On December 9, 2024 Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, reported that the results of SON-1010 at the highest dose have been formally evaluated by the Safety Review Committee in the Phase 1 SB101 clinical trial of SON-1010 (IL12-FHAB) in adult patients with advanced solid tumors. SB101 is the Company’s open-label, adaptive-design dose-escalation study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SON-1010 administered to patients with advanced solid tumors (Press release, Sonnet BioTherapeutics, DEC 9, 2024, View Source [SID1234648915]). The study has enrolled 24 subjects to date. Primary outcome measures for the study were to evaluate the safety and tolerability of SON-1010 and establish the MTD. Additionally, the Company announced the release of a "What This Means" segment to discuss the data which is now available here.

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SON-1010 is the Company’s proprietary version of recombinant human interleukin-12 (rhIL-12), configured using genetic fusion to Sonnet’s Fully Human Albumin Binding (FHAB) platform, which extends the half-life and bioactivity of the IL-12 component due to binding native albumin in the serum and also targets the tumor microenvironment (TME) by strong binding to gp60 and Secreted Protein Acidic and Rich in Cysteine (SPARC).

"We are encouraged by this topline safety data generated to date in our Phase 1 study. Given the history of safety concerns with rhIL-12 in its first human trials over 25 years ago, it is exciting to see higher doses of SON-1010 demonstrating minimal toxicity, which is likely due to its unique biodistribution and albumin binding profile, with delivery to and retention in the tumor microenvironment," said Richard Kenney, M.D., Sonnet’s Chief Medical Officer. "We may finally be able to realize the promising antitumor effect that has been associated with this cytokine in preclinical models for decades. The IFNγ response, which is considered to be important for anti-tumor control, has been robust but controlled with a much longer return to baseline. While the clinical benefit we have been seeing during dose escalation has been reassuring, the PR at the highest dose is particularly important, as this suggests that there may be a synergistic effect in combination with checkpoint inhibitors and/or chemotherapy."

All enrolled patients have had advanced solid tumors. The final 1200 ng/kg dose-escalation cohort was increased in size to 6 patients to enhance the assessment of PK and PD at the MTD. The SB101 trial employed a ‘desensitizing’ first dose of 300 ng/kg to take advantage of the known tachyphylaxis with rhIL-12, with the intention of minimizing toxicity and allowing for higher maintenance doses. No dose-limiting toxicities or related serious adverse events (SAE) have occurred to date. The safety and toxicity profile that has developed is typical for a Phase 1 oncology trial, with the majority of adverse events (AEs) being reported as mild. All AEs seen to date have been transient, with no evidence of cytokine release syndrome. Of the 24 patients dosed to date, 17 (71%) had SD at the first follow-up CT, 12 of whom were progressing at study entry. 10 of the 21 evaluable patients (48%) remained stable at four months, suggesting SON-1010 clinical benefit, and one of those patients in the highest dose cohort, who has clear cell sarcoma, had a PR with a 45% reduction in tumor size by RESIST criteria. As previously disclosed, one patient in the first dose cohort with endometrial sarcoma who was progressing at study entry had evidence of improvement after 11 months, with smaller tumors and complete resolution of ascites. This patient later progressed at 23 months and started chemotherapy.

"This topline safety data release on our lead program is a significant milestone for Sonnet’s clinical development. We have now successfully completed dose escalation in our first trial with SON-1010 and are pleased to see a partial response in one patient at the highest dose, in addition to clinical benefit in almost half of the evaluable patients," said Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer. "Safety of this extended PK version of IL-12 has been within expected levels and the comparison with dosing in healthy volunteers provided strong evidence of tumor targeting in humans. We have used this trial to establish the MTD and will continue to follow the patients currently being treated to assess longer-term safety and tumor responses. Sonnet is currently seeking partnership opportunities to help support later stage development of SON-1010."

For more information about the Phase 1 SB101 trial in adult patients with advanced solid tumors visit www.clinicaltrials.com and reference identifier NCT05352750.

SON-1010 is also being evaluated in a Phase 1b/2a dose-escalation and proof-of-concept study (SB221) in combination with SON-1010 and atezolizumab (in collaboration with Genentech, a member of the Roche Group), which is focused on platinum-resistant ovarian cancer (PROC) (NCT05756907). Enrollment remains ongoing and an update on safety at the MTD in that trial is expected in Q1 2025.

