Median Lines Research Articles

A new species of Nemophora from Korea (Lepidoptera, Adelidae, Adelinae).

A new species of the genus Nemophora Hoffmannsegg, Nemophora lutea Ko & Hirowatari sp. nov. is described from Korea, which is very similar to N. smaragdaspis (Meyrick) found in India and Nepal but distinguished by its the straight deep orange median band and metallic white lines on the forewing in both sexes. Illustrations of adults and genitalia are provided, with habitat information.

Impact of Salvage Versus Palliative Dose Bridging Radiation Therapy on Local Control and Overall Survival in Patients with DLBCL Receiving CD19 CAR T Cell Therapy.

In patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), radiation therapy (RT) can be used to "bridge" patients during the period of chimeric antigen receptor T cell (CAR T) manufacturing. Although RT has been shown to improve local control (LC) in patients who receive RT versus do not, it is unknown whether there is an optimal dose. This was a retrospective study of patients with DLBCL who received bridging RT and CAR T cell therapy between 8/2021 and 12/2022 at a single institution (IRB #202103122). Patient, disease, and treatment characteristics were abstracted. PET/CT and laboratory data were collected at various time points. RT data including dose, planning target volume (PTV), and body volume receiving 2Gy and 4 Gy were tested for associations with LC, overall survival (OS), cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). Statistical tests were performed using Python libraries. Twenty-two patients with DLBCL were included for analysis. The median patient age was 68 (range 35-82) and the median prior lines of failed therapies was two. All patients had successful apheresis and subsequent CAR T manufacturing. No patients died before CAR T infusion. All patients had a pre-radiation PET/CT scan that showed Deauville 5 disease. Patients with limited stage disease received salvage dose RT (EQD2∼40Gy, n = 8) while patients with advanced disease received palliative dose RT (n = 14). The median PTV volume was 1332 cm3. With a median follow-up of 156 days (IQR 63 - 252 days) from CAR T infusion, 10 patients had died and six progressed at an RT target. A higher salvage RT dose was not associated with LC at the day 30 PET or day 90 PET time points. In a Cox regression model, no independent variable, including RT dose, was significantly associated with LC or OS, but post-RT residual target SUV trended toward an association with OS (HR 6.2, 95% CI 0.9 - 471.0, p = 0.06). Post-RT LDH was associated with CRS grade (ρ = -0.39, p = 0.05). Other non-significant associative trends were noted between CRS grade and post-RT absolute lymphocyte count (ALC) (ρ = - 0.33, p = 0.09) and residual target SUV max (ρ = - 0.37, p = 0.08) and between ICANS grade and pre- to post-RT LDH change (ρ = -0.38, p = 0.06) and post-RT lymphocyte count (ρ = 0.36, p = 0.07). In an exploratory analysis of body volume receiving integral doses of 4Gy or 2Gy and pre- and post-RT ALC change, it appeared that higher integral dose did lead to larger decreases in ALC (ρ = -0.32, p = 0.15 and ρ = -0.3, p = 0.18, respectively). In this small series of patients with r/r DLBCL treated with bridging RT prior to CAR T therapy, RT dose was not associated with LC. However, higher post-RT target residual SUV was associated with worse OS. The impact of post-RT LDH on CRS and ICANS grades should be explored further.

Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas

Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

Understanding representations of uncertainty, an eye-tracking study – Part 1: The effect of anchoring

Abstract. Geoscience communicators must think carefully about how uncertainty is represented and how users may interpret these representations. Doing so will help communicate risk more effectively, which can elicit appropriate responses. Communication of uncertainty is not just a geosciences problem; recently, communication of uncertainty has come to the forefront over the course of the COVID-19 pandemic, but the lessons learned from communication during the pandemic can be adopted across geosciences as well. To test interpretations of environmental forecasts with uncertainty, a decision task survey was administered to 65 participants who saw different hypothetical forecast representations common to presentations of environmental data and forecasts: deterministic, spaghetti plot with and without a median line, fan plot with and without a median line, and box plot with and without a median line. While participants completed the survey, their eye movements were monitored with eye-tracking software. Participants' eye movements were anchored to the median line, not focusing on possible extreme values to the same extent as when no median line was present. Additionally, participants largely correctly interpreted extreme values from the spaghetti and fan plots, but misinterpreted extreme values from the box plot, perhaps because participants spent little time fixating on the key. These results suggest that anchoring lines, such as median lines, should only be used where users should be guided to particular values and where extreme values are not as important in data interpretation. Additionally, fan or spaghetti plots should be considered instead of box plots to reduce misinterpretation of extreme values. Further study on the role of expertise and the change in eye movements across the graph area and key is explored in more detail in the companion paper to this study (Williams et al., 2023; hereafter Part 2).

