Daiichi Sankyo Research Articles

Outcomes of female fertility preservation with cryopreservation of oocytes or embryos in the Netherlands: a population-based study.

What are the reproductive outcomes of patients who cryopreserved oocytes or embryos in the context of fertility preservation in the Netherlands? This study shows that after a 10-year follow-up period, the utilization rate to attempt pregnancy using cryopreserved oocytes or embryos was 25.5% and the cumulative live birth rate after embryo transfer was 34.6% per patient. Fertility preservation by freezing oocytes or embryos is an established treatment for women with a risk of premature ovarian failure (caused by a benign or oncological disease) or physiological age-related fertility decline. Little is known about the success of cryopreservation, the utilization rate of oocytes or embryos, or the live birth rates. A retrospective observational study was performed in the Netherlands. Data were collected between 2017 and 2019 from 1112 women who cryopreserved oocytes or embryos more than 2 years ago in the context of fertility preservation in 10 IVF centers in the Netherlands. A total of 1112 women were included in this study. Medical files and patient databases were used to extract data. Women were categorized based on indication of fertility preservation: oncological, benign, or non-medical. To indicate statistical differences the t-test or Mann-Whitney U test was used. Kaplan-Meier analyses were used for time endpoints, and log-rank analyses were used to assess statistical differences. The study protocol was approved by the medical ethics committee. Fertility preservation cycles have been performed increasingly over the years in the Netherlands. In the first years, less than 10 cycles per year were performed, increasing to more than 300 cycles per year 10 years later. Initially, embryos were frozen in the context of fertility preservation. In later years, cryopreservation of oocytes became the standard approach. Cryopreservation of oocytes versus embryos resulted in comparable numbers of used embryos (median of 2) for transfer and comparable live birth rates (33.9% and 34.6%, respectively). The 5-year utilization rate was 12.3% and the 10-year utilization rate was 25.5%. The cumulative clinical pregnancy rate was 35.6% and the cumulative live birth rate was 34.6% per patient. Those who had fertility preservation due to benign diseases returned earlier to use their cryopreserved embryos or oocytes. The follow-up period after the fertility preservation procedure varied between patients in this study and not all frozen oocytes or embryos had been used at the end of this study. This might have led to underestimated outcomes reported in this study. Furthermore, intention to treat cannot be fully determined since women who started the fertility preservation procedure without success (cancellation due to low response) were not included in this study. This study provides data on the reproductive outcomes after various indications of fertility preservation. This knowledge can be informative for professionals and future patients to improve counseling and informed decision making regarding ovarian stimulation in the context of fertility preservation. No funding was obtained for this study. The authors have no conflicts of interest to declare related to this study. V.T.H. received grants paid to the institute for studies outside the present work from AstraZeneca, Gilead, Novartis, Eli Lily, Pfizer, and Daiichi Sankyo. V.T.H. received consulting fees from Eli Lily outside the present work. M.G. received grants paid to the institute for studies outside the present work from Guerbet and Ferring. E.M.E.B. received a grant from The Dutch Network of Fertility Preservation for a study outside the present work. N/A.

6503 A Randomized, Placebo-Controlled Phase 3 Study of Olezarsen In Patients With Familial Chylomicronemia Syndrome: The Balance Trial