About SON-1010

SON-1010 is a candidate immunotherapeutic recombinant drug that links unmodified single-chain human IL-12 with the albumin-binding domain of the single-chain antibody fragment A10m3. This was selected to bind albumin both at normal pH, as well as at the acidic pH typically found in the TME. The FHAB technology targets tumor and lymphatic tissue, providing a mechanism for dose sparing and an opportunity to improve the safety and efficacy profile of not only IL-12, but a variety of potent immunomodulators that can be linked using the platform. Interleukin-12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as the Secreted Protein and Rich in Cysteine (SPARC) and glycoprotein 60 (GP60), several types of cancer such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers are particularly relevant for this approach. SON-1010 is designed to deliver IL-12 to local tumor tissue, turning ‘cold’ tumors ‘hot’ by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases the production of Programed Death Ligand 1 (PD-L1) on tumor cells.

About the Phase 1 SB101 Trial

This first-in-human study is primarily designed to evaluate the safety of multiple ascending doses of SON-1010 in cancer patients and is being conducted at several sites across the United States. While the optimal dose is unknown at this stage, the potential to target tumors, the extended PK mechanism, and our preclinical data suggest the therapeutic dose may be lower compared to native human IL-12. The study, utilizing a standard 3+3 oncology design in at least five cohorts, should establish the MTD using subcutaneous injections of SON-1010 every 3 to 4 weeks. The primary endpoint explores the safety and tolerability of SON-1010, with key secondary endpoints intended to measure PK, PD, immunogenicity, and anti-tumor activity. This study will form the basis for potential combinations with other types of immunotherapies and the future development of bispecific candidates using the FHAB platform.

On December 9, 2024 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology company that plans to change its name to BeOne Medicines Ltd., reported the presentation of new clinical data at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, underscoring its leadership in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) through continued clinical success with BRUKINSA (zanubrutinib) and promising advancements in its pipeline assets (Press release, BeiGene, DEC 9, 2024, View Source [SID1234648931]).

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"The breadth of data we’re presenting at ASH (Free ASH Whitepaper) underscores BRUKINSA’s role as a best-in-class treatment for CLL and highlights BeiGene’s leadership in advancing the treatment landscape for B-cell malignancies," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "BRUKINSA shows tremendous promise for patients as a monotherapy and as a backbone for best-in-class combinations. The combination of BRUKINSA and our investigational BCL2 inhibitor, sonrotoclax, demonstrated significant potential as a first-line therapy in CLL, with a 99% overall response rate, best uMRD rate of 92%, and was generally well-tolerated at a median follow-up of 19.4 months; this combination is expected to offer better efficacy than a fixed-dose V-O regimen. Additionally, our investigational BTK degrader could become a first-in-class treatment option for patients with CLL and other BTK-driven B-cell malignancies based on the results of data presented at ASH (Free ASH Whitepaper). BeiGene is primed to shape the future of CLL treatment and aims to meet the needs of CLL patients globally."

Long-term follow-up results from the ongoing Phase 3 SEQUOIA study presented during ASH (Free ASH Whitepaper), which were simultaneously published in the Journal of Clinical Oncology, reaffirm BRUKINSA’s durable efficacy and differentiated safety profile across diverse CLL patient populations, including those with high-risk features. Additional findings spotlight the promising potential of BeiGene’s BTK-targeted chimeric degradation activation compound (CDAC), BGB-16673, which has shown rapid and deep responses in B-cell malignancies in phase 1/2 clinical trials. BeiGene is also developing a next-generation BCL2 inhibitor, sonrotoclax, aiming to improve the safety profile and feasibility of use for this class of drugs and deliver deeper and more durable responses. Together, these advancements reflect BeiGene’s comprehensive approach to addressing the complexities of CLL and its commitment to reshaping the treatment landscape for B-cell malignancies.