Understanding representations of uncertainty, an eye-tracking study – Part 2: The effect of expertise

Abstract. As the ability to make predictions regarding uncertainty information representing natural hazards increases, an important question for those designing and communicating hazard forecasts is how visualizations of uncertainty influence understanding amongst the intended, potentially varied, target audiences. End-users have a wide range of differing expertise and backgrounds, possibly influencing the decision-making process they undertake for a given forecast presentation. Our previous, Part 1 study (Mulder et al., 2023) examined how the presentation of uncertainty information influenced end-user decision making. Here, we shift the focus to examine the decisions and reactions of participants with differing areas of expertise (meteorology, psychology, and graphic-communication students) when presented with varied hypothetical forecast representations (boxplot, fan plot, or spaghetti plot with and without median lines) using the same eye-tracking methods and experiments. Participants made decisions about a fictional scenario involving the choices between ships of different sizes in the face of varying ice thickness forecasts. Eye movements to the graph area and key and how they changed over time (early, intermediate, and later viewing periods) were examined. More fixations (maintained gaze on one location) and more fixation time were spent on the graph and key during early and intermediate periods of viewing, particularly for boxplots and fan plots. The inclusion of median lines led to less fixations being made on all graph types during early and intermediate viewing periods. No difference in eye movement behaviour was found due to expertise; however, those with greater expertise were more accurate in their decisions, particularly during more difficult scenarios. Where scientific producers seek to draw users to the central estimate, an anchoring line can significantly reduce cognitive load, leading both experts and non-experts to make more rational decisions. When asking users to consider extreme scenarios or uncertainty, different prior expertise can lead to significantly different cognitive loads for processing information, with an impact on one's ability to make appropriate decisions.

Free Vibration Analysis of Trapezoidal Bi-Stable Laminates Supported at the Elastic Midpoint of the Median Line

This study investigates the natural vibration of trapezoidal bi-stable laminates (TBL) with elastic supports at the midpoints of the median lines. Configuration of the midplane of the TBL is expressed by a polynomial with 17 parameters. Then, the first order shear deformation theory, curing temperature, and nonlinear strain displacement relations combining energy principles are applied to obtain the bi-stable shapes numerically. Three translational springs and two rotational springs are added at the midpoint of the median line in the trapezoidal bi-stable laminate to acquire elastic point supports. And, by varying the stiffness of the springs, arbitrary elastic point support boundary conditions can be achieved. Chebyshev polynomials are applied to characterize the mode shape function of the TBL. The vibration mode functions of the TBL are mapped to a square area under the new coordinate system by using the coordinate mapping method. Furthermore, the effects of geometry, layup sequence, and spring stiffness on the natural vibrations of the TBL are analyzed, which provides a reference for research in this field. The innovation and highlights lie in the following: (1) the natural frequencies and modes of trapezoidal bi-stable plates are solved; (2) arbitrary elastic support is achieved by a set of artificial springs; (3) the influences of spring stiffness, layer sequence, and trapezoidal base angle on the natural vibration of a trapezoidal bi-stable plate are studied.

Seismic fragility assessment of aqueduct bent structures subjected to mainshock-aftershock sequences

This study aims to assess the seismic fragility of the aqueduct bent structure subjected to mainshock-aftershock (MS-AS) ground motion sequences by double incremental dynamic analysis method. The finite element model of the aqueduct bent structure is developed in OpenSees platform and numerical simulation technique is validated through physical test results. A series of nonlinear dynamic time-history analysis is carried out on the aqueduct bent structure to obtain its seismic response under different ground motion intensities. Furthermore, the incremental dynamic analysis (IDA) data cluster and median lines of the damage measure of the aqueduct bent structure are constructed. The advanced probabilistic seismic demand model (PSDM) of the aqueduct bent structure subjected to MS-AS ground motion sequences is proposed. Based on the proposed PSDM and the predefined damage states, the fragility surfaces of the aqueduct bent structure are also developed by adopting the vector-valued intensity measures considering the mainshock intensities (IMm) and aftershock intensities (IMa). Meanwhile, for the sake of comparation, the aftershock fragility curves of the aqueduct bent structure under different mainshock intensities are drawn, which emphasizes the importance of aftershocks in the seismic risk assessment. The analysis results indicate that the proposed piecewise probabilistic seismic demand model can better fit the logarithmic relationship between the aftershock intensities and the median of the reinforcement longitudinal tensile strain. The structural fragility probability increase with the increase of mainshock and aftershock intensities. It turns out that the mainshock intensities play a leading role in the damage probability of the aqueduct structure subjected to MS-AS ground motion sequences, the aftershock can cause additional damage to the aqueduct bent structure and reduce its seismic capacity. The meaningful results can provide supports for seismic optimization design, resilience improvement and post-earthquake repair-demand of the aqueduct structure in Southwest China.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥1 (but ≤3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of 30 November 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 yrs; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Encore Abstract—previously submitted to ASCO 2023 Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract W. Yu Employment or leadership position: Employed by Dizal Pharmaceutical

Phase I Beamion Lung 1 trial of BI 1810631, a HER2 tyrosine kinase inhibitor (TKI), as monotherapy in patients (pts) with advanced/metastatic solid tumors with HER2 aberrations: Updated data.