Abstract Disclosure: E.S. Stroes: Advisory Board Member; Self; Amgen Inc, Sanofi, Novartis Pharmaceuticals, AstraZeneca, Novo Nordisk, Ionis Pharmaceuticals Inc., Merck, Daiichi Sankyo. Grant Recipient; Self; Ionis Pharmaceuticals Inc., Novo Nordisk, Novartis Pharmaceuticals, Sanofi. V. Alexander: Employee; Self; Ionis Pharmaceuticals Inc. E. Prokopczuk: Employee; Self; Ionis Pharmaceuticals Inc. R.A. Hegele: Consulting Fee; Self; Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Amgen Inc, Novartis Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Sanofi, Ultragenyx, Acasti, and HLS Therapeutics. M. Arca: Grant Recipient; Self; Amgen Inc, Ionis Pharmaceuticals Inc., Novartis Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Sanofi, Ultragenyx, Daiichi Sankyo, Alfasigma, Amryt, Sobi, and Viatris. C.M. Ballantyne: Consulting Fee; Self; 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma Inc, Merck, New Amster. Grant Recipient; Self; Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, Novo Nordisk, Regeneron, Roche Diagnostic, NIH, AHA, ADA. H. Soran: Grant Recipient; Self; Akcea Therapeutics, Alexion, Amryt, Kowa, MSD, NAPP, Novartis, Pfizer, Sanofi, Synageva, and Takeda. T.A. Prohaska: Employee; Self; Ionis Pharmaceuticals Inc. S. Xia: Employee; Self; Ionis Pharmaceuticals Inc. H.N. Ginsberg: Research Investigator; Self; Ionis Pharmaceuticals Inc. J.L. Witztum: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S. Tsimikas: Consulting Fee; Self; Novartis. Employee; Self; Ionis Pharmaceuticals Inc.. Stock Owner; Self; Kleanathi, Oxitope. Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of lipoprotein lipase deficiency that results in severe hypertriglyceridemia and an increased risk of potentially life-threatening acute pancreatitis (AP). Decreasing high plasma levels of apolipoprotein C-III (apoC-III) reduces hypertriglyceridemia. Olezarsen is an investigational ligand-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to reduce triglycerides (TG). Methods: Balance is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in 66 patients with genetically confirmed FCS and fasting TG ≥880 mg/dL at screening. Patients were advised to consume <20g fat/day and randomized 2:1 to olezarsen (50 mg or 80 mg) or placebo sc every 4 weeks for 53 weeks. The two primary endpoints were the placebo-adjusted % change in fasting TG from baseline to 6-months for (1) olezarsen 80 mg and (2) olezarsen 50 mg. Secondary endpoints included change in 12-month TG and apoC-III levels, and incidence of independently adjudicated AP events. Results: At baseline, TG levels were ∼2600 mg/dL and 47/66 (71%) of FCS patients had a history of AP. Placebo-corrected TG levels at 6 months were significantly reduced in olezarsen 80 mg (-43.5%, P=0.0009), and were numerically lower in the olezarsen 50 mg group (-22.4%, P=0.0775). Placebo-corrected TG levels at 12 months were reduced -59.4% in the olezarsen 80 mg group and -43.8% in the olezarsen 50 mg group. ApoC-III levels were reduced in both dose groups at 6 months (olezarsen 50 mg: -65.5%; olezarsen 80 mg: -73.7%) and 12 months (olezarsen 50 mg: -77.1%; olezarsen 80 mg: -81.3%). During 53 weeks of randomized treatment, 11 episodes of AP were observed in 23 patients on placebo versus 2 episodes in 43 olezarsen-treated patients (1 in 50 mg and 1 in 80 mg group). A favorable safety and tolerability profile was noted with more treatment emergent adverse events (TEAEs) and serious TEAEs in the placebo group. No serious TEAEs were related to study drug. Conclusion: In patients with FCS, olezarsen 80 mg significantly reduced TG levels and both olezarsen 50 and 80 mg groups demonstrated a marked reduction in AP events with a favorable safety and tolerability profile. Presentation: 6/1/2024

12509 Identification Of Novel Exercise Training-induced Circulating Proteins: Hemostatic, Apoptotic, And Key Neuronal Factors