With a median follow-up of 61.2 months, data from the SEQUOIA study of patients with treatment-naïve CLL/SLL demonstrated that treatment with BRUKINSA reduced the risk of progression or death by 71% (HR, 0.29; 95% CI, 0.21-0.40; P<.0001*) compared to bendamustine-rituximab (BR). At 54 months, 80.1% of patients who received BRUKINSA remained progression-free (95% CI, 74.3, 84.7) while only 44.6% of patients who received BR remained progression-free (95% CI, 37.6, 51.3). At 60 months, PFS rates were 75.8% (95% CI, 69.0, 81.3) and 40.1% (95% CI, 32.7, 47.3) for BRUKINSA and BR, respectively. Notably, for patients in the study with unmutated IGHV, a prognostic biomarker that indicates a patient’s CLL may be more aggressive, treatment with BRUKINSA reduced the risk of progression or death by 79% compared to BR (HR, 0.21; 95% CI, 0.14-0.33; P<.0001*). The safety profile of BRUKINSA was consistent with the results of prior studies, and no new safety signals were identified. Grade ≥3 treatment-emergent adverse events of interest (AEIs) with BRUKINSA and BR included infection (30.0% and 22.5%, respectively), neutropenia (12.5%; 51.1%), bleeding (7.5%; 1.8%), thrombocytopenia (2.5%; 8.4%), and anemia (0.8%; 2.6%). Rates of atrial fibrillation were 7.1% with BRUKINSA and 3.5% with BR. The rate of discontinuation due to AEs was 20% in the BRUKINSA arm; 13% of patients discontinued BR early due AEs.(Abstract 3249)

"The long-term follow-up of SEQUOIA confirms the sustained efficacy of zanubrutinib over chemotherapy, regardless of IGHV status, in patients with treatment-naïve CLL," said Mazyar Shadman, M.D. M.P.H., Associate Professor and Innovators Network Endowed Chair, Medical Director, Cellular Immunotherapy and the Bezos Family Immunotherapy Clinic at Fred Hutch Cancer Center. He also holds the Innovators Network Endowed Chair at Fred Hutch and is Associate Professor at Fred Hutch and University of Washington. "Notably, there is a deepening of responses, with a complete remission/complete remission with incomplete count recovery rate in the range of 20%, which, based on cross-trial comparison is higher than a typical BTK inhibitor used as monotherapy. Additionally, the incidence of adverse events of interest, such as atrial fibrillation and hypertension, appears comparable to the background risk of this patient population."

In addition to BRUKINSA, BeiGene is advancing a robust pipeline to address the needs of CLL patients, including:

Sonrotoclax (BCL2 Inhibitor): Presented data from the Phase 1/1b study (NCT04277637) demonstrated sonrotoclax, in combination with BRUKINSA, was generally well-tolerated and no cases of tumor lysis syndrome (TLS) were reported in patients with treatment-naïve CLL/SLL. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 49.6% of patients, with the most common (≥20%) being neutropenia (24% in 160mg cohort; 23% in 320mg cohort). With a median follow-up of 19.4 months (0.4–33.3 months), the combination achieved a 99% overall response rate (ORR), including in patients with high-risk features (51% had unmutated IGHV, 20% had TP53 mutation, and 9% had del(17p)). High and early rates of undetectable minimal residual disease (uMRD) were seen by week 24 of combination therapy, with responses continuing to deepen with time through week 48. Best uMRD rate was achieved in 92% of patients (n=112). At a median follow-up of over a year and a half, no progression has been observed in the 320 mg dose cohort. These data support continued evaluation of this combination in the ongoing registrational Phase 3 fixed-duration CELESTIAL-TNCLL study (NCT06073821) (Abstract 1012)
BGB-16673 (BTK CDAC): Data from the Phase 1/2 CaDAnCe-101 CLL study (NCT05006716) demonstrated that treatment with BGB-16673 was generally well tolerated in this heavily pretreated population of patients. Promising antitumor activity was observed in patients with high-risk features, including in patients with BTK inhibitor-resistant mutations and those previously exposed to covalent BTK inhibitors, noncovalent BTK inhibitors, and BCL2 inhibitors. No atrial fibrillation was observed in either the CLL/SLL or WM cohorts.
From the cohort of CLL/SLL patients, BGB-16673 demonstrated an ORR of 94% at the 200mg dose. Furthermore, amongst all doses delivered, 2 patients achieved a complete remission/complete remission with incomplete count recovery (CR/CRi). Grade ≥3 TEAEs were reported in 57% of patients. The most common grade ≥3 TEAEs (≥10%) were neutropenia/neutrophil count decreased (20%) and pneumonia (10%). (Abstract 885)
From the cohort of Waldenström’s macroglobulinemia patients, BGB-16673 demonstrated a 93% disease control rate (DCR) and 26% very good partial response (VGPR). Grade ≥3 TEAEs were reported in 45% of patients. The most common grade ≥3 TEAE (≥20%) was neutropenia/neutrophil count decreased. (Abstract 860)
For additional information about BeiGene’s presence at ASH (Free ASH Whitepaper) 2024, please visit our meeting hub: congress.beigene.com.