8545 Background: There is an unmet need for effective TKIs against HER2 mutations in solid tumors, especially NSCLC. BI 1810631 is a highly potent and selective HER2 TKI that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertions (ex20ins), while sparing EGFR. Beamion Lung 1 is an ongoing Phase Ia/Ib study to determine the safety, MTD, PK, PD, and preliminary efficacy of BI 1810631 in pts with HER2 aberration-positive solid tumors (NCT04886804). Preliminary results from Phase Ia are presented. Methods: In Phase Ia, pts with advanced/unresectable/metastatic solid tumors who were refractory or unsuitable for standard treatment (Tx) and had HER2 aberrations (e.g. overexpression, gene amplification, somatic mutation, or gene rearrangements) were enrolled. Pts received escalating doses of BI 1810631 BID starting from 15 mg or BI 1810631 QD starting from 60 mg via a Bayesian model. Phase Ib will initially include 30 pts with advanced HER2 tyrosine kinase domain mutation-positive, pre-treated NSCLC. Additional cohorts may be included. Primary endpoints: MTD based on DLTs; pts with DLTs (Phase Ia); ORR (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire Tx period and PK parameters (Phase Ia/Ib); DoR, DCR, duration of disease control, and PFS (Phase Ib). Results: As of 23 January 2023, 36 pts had been treated in the US, The Netherlands, Japan, and China. Pts had NSCLC (n = 22), colorectal cancer (n = 3), or other tumors (n = 11). Most pts (n = 26; ex20ins: n = 23) had a pathological HER2 mutation. Median (range) lines of prior systemic Tx: 2.5 (1–8). Prior HER2-targeted Tx: 12 (33%). Pts received BI 1810631 at 15, 30, 60, 100, 150 mg BID (n = 3/3/4/4/3) or 60, 120, 180, 240, 300 mg QD (n = 5/4/5/4/1). Median number of cycles was 4 (range 1–14). Tx is ongoing in 20 pts. To date, 3 DLTs have been observed (grade 2 edema [60 mg BID], grade 3 anemia [60 mg QD], grade 3 elevated ALT [180 mg QD]). The MTD has not been reached with either schedule. Tx-related adverse events (TRAEs) were reported in 25 pts (69%). The most common TRAEs were diarrhea (n = 10), anemia (n = 5), increased alkaline phosphatase, increased creatinine, increased ALT, hypoalbuminemia (all n = 4), hypocalcemia, increased AST, dry skin, increased GGT (all n = 3). Three pts had grade 3 TRAEs (anemia/increased GGT [n = 1], increased ALT [n = 2]). Strong preliminary efficacy signals were observed across all dose levels. Of 22 evaluable NSCLC patients, 10 responded (all PRs; all ex20ins) and 11 had SD. Two patients with other tumors (esophagus; cholangiocarcinoma) also achieved PR. Conclusions: These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Updated data, including durability endpoints, will be presented. Clinical trial information: NCT04886804 .

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART SWOG 1609) in patients with refractory gallbladder cancer (cohort 48).

e16330 Background: Immune checkpoint blockade has improved outcomes in multiple tumor types, however little is known about the efficacy of these agents in rare tumors. We report the results of the gallbladder cohort of SWOG S1609 Dual Anti–CTLA-4 and anti–PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the gallbladder cohort reported here. Eligible patients had progressed following at least one line of standard systemic therapy, and did not have an approved or standard therapy available that had been shown to prolong survival. All participants received nivolumab 240 mg i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks on a continuous schedule. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity Results: Nineteen patients (79% female) with a median age of 60 years were enrolled and received treatment. The median prior lines of therapy was 2 (range 1-6). The confirmed overall response rate was 16% [complete response, n=1 (5%); partial response, n=2 (11%)] (duration = 35+, 16, 13 mo). The unconfirmed overall response rate and clinical benefit rate were both 32% [complete response, n=1 (5%); partial response, n=5 (26%); stable disease > 6 months, n=0 (0%)]. The 6-month progression-free survival was 26% (95% CI 12-55%); median overall survival was 7.0 months (95% CI, 3.9-19.1 months). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was one death from hepatic failure possibly related to treatment in the setting of progressive liver metastasis and biliary infection. Conclusions: Ipilimumab plus nivolumab demonstrated a 16% ORR in patients with gallbladder cancer including a complete response lasting 35+ months; The unconfirmed overall response rate was 32%. Clinical trial information: NCT02834013 . [Table: see text]

A phase II clinical trial of chidamide in combination with toripalimab in patients with advanced soft tissue sarcoma.

