcription offers an efficient escape mechanism for cells to bypass the effects of "OFF" inhibitors. Similarly, receptor tyrosine kinase (RTK) activation can effectively overcome "OFF" only inhibitors by maintaining a high level of KRASG12C in its "ON" state. This study shows that the presence of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) significantly impairs the potency of "OFF" inhibitors in vitro, while amplification of KRASG12C is also detrimental in vivo. In contrast, BBO-8520 maintains exquisite potency in the presence of growth factors, mutant allele amplification, as well as when mutations are engineered to maintain KRASG12C in the "ON" form.

BBO-8520 is currently being evaluated in a Phase 1 study (NCT06343402) of KRASG12C NSCLC patients pre-treated with first generation KRASG12C "OFF" inhibitors or with no prior KRASG12C targeted therapy experience. The discovery of BBO-8520 was the result of a collaboration between the National Cancer Institute RAS Initiative at Frederick National Laboratory for Cancer Research, Lawrence Livermore National Laboratory, and BBOT.