Abstract Disclosure: A. Shalit: None. M. Vamvini: None. P. Nigro: None. L.K. Simpson: None. H. Pan: None. J.M. Dreyfuss: None. L.J. Goodyear: Grant Recipient; Self; Daiichi Sankyo. R.J. Middelbeek: None. Exercise training induces a plethora of health benefits including improved glucose homeostasis, decreased cardiovascular disease, and improved cognitive function. An emerging concept is that many of these beneficial effects of exercise are mediated through the secretion of humoral factors into the blood. Identification of these exercise-regulated factors hold promise for novel treatments for disease. Here, we performed proteomic analysis to discover novel circulating factors in response to endurance exercise training in human participants. Given that nutritional status can affect the circulating proteome, another aim was to determine if proteomic adaptations to exercise training have similar effects under both fasted and random-fed conditions. Sedentary normoglycemic participants (3M/5F, age 22-41y) performed a supervised 10-week exercise training program, which by week 4 was 4x60 min exercise at 65-70% V̇O2peak. Fasted and random-sampling morning blood draws were collected pre-training and between 24-72 hours following the final training session. Proteomic detection was by SOMAscan. Exercise training significantly improved V̇O2peak by 17% (p=0.003). Out of 1,310 detected proteins, exercise training significantly changed 293 proteins in the fasted state and 360 proteins in the random-sampling state (p<0.05). Integration showed that 172 proteins were changed under both nutritional conditions (123 upregulated and 49 downregulated). Gene Set Enrichment Analysis (GSEA) of the commonly upregulated proteins showed that training resulted in enrichment in neuronal, hemostatic, and apoptotic pathways, whereas the downregulated proteins were enriched in neuronal and extracellular matrix processes. Since neuronal pathways were identified in both up and downregulated proteins, we focused our analysis there, identifying 31 upregulated and 4 downregulated neuronally-associated proteins. Importantly, exercise training reduced levels of CDK5, a protein that is hyperactivated in neurodegeneration and Alzheimer's disease. Moreover, GSTP1, a direct inhibitor of CDK5, along with downstream proteins inhibited by CDK5 (RAC1, STUB1, 14-3-3ε/YWHAE, HSP90AA1, CFL1), were significantly increased following exercise training.In conclusion, exercise training regulates circulating factors involved in neuronal, hemostatic, apoptotic, and extracellular matrix pathways, with these effects being independent of nutritional status. Our finding of exercise training-induced decreases in multiple proteins of the CDK5 pathway, a pathway whose downregulation is associated with neuroprotection, identify CDK5 as a novel and potentially important mediator of the beneficial effects of exercise training on cognitive function. Presentation: 6/1/2024

Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study.

Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas. This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting. Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4-17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3-4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6-65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150-250 mg per day. The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting. Daiichi Sankyo.

Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study.

Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma. VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment. Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0-74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0-73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8-13·8). 52 (44%; 95% CI 35-53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3-4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported. These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile. Daiichi Sankyo.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial

Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer. DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting). Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5). The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both. Daiichi Sankyo and AstraZeneca.

FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).

e20537 Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .

The Heidelberg registry of atrial fibrillation. a summary in the era of transition of oral anticoagulation regimes over an 11-year period

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The study was supported by a research grant from Daiichi Sankyo and Bayer diagnostics. The sponsor had no influence on the study concept, data collection, or interpretation. Background Management of patients with atrial fibrillation (AF) has improved in recent years. Particularly, the shift from vitamin-k containing (VKA) oral anticoagulation (OAC) regimes to factor Xa or thrombin inhibitor containing non-vitamin K regimes (NOAC) regimes has revolutionized stroke prevention in AF patients. Purpose This study aimed to illustrate the shift from VKA to NOAC regimes over an 11-year period in an emergency department (ED) setting. Methods The Heidelberg Registry of Atrial Fibrillation (HERA-FIB) is a retrospective, observational single-center study and collected data from patients with AF presenting to the ED of our hospital between 2009 and 2020. Inclusion criteria were (a) diagnosis of AF and (b) age &amp;gt;18 years. Exclusion criteria were (a) non-availability of at least one high sensitive troponin T value and (b) lost to follow-up for all-cause mortality. Repeated visits to the ED were also excluded. Clinical data was accessed retrospectively from available medical records. A sequential follow-up was performed for all-cause mortality, stroke, major bleeding and myocardial infarction. This study was conducted according to ethical principles stated in the Declaration of Helsinki (2008). Results Within the inclusion period of HERA-FIB a total of 76,528 visits to CPU were screened over an 11-year time period. 24.4% were excluded for other diagnosis than AF, resulting in a total of 12,279 visits to ED within the inclusion period. Here, a total of 5.4% of the patients were excluded after re-adjustment of AF diagnosis, 1,5% for non-sufficient laboratory values and 10% for lost-to follow-up. The total study population of HERA-FIB included 10,222 patients with the diagnosis of AF. Within the inclusion period of HERA-FIB, a significant change form VKA containing to NOAC containing anticoagulation regimes could be detected among patients presenting to the ED. Additionally, the number of patients on OAC compared to the number of patients without any OAC regime increased over time. Within the inclusion period, a total of 69.7% received an OAC regime. Here 59.5% of the AF patients received a NOAC and 40.5% VKA at discharge. Hazard ratio for patients on VKA for all-cause mortality was 1.25 (95%CI: 1.11-1.41), p=0.0003. Conclusions HERA-FIB is one of the largest real-world retrospective single-center databases for patients with AF, reflecting the shift from NOAC to VKA containing anticoagulation regimes in AF patients presenting to an ED over an 11-year period.