11566 Background: Chidamide is an oral subtype-selective histone deacetylase inhibitor which is effective on the patients with hematological tumors and reported to enhance the efficacy of checkpoint blockade therapies and regulate the host immune response. Here, we report preliminary results of Chidamide in combination with Toripalimab in soft tissue sarcoma (STS) patients. Methods: An open, single arm, phase II study of Chidamide with Toripalimab in patients with advanced soft tissue sarcoma after failure of standard treatment was conducted. Eligible patients could have any number of prior therapies, excluding HDAC inhibitors and immune checkpoint inhibitors treatment. All patients received Chidamide orally at 30mg twice weekly in combination with intravenous Toripalimab 240mg every 21 days until progression or unaccepted toxicity. The primary endpoint was RECIST1.1 objective response rate (ORR). The secondary endpoint included progression free survival (PFS), overall survival (OS), disease control rate(DCR) and safety. Results: Forty-six patients with advanced soft tissue sarcoma were enrolled. The median age of the patients was 47 years and the median prior lines of therapy were 3. The main subtypes included leiomyosarcoma (30.4%), well/dedifferentiated liposarcoma (30%), myxoid/round cell liposarcoma (7%), undifferentiated sarcoma(9%), and osteosarcoma (7%). Treatment was well tolerated with the most common adverse events mainly in grade Ⅰ and grade Ⅱ, including thrombocytopenia (43.5%), nausea(28.3%), neutropenia(23.9%), fatigue (17.4%) and hypothyroidism(15.2%). Among 46 efficacy-evaluable patients, the overall response rate and disease control rate were 23.9% and 80.4%, respectively. The median time to an initial response was 3 months (range, 2 to 14), and the 3-mon and 6-mon progression-free survival rate were 92.7% and 58.9%, respectively. Conclusions: Chidamide with Toripalimab every 21 days was well tolerated and showed promising efficacy in patients with advanced STS. Clinical trial information: NCT04025931 .

Golidocitinib in treating refractory or relapsed peripheral T-cell lymphoma: Primary analysis of the multinational pivotal study results (JACKPOT8).

7503 Background: Currently there is no consensus on the treatment of relapsed/refractory (r/r) PTCL, and patient prognosis was poor. Golidocitinib is an orally available, JAK1-selective inhibitor currently being evaluated in a multinational, pivotal study in r/r PTCL (JACKPOT8 Part B, NCT04105010). Here we reported the primary analysis of efficacy and safety results of this study. Methods: PTCL patients who had relapsed from or had been refractory/intolerant to ≥ 1 (but ≤ 3) prior systemic therapy(ies) were enrolled to receive golidocitinib at 150 mg once daily until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was CT-based objective response rate (ORR) assessed by an independent review committee (IRC) according to Lugano 2014 classification. The efficacy analysis set included patients whose pathological diagnosis of PTCL had been retrospectively confirmed by a central laboratory and who had at least one measurable lesions at baseline. The safety analysis set included all dosed patients. Results: As of November 30, 2022, a total of 104 patients with r/r PTCL were enrolled and dosed with golidocitinib. Baseline characteristics: median age was 58 years old; 64.4% were male; 20.2% had baseline bone marrow involvement. Major subtypes included NOS (46.2%), AITL (15.4%) and ALCL (9.6%). The median prior lines of therapies were two. All of the patients had been treated with chemotherapies, and 48.1% had also been treated with histone deacetylase inhibitors. By the data cut-off (DCO) date, a total of 80 patients had both IRC assessment and central pathology review results available, and thus were included in the efficacy analysis. Among them, 35 patients achieved tumor response (ORR = 43.8%), including 20 patients (25.0%) achieved complete responses. Tumor response was observed in various subtypes, including AITL (56.3%), NOS (45.7%), ALCL (11.1%) and others (44.4%). In patients who relapsed from HDAC inhibitor treatment, 54.8% achieved tumor response. With a median follow-up of 5.5 months for responders, the median duration of response (DoR) has not been reached. Golidocitinib was tolerated in patients with r/r PTCL. By the DCO date, the longest duration on treatment was 15.7 months (still responding). The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hematological in nature, including neutrophil count decreased (26.0%), white blood cell count decreased (25.0%), platelet count decreased (16.3%) and lymphocyte count decreased (16.3%). TRAEs leading to dose interruption, reduction, and discontinuation were 37.5%, 5.8%, and 7.7%, respectively. The majority of TRAEs were reversible or clinically manageable. Conclusions: Golidocitinib demonstrated its potential as a novel targeted therapy for the treatment of r/r PTCL. The updated data will be presented at the conference. Clinical trial information: NCT04105010 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of TRANSCEND CLL 004.

7501 Background: In patients (pts) with R/