The Company recently announced its intent to change its name to BeOne Medicines, reaffirming its commitment to develop innovative medicines to eliminate cancer by partnering with the global community to serve as many patients as possible.

*P-value was one-sided and descriptive.

About Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a life-threatening cancer of adults. It is a type of mature B-cell malignancy in which abnormal leukemic B lymphocytes (a type of white blood cells) arise from the bone marrow and flood peripheral blood, bone marrow, and lymphoid tissues.1,2 CLL is the most common type of leukemia in adults, accounting for about one-third of new cases.2,3 Approximately 20,700 new cases of CLL will be diagnosed in the U.S. in 2024.3

About Sonrotoclax (BGB-11417)

Sonrotoclax is designed to block the B-cell lymphoma 2 (BCL2) protein, which helps cancer cells survive. It is part of a group of drugs called BH3 mimetics, which mimic natural cell death signals. Studies in the lab and during early drug development have shown that sonrotoclax is a potent and specific inhibitor of BCL2 with a short half-life and no accumulation. Sonrotoclax has shown promising clinical activity across a range of B-cell malignancies, and more than 1,300 patients have been enrolled to date across the global development program. The U.S. Food and Drug Administration (FDA) granted sonrotoclax Fast Track Designation for the treatment of patients with mantle cell lymphoma (MCL) and Waldenström macroglobulinemia (WM).

About BGB‑16673

BGB‑16673 is an orally available, brain-penetrating Bruton’s tyrosine kinase (BTK) targeting chimeric degradation activation compound (CDAC) designed to promote the degradation, or breakdown, of both wildtype and mutant forms of BTK, including those that commonly result in resistance to BTK inhibitors in patients who experience progressive disease. BGB-16673 is the most advanced BTK degrader in the clinic, with more than 350 patients treated to date across the global clinical development program. The U.S. Food and Drug Administration (FDA) granted Fast Track Designation to BGB-16673 for the treatment of adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have been previously treated with at least two prior lines of therapy, including BTK inhibitor (BTKi) and B-cell lymphoma 2 (BCL2) inhibitor, and adult patients with R/R mantle cell lymphoma (MCL).

About BRUKINSA (zanubrutinib)

BRUKINSA is an orally available, small molecule inhibitor of Bruton’s tyrosine kinase (BTK) designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.

BRUKINSA has the broadest label globally of any BTK inhibitor and is the only BTK inhibitor to provide the flexibility of once or twice daily dosing. The global BRUKINSA clinical development program includes about 6,000 patients enrolled in 30 countries and regions across more than 35 trials. BRUKINSA is approved in more than 70 markets, and more than 100,000 patients have been treated globally.

U.S. Indications and Important Safety Information for BRUKINSA (zanubrutinib)

INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Waldenström’s macroglobulinemia (WM).
Mantle cell lymphoma (MCL) who have received at least one prior therapy.
Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen.
Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy.
The MCL, MZL and FL indications are approved under accelerated approval based on overall response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.3% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including BRUKINSA.

Evaluate bilirubin and transaminases at baseline and throughout treatment with BRUKINSA. For patients who develop abnormal liver tests after BRUKINSA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold BRUKINSA. Upon confirmation of DILI, discontinue BRUKINSA.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions (≥30%), including laboratory abnormalities, in patients who received BRUKINSA (N=1729) are decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

Please see full U.S. Prescribing Information including U.S. Patient Information.

On December 9, 2024 IASO Biotherapeutics ("IASO Bio"), a biopharmaceutical company focused on the discovery, development, manufacturing, and commercialization of innovative cell therapies and biologics, reported findings via a poster presentation of the results on the impact of CAR T-Cell Persistence on Clinical Outcomes in Relapsed/Refractory Multiple Myeloma(R/RMM) with Equecabtagene Autoleucel (Eque-cel, FUCASO) at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, IASO Biotherapeutics, DEC 9, 2024, View Source [SID1234648947]). The results highlighted the importance of the efficacy-to-target ratio in the treatment of multiple myeloma, emphasizing the crucial role of sustained CAR T-cell persistence, unaffected by baseline soluble B-cell maturation antigen (sBCMA) levels, to achieve optimal disease control.