The role of rhythm control in patients with first diagnosed atrial fibrillation in a real world collective

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Bayer. Background There has been conflicting evidence regarding the importance of rhythm control as opposed to rate control in patients with atrial fibrillation (AF). Thus, no clear recommendation on early rhythm control for risk reduction is given in the current guidelines. However, some evidence suggests that rhythm control is superior to rate control in patients with a recent diagnosis of AF. Purpose We aim to characterize patients with first diagnosed AF and evaluate the effect of a rhythm control strategy at the time of diagnosis on long term cardiovascular outcomes. Methods This is a single center, retrospective observational sub study based as a part of the HERA-FIB project. HERA-FIB included 10.222 patients presenting to the emergency department (ED) of the department of cardiology of a university hospital from June 2009 to March 2020. We consecutively included all patients with a history AF or current AF upon presentation, regardless of the reason for presentation. A structured follow-up regarding survival and major cardiovascular events was performed. Mean follow up was 23 months (IQR 12-35). Patient care was not influenced. The project was performed according to the declaration of Helsinki and was approved by the local ethics committee and registered at ClinicalTrials.gov (Identifier: NCT05995561). Results. After adjudication we included 10.222 patients in this study. Of those 2758 (27%) had no previous history of AF and were first diagnosed with AF upon presentation. There were major differences in baseline characteristics as patients with first diagnosed AF were younger (73 years vs 76 years, p&amp;lt;0.0001), showed a normal left ventricular function more often (47.9% vs 40.2%, p&amp;lt;0.0001) and had fewer histories of coronary artery disease (CAD) (30.2% vs 48.0%, p&amp;lt;0.0001) and fewer histories of stroke or transient ischemic attack (TIA) (9.0% vs 14.0%, p&amp;lt;0.0001). In contrast they had higher heart rates (113 bpm vs 84 bpm, p&amp;lt;0.0001) on admission. Among the patients with first diagnosed AF 24.6% received a cardioversion (either pharmacological of electrical). Patients with first diagnosed AF undergoing rhythm control treatment showed lower rates for all-cause mortality (10.4% vs 18.2%, p&amp;lt;0.0001) and myocardial infarction (2.4% vs. 5.2%, p=0.0045) as compared to patients first diagnosed with AF not recieving a cardioversion. However, no differences for strokes (2.7% vs 3.3%, p=0.6158) or severe bleeding according to ISTH major bleeding criteria (4.0% vs. 5.3%, p=0.2252) could be detected. Conclusions Patients presenting to an ED with first diagnosed AF are younger and show fewer comorbidities compared to patients with pre-existing AF. Patients with first diagnosed AF seem to profit from early rhythm control strategies showing a reduction for the rates of all-cause mortality and myocardial infarction. However, no difference for stroke or major bleeding events could be detected. Additional, prospective studies are required to verify this hypothesis.

Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. AstraZeneca and Daiichi Sankyo.

Abstract PO2-04-04: Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM)

Abstract Background: ROSET-BM (UMIN000044995) was a multicenter, retrospective chart review study of patients (pts) who received trastuzumab deruxtecan (T-DXd) treatment for HER2-positive (HER2+) metastatic breast cancer (MBC) with brain metastases (BM) and/or leptomeningeal carcinomatosis (LMC). Primary results (data cutoff, October 31, 2021) were presented at SABCS2022 (median progression-free survival [PFS], 16.1 months; 1-year overall survival [OS] rate, 74.9%; and median follow-up duration, 11.2 months). To confirm the long-term effectiveness of T-DXd in HER2+ MBC pts with BM and/or LMC, we conducted an updated analysis using additional 1-year follow-up data. Methods: Pts who started T-DXd treatment between May 25, 2020, and April 30, 2021, were registered for ROSET-BM. For this updated OS analysis, the extended observation period ended on October 31, 2022. OS, PFS, and time to treatment failure (TTF) were evaluated. Median survival times and 95% CIs were calculated using the Kaplan–Meier method. In addition, prespecified and exploratory subgroup analyses were performed based on patient background characteristics. Univariate and multivariate Cox proportional hazards regression models were used to evaluate baseline prognostic factors for OS. Results: 104 pts from 62 institutions were included in this updated OS analysis. Median duration of follow-up was 20.4 months. Median number of prior lines of therapy was 4 (range, 1–15). Median time from first diagnosis of MBC to first administration of T-DXd was 37.5 months. Median time from first diagnosis of BM to first administration of T-DXd was 18.9 months. The prevalence of active BM, stable BM, LMC, and unclassified (image not evaluated) was 64.4% (n=67), 11.5% (n=12), 18.3% (n=19), and 5.8% (n=6), respectively. Median OS was not reached (NR) among all pts (1-year OS rate, 74.8%; 2-year OS rate, 56.0%). Subgroup analyses showed that median OS in pts with active BM was 27.0 months (95% CI, 16.4 to NR) and that median OS was NR in pts with stable BM or LMC (2-year OS rate for pts with stable BM, 71.6%; 2-year OS rate for pts with LMC, 61.6%). The results of univariate and multivariate analyses for OS showed no relevant baseline prognostic factors. Among all pts, median PFS was 14.6 months (95% CI, 10.6–20.8). Subgroup analyses showed that in pts with active BM, stable BM, and LMC, median PFS was 13.2 months (95% CI, 10.0–20.3), NR (95% CI, 5.3 to NR), and 17.5 months (95% CI, 8.3–22.1), respectively. Among all pts, median TTF was 9.3 months (95% CI, 6.3–11.8). The most common event and adverse event leading to discontinuation of T-DXd was progressive disease (37 pts, 35.6%) and interstitial lung disease (ILD; 24 pts, 23.1%), respectively. Median time to onset of an ILD event was 5.3 months (range, 0.7–20.0). ILD was grade 1 in 14 pts (13.5%), grade 2 in 3 pts (2.9%), grade 3 in 5 pts (4.8%), grade 4 in 2 pts (1.9%), and grade 5 in 0 pts. The Table summarizes the primary and updated results of ROSET-BM. Conclusion: The updated OS results of this retrospective chart review show that T-DXd has promising effectiveness in HER2+ MBC pts with long-term and heavily pretreated BM and LMC. This study was funded by Daiichi Sankyo Co., Ltd. Primary and updated results from the ROSET-BM study The updated results show that T-DXd has promising effectiveness in HER2+ MBC pts with long-term and heavily pretreated BM and LMC. Citation Format: Takashi Yamanaka, Naoki Niikura, Takahiro Nakayama, Mitsugu Yamamoto, Kazuo Matsuura, Kenichi Inoue, Sachiko Takahara, Hironori Nomura, Shosuke Kita, Miki Yamaguchi, Tomoyuki Aruga, Nobuhiro Shibata, Akihiko Shimomura, Yuri Ozaki, Shuji Sakai, Daisuke Takiguchi, Takehiko Takata, Armin Bastanfard, Kazuhito Shiosakai, Junji Tsurutani. Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: an updated overall survival analysis using data from a multicenter retrospective study (ROSET-BM) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-04.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial

In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. Daiichi Sankyo and AstraZeneca.

P117 Efficacy of filgotinib in patients with rheumatoid arthritis: Week 156 results from a long-term extension study

Abstract Background/Aims In the treatment of RA, JAK inhibitors are a valuable option to meet remission or low disease activity (LDA) treatment targets following an inadequate response (IR) or intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (DMARD). FIL is a JAK1 preferential inhibitor available in two doses for the treatment of moderate to severe RA. Objectives: To evaluate long-term efficacy of two doses of FIL in clinically relevant pt populations. Methods In this interim analysis, efficacy (non-responder imputation) of FIL 200 mg (FIL200) and 100 mg (FIL100) was assessed from LTE baseline (BL) to W156 in pts with an IR to methotrexate (MTX-IR) and biologics (bDMARD-IR), enrolled from FINCH 1 (NCT02889796) and 2 (NCT02873936) parent studies (PS), respectively, receiving ≥1 FIL dose in FINCH 4 (NCT03025308). Results Study design, BL characteristics and W48 outcomes for MTX-IR1 and bDMARD-IR2 pts were reported previously. For MTX-IR and bDMARD-IR pts who received FIL200 or FIL100 in the PS, W156 remission rates using Boolean 1.0 criteria were 20.5% and 15.8%, and 18.2% and 8.9%, respectively. Adopting the Boolean 2.0 criteria slightly increased remission rates for FIL200 and FIL100 at W156: +4.2% and +4.9% for MTX-IR pts, and +1.5% and +2.4% for bDMARD-IR pts, respectively. For pts rerandomized to FIL on entering the LTE, Boolean 2.0 criteria also increased remission rates vs Boolean 1.0. Both MTX-IR and bDMARD-IR pts maintained long-term Boolean remission through W156 with FIL200 and FIL100, irrespective of prior FIL. Results for Disease Activity Score 28 with C-reactive protein (DAS28-CRP) &amp;lt;2.6, Clinical Disease Activity Index (CDAI) ≤2.8, and Simplified Disease Activity Index (SDAI) ≤3.3, and mean change from PS BL in Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain are shown (Table). Similar trends in efficacy were seen for LDA and ACR response criteria. Conclusion In FINCH 4, both FIL200 and FIL100 showed sustained efficacy up to W156 in clinically relevant pt populations. Boolean 2.0 criteria classified more pts in remission, in line with the range reported in the validation study. Disclosure M.H. Buch: Consultancies; AbbVie, CESAS Medical, Galapagos, Gilead, and Pfizer (all paid to host institution). Member of speakers’ bureau; AbbVie (paid to host institution). Grants/research support; Gilead (paid to host institution). D. Aletaha: Consultancies; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Member of speakers’ bureau; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Grants/research support; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. R. Caporali: Consultancies; AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB. Member of speakers’ bureau; AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB. B. Combe: Consultancies; AbbVie, Galapagos, Gilead, Janssen, Lilly, Novartis, and Roche-Chugai. Member of speakers’ bureau; AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pfizer, and Roche-Chugai. H. Schulze-Koops: Consultancies; AbbVie, Galapagos, Lilly, and Pfizer. Member of speakers’ bureau; AbbVie, Galapagos, Lilly, and Pfizer. J. Gottenberg: Consultancies; AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis, and Pfizer. Grants/research support; BMS and Pfizer. Y. Tanaka: Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Mitsubishi-Tanabe, and Pfizer. Grants/research support; AbbVie, Asahi-Kasei Pharma, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Takeda. R. Blanco: Consultancies; AstraZeneca, Galapagos, Janssen, Novartis, and Pfizer. Member of speakers’ bureau; AbbVie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi. Grants/research support; AbbVie and Roche. T. Takeuchi: Consultancies; AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, and Pfizer Japan Inc. Member of speakers’ bureau; AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, Pfizer Japan Inc., and Sanofi K.K. Grants/research support; AbbVie GK, Asahi-Kasei Pharma, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi-Tanabe, Nippon Kayaku, and UCB Japan. E. V. Ekoka Omoruyi: Consultancies; Galapagos and Janssen. Shareholder/stock ownership; UCB. K. Van Beneden: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. V. Rajendran: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. C. Watson: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. F. De Leonardis: Other; Employee of Galapagos. P. Emery: Consultancies; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung.