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Title: Impact of CAR T-Cell Persistence on Clinical Outcomes in Relapsed/Refractory Multiple Myeloma: Insights from the Phase 2 FUMANMA-1 Study
Publication Number: 4761
Presentation Time: 6:00 PM -8:00 PM, Monday, December 9, 2024（San Diego）

Conclusions

The efficacy-to-target ratio is a crucial determinant of clinical outcomes in patients treated with Eque-cel, underscoring the importance of CAR T-cell persistence.
This ratio may serve as a biomarker for future treatment planning, highlighting the need for sustained CAR T-cell persistence to achieve optimal disease control.
Baseline sBCMA levels do not negatively affect the persistence and efficacy of Eque-cel.
This post-hoc analysis of the Phase 2 study of FUMANBA-1 primarily investigated the relationship between CAR T-cell persistence and progression-free survival (PFS) as well as time to progression (TTP). It also examined the impact of sBCMA levels through the lens of the efficacy-to-target ratio, measured by the ratio of vector copy number (VCN) duration to baseline sBCMA levels. With a median follow-up of 24.67 months, 107 patients in 14 centers were treated with Eque-cel.

At the data cutoff, the ongoing remission group showed a longer median VCN duration than those with progression or relapse（12.52m vs 9.03m）,as shown in Figure 1.The median efficacy-to- target ratio for the 107 subjects was 1.05 (days*mL/ng). As shown in Figure 2, those with a lower ratio had a significantly higher risk of disease progression, with a hazard ratio (HR) for TTP of 3.07 (95% CI: 1.51–6.24, p=0.0011) and for PFS of 2.3 (95% CI: 1.27–4.14, p=0.0045), both indicating a strong correlation between the efficacy-to-target ratio and the risk of disease progression.

Among baseline characteristics—including ECOG score, R-ISS and ISS disease stages, tumor BCMA expression, tumor burden, baseline sBCMA level, previous autologous stem cell transplantation (ASCT), triple-class exposure, bridging therapy, prior CAR-T treatment, and lymphodepleting conditioning—only previous ASCT (n=30) and ADA as post-infusion factors were significantly associated with Eque-cel persistence, with hazard ratios (HR) 0.35 and 5.79, respectively, as shown in Table 1.

Among the 107 subjects, only 14 exhibited an aplastic neutrophil recovery phenotype, characterized by persistent neutrophil counts below 500/μl for 14days or more. This phenotype did not significantly affect VCN duration compared to patients without the condition, indicating that the long-term persistence of Eque-cel does not increase hematological toxicity.

The principal investigator of this study, Professor Lugui Qiu, from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and Professor Chunrui Li, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, stated:

"This post-hoc analysis explored the determinants of long-term efficacy after CAR-T treatment through the lens of the efficacy-to-target ratio (VCN persistence/sBCMA). It confirmed the significance of this ratio in achieving long-term control of multiple myeloma (PFS and TTP). The findings suggest that a CAR-T product with long-lasting efficacy, unaffected by the target, which means not affected by sBCMA levels, would be a more optimal choice in the treatment of MM.

The result further highlighted the crucial role of sustained persistence of CAR-T cells in improving the prognosis of patients with R/RMM. In our 2023 ASH (Free ASH Whitepaper) oral report, we previously confirmed a positive correlation between Eque-cel persistence and the maintenance of MRD negativity. The median duration time of CAR-T cells for Eque-cel was 419 days, which may be a key factor in achieving the high MRD negativity rate of 97.8% and the sustained MRD negativity rate of 81.7% at 12 months post-infusion.

Notably, only 14 of 107 subjects exhibited aplastic neutrophil recovery lasting 14 days or more. This finding indicates that the long-term persistence of Eque-cel does not increase hematological toxicity, further validating the safety of this therapy."

Dr. Jie Chen, Chief Medical Officer of IASO Bio, stated:
The outcomes presented by IASO Bio at the ASH (Free ASH Whitepaper) Annual Meeting highlighted the significant impact of the efficacy-to-target ratio on disease control in multiple myeloma. The data demonstrated that subjects with an efficacy-to-target ratio above the median value had a better prognosis in terms of PFS and TTP. These findings further confirmed the positive effect of long-term CAR-T cells persistence in achieving sustained remission. Eque-cel was deliberately selected in its early development to be a candidate molecule not influenced by sBCMA levels, offering patients deeper and more durable remission. Additionally, the study showed that only a small number of patients experienced neutropenia lasting more than 14 days after treatment with Eque-cel. The result affirmed that the long-term persistence of Eque-cel does not increase the hematological toxicity, further validating its safety profile.

We are fully confident in the outstanding efficacy and safety of Eque-cel. Currently, We have initiated and are rapidly advancing a randomized controlled Phase 3 clinical study of this therapy for second- and third-line multiple myeloma. We look forward to bringing this advanced therapy to a broader population of multiple myeloma patients both domestically and internationally as soon as possible."

About FUMANBA-1 Study
FUMANBA-1 is a single-arm, open-label phase 1b/2 registrational clinical study conducted in 14 Chinese centers to assess the efficacy and safety of the Equecabtagene Autoleucel in patients with R/RMM who have received ≥3 lines of prior therapies. The trial enrolled patients with RRMM who had previously received at least three lines of therapy, including proteasome inhibitors and immunomodulatory agents-based chemotherapy regimens, and had disease progression on their last line of therapy. Patients who had previously received BCMA CAR-T therapy were also eligible for enrollment.

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 9, 2024 Genmab A/S (Nasdaq: GMAB) reported new long-term results from two ongoing clinical trials evaluating epcoritamab, a T-cell engaging bispecific antibody administered subcutaneously, in adult patients with diffuse large B-cell lymphoma (DLBCL) (Press release, Genmab, DEC 9, 2024, View Source [SID1234648900]). Results from Arm 1 of the Phase 1b/2 EPCORE NHL-2 trial (NCT04663347), evaluating fixed-duration epcoritamab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), demonstrated an overall response rate (ORR) of 100 percent and a complete response (CR) rate of 87 percent in high-risk patients (n=46) with previously untreated DLBCL. Among complete responders, 83 percent remained in remission after two years. Separately, results from the Phase 2 EPCORE NHL-1 trial (NCT03625037), evaluating epcoritamab monotherapy in challenging-to-treat adult patients (n=157) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL; including 148 patients with R/R DLBCL), showed that among the 41 percent of patients who achieved a CR, an estimated 52 percent were still responding at three years (median CR duration: 36.1 months). Both analyses were presented at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper).

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"The unprecedented durability of response seen in these data reinforce the potential of epcoritamab to become a core therapy for the treatment of multiple B-cell malignancies to benefit more patients," said Dr. Judith Klimovsky, Executive Vice President and Chief Development Officer of Genmab. "These results support our ongoing Phase 3 trials for epcoritamab, including as an investigational first-line combination therapy in patients with previously untreated diffuse large B-cell lymphoma."

EPCORE NHL-2 Results in First-Line DLBCL (Abstract #581)
The EPCORE NHL-2 trial enrolled 46 patients considered to have high-risk DLBCL, identified by International Prognostic Index (IPI) scores of 3 to 5, a range associated with poor long-term outcomes. The IPI is a key tool used by oncologists to predict the prognosis of aggressive B-cell lymphomas.i At screening, 35 percent of patients (n=16) had bulky disease (>10 cm) and 21 percent (n=6) of evaluable patients (n=28) had double-hit/triple-hit LBCL based on gene rearrangements identified by central analysis.

With a median follow-up of 27.4 months (range, 0.8-33.9), 87 percent of patients remained alive at two years and 74 percent were progression free.
At two years, a minimal residual disease (MRD) analysis showed MRD negativity was achieved in 91 percent of evaluable patients (30/33), indicating no detectable disease.
Epcoritamab in combination with R-CHOP is being studied further in the ongoing, randomized, Phase 3 EPCORE DLBCL-2 trial (NCT05578976).

"More first-line treatment options for diffuse large B-cell lymphoma are needed, especially for patients with aggressive disease prognostic markers that may impact the efficacy of current standard first-line therapies," said Lorenzo Falchi, MD, Lymphoma Specialist, Department of Medicine, Memorial Sloan Kettering Cancer Center.ii "Relapse rates with the R-CHOP treatment regimen can reach 50 percent, so the durable responses observed in the study suggest significant potential for this first-line epcoritamab-based combination."