P118 Patient-reported outcomes, disease activity and safety in UK patients with rheumatoid arthritis treated with filgotinib: up to six-month interim results from a prospective observational study (FILOSOPHY)

Abstract Background/Aims FILOSOPHY (NCT04871919), an ongoing, observational Phase 4 study, will assess the effectiveness and safety of filgotinib, a JAK1-preferential inhibitor, in patients with RA in a real-world setting in Europe. We report interim UK data. Methods FILOSOPHY will enroll approximately 1,500 adults with moderate-to-severe active RA, upon first exposure to filgotinib, prescribed according to the product label and local standard-of-care. DAS28-CRP and CDAI were assessed at baseline, Month one, three and six and pain (visual analog scale [VAS]) and FACIT-Fatigue score at baseline, Week one, two and three and Month one, three and six. A reduction of ≥ 10 mm in VAS pain or increase of ≥ 4 in FACIT-Fatigue score were considered a clinically meaningful change from baseline (CFB). Treatment-emergent adverse events (TEAEs) on study were reported. Results By January 31, 2023, 130 patients had been treated in the UK; baseline characteristics and study treatment are reported in the Table. Median (IQR) CFB in DAS28-CRP was -1.1 (-2.5, -0.5) at Month one (N = 29), -1.7 (-2.6, -1.2) at Month 3 (N = 32) and -2.5 (-3.2, -1.0) at Month six (N = 27). Median (IQR) CFB in CDAI was -15.0 (-26.0, -8.0) at Month one (N = 31), -17.0 (-27.0, -12.0) at Month three (N = 31) and -25.0 (-30.0, -16.0) at Month 6 (N = 30). The proportion of patients with a clinically meaningful CFB in FACIT-Fatigue score was 45.0% (n = 18/40) at Week 1 and 65.6% (n = 21/32) at Month six. For VAS pain, the proportions were 47.5% (n = 19/40) at Week 1 and 66.7% (n = 22/33) at Month six. Similar trends were seen in the monotherapy and combination groups. No unexpected TEAEs occurred. Six patients discontinued the study prematurely; there was one death (lobar pneumonia); none were lost to follow-up. Conclusion Interim UK data showed pain and fatigue improved with filgotinib treatment as early as Week one and disease activity as early as Month one, the first timepoint that DAS28-CRP and CDAI were assessed; improvements were maintained up to Month six. While conclusions regarding safety cannot be made due to the short follow-up and small sample size, no new safety findings were observed. Long-term follow-up is needed to further evaluate effectiveness and safety. Disclosure B. Kirkham: Consultancies; AbbVie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB. Member of speakers’ bureau; AbbVie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, UCB. Grants/research support; Eli Lilly, Novartis. N.D. McKay: Consultancies; Gilead, UCB. Member of speakers’ bureau; Galapagos. Other; Registration for conference fees from AbbVie, Novartis, UCB. His department has received grants and payments from a wide range of pharmaceutical companies for research and education. A.G. Pratt: Consultancies; Inflection Biosciences (paid to Newcastle University). Grants/research support; Galapagos, GSK, Pfizer (paid to Newcastle University). J. Barry: Other; Employee of Galapagos. O. Bouzid: Consultancies; Galapagos. T.P.A. Debray: Consultancies; Biogen, Daiichi Sankyo, Galapagos, Gilead. S. Bhat: None. L. Robertson: Other; Financial support for conference attendance from UCB. J. Galloway: Consultancies; AbbVie, Galapagos, Janssen, Lilly, Pfizer. Honoraria; AbbVie, Galapagos, Janssen, Lilly, Pfizer, UCB. Member of speakers’ bureau; AbbVie, Galapagos, Janssen, Lilly, Pfizer, UCB. Grants/research support; AstraZeneca, Janssen, Pfizer.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial

DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. Daiichi Sankyo and AstraZeneca.

Abstract 7627: First NGS-based companion diagnostic to aid in selecting non-small cell lung cancer patients with ERBB2 (HER2) activating mutations for treatment with trastuzumab deruxtecan

Abstract Introduction The ERBB2 companion diagnostic program aims to expand the intended use of the Oncomine ™ Dx Target Test (ODxTT) to determine ERBB2 single nucleotide variants (SNVs) in exons 8, 17, 18, 19, 20, 21 and 22 and exon 20 insertions from formalin-fixed, paraffin-embedded (FFPE) tumor samples in non-small cell lung cancer (NSCLC) patients who may benefit from targeted drug therapy. Methods The ODxTT is a qualitative in vitro diagnostic test that uses targeted high throughput, parallel-sequencing technology to detect SNVs, deletions, insertions, and CNVs in genes from DNA and fusions from RNA isolated from FFPE tissue samples using the Ion PGM ™ Dx System. Analytical validation (AV) studies interrogated ODxTT’s ability to detect ERBB2 mutations. The clinical validation (CV) study involved a method comparison/concordance analysis of ERBB2 mutations between the ODxTT and the TruSight Tumor 170 (TST170) assay, as well as a series of clinical trial assays (CTAs). The CV study was conducted using clinical specimens from 91 patients enrolled in Destiny-Lung01 and 121 stage-matched commercially procured samples. The aim was to evaluate positive percent agreement (PPA), negative percent agreement (NPA) and overall percent agreement (OPA) for CTAs and TST170 assay. Results A total of 91 ERBB2 subjects were included in the full analysis of the Destiny-Lung01 clinical trial. 49 samples had valid ODxTT results available and 42 samples were unevaluable which included 13 unknowns and 29 test not performed. The 49 patient samples that were evaluable were used to assess the clinical efficacy based on ODxTT results. In the series of 121 samples that were used to assess clinical efficacy in the CV study, 109 had evaluable ODxTT results. The PPA, NPA and OPA of ODxTT to the CTAs when excluding unknowns were 98%, 100% and 99.4%, respectively, and based off the Clopper-Pearson method for binomial distribution a 95% lower bound confidence interval (CI) were 89.6%, 96.6% and 96.5%, respectively. There was one discordant sample with a negative ODxTT and a positive CTA result (false negative). The PPA, NPA and OPA of ODxTT to TST170 assay were 100%, 99.1% and 99.3% respectively with a 95% lower bound CI of 90.8%, 95.0% and 96.3%, respectively. There was one discordant sample with a negative TST170 and a positive ODxTT result (false positive). Conclusion AV and CV studies successfully verified and validated the ODxTT for the detection of ERBB2 mutations in NSCLC FFPE samples. The 6 AV studies met the necessary product requirements and acceptance criteria to detect clinical samples with ERBB2 mutations. Additionally, the CV study clinical accuracy and clinical efficacy results demonstrated the safety and effectiveness of the use of the ODxTT in FFPE samples as an aid to identify NSCLC patients eligible for treatment with the Daiichi Sankyo lung cancer therapeutic T-DXd. Citation Format: Thomas Ha. First NGS-based companion diagnostic to aid in selecting non-small cell lung cancer patients with ERBB2 (HER2) activating mutations for treatment with trastuzumab deruxtecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7627.

No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis.

No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis.

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.