The most common treatment-emergent adverse events (TEAEs) were neutropenia (70 percent), anemia (69 percent), cytokine release syndrome (CRS; 60 percent), fatigue (49 percent), nausea (47 percent), pyrexia (42 percent), and injection-site reaction (40 percent). Four patients (9 percent) discontinued epcoritamab due to TEAEs; fatal TEAEs occurred in two patients (COVID-19 and septic shock). CRS events were mostly low grade (45 percent Grade 1, 11 percent Grade 2, 4 percent Grade 3) and mainly occurred after the first full dose. All CRS cases resolved, and none led to discontinuation. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in two patients (one Grade 1; one Grade 2) and resolved in a median of 2.5 days without leading to discontinuation.

Use of epcoritamab + R-CHOP in first-line DLBCL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use as a combination therapy in DLBCL have not been established.

EPCORE NHL-1 Results in Third-Line LBCL (Abstract #4480)
Three-year follow-up results from the Phase 2 EPCORE NHL-1 trial evaluated epcoritamab monotherapy in 157 patients with R/R LBCL and demonstrated that epcoritamab continues to deliver durable responses in challenging-to-treat patients.

The ORR was 59 percent, and the CR rate was 41 percent. Median duration of response was 20.8 months (95 percent CI, 13.0-32.0) and median duration of CR was 36.1 months (95 percent CI, 20.2 to not reached [NR]).
52 percent of patients who experienced a CR were still responding at three years (median CR duration: 36.1 months).
Of the 119 patients who were MRD-evaluable, 54 (45 percent) achieved MRD-negativity. In a cycle 3-day 1 landmark analysis, 3-year PFS rates were 52 percent among MRD-negative patients and 18 percent among MRD-positive patients.

The most common TEAEs were CRS (51 percent; 32 percent Grade 1, 16 percent Grade 2, 3 percent Grade 3), fatigue (25 percent), and pyrexia (25 percent); CRS rates remained unchanged since prior reports. Fatal TEAEs were reported in 20 patients; 10 patients had Grade 5 COVID-19 (including COVID-19 pneumonia). Seventy-three percent of patients treated with epcoritamab for two or more years did not experience a Grade 3 or higher infection after two years (median follow-up after 2 years, 12.3 months). Incidence of Grade 3 or higher cytopenias was highest (27 percent) during the first eight weeks of treatment and rates were within 0-13 percent in subsequent 12-week time periods up to week 144. Immunoglobulin G levels decreased by a median of approximately 20 percent after the start of epcoritamab treatment (baseline median, 540.0 mg/dL) and remained stable over time.

About Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is the most common type of non-Hodgkin’s lymphoma (NHL) worldwide, accounting for approximately 25-30 percent of all NHL cases.iii,iv In the U.S., there are approximately 25,000 new cases of DLBCL diagnosed each year.v DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system, occurs more commonly in the elderly and is slightly more prevalent in men.vi,vii DLBCL is a fast-growing type of NHL, a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. For many people living with DLBCL, their cancer either relapses, which means it may return after treatment, or becomes refractory, meaning it does not respond to treatment. Although new therapies have become available, treatment management can remain a challenge. viii,ix

About the EPCORE NHL-2 Trial
EPCORE NHL-2 is a Phase 1b/2 open-label interventional trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab as a monotherapy and in combination with other standard of care agents in patients with B-cell non-Hodgkin’s lymphoma (B-NHL). The trial consists of two parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion). The primary objective of Part 1 is safety, and the primary goal of Part 2 is preliminary efficacy. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint.

Arm 1 of the trial is epcoritamab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL). More information on this trial can be found at View Source (NCT: 04663347).

About the EPCORE NHL-1 Trial
EPCORE NHL-1 is an open-label, multicohort, single-arm, Phase 1/2 trial of epcoritamab in participants with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL). The trial was conducted at 88 sites across 15 countries and consisted of three parts: a Phase 1 first-in-human, dose escalation part; a Phase 2a expansion part; and a Phase 2a dose optimization part. More information on this trial can be found at View Source (NCT: 03625037).

About Epcoritamab
Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.x

Epcoritamab (approved under the brand name EPKINLY in the U.S. and Japan, and TEPKINLY in the EU) has received regulatory approval in certain lymphoma indications in several territories. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for the investigational R/R FL indication and additional approvals for the R/R DLBCL indication.

Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes five ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigator’s choice chemotherapy (NCT04628494), a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT05578976), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT05409066), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) compared to chemoimmunotherapy in patients with previously untreated FL (NCT06191744), and a trial evaluating epcoritamab in combination with lenalidomide compared to chemotherapy infusion in patients with R/R DLBCL (NCT06508658). The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit www.clinicaltrials.gov for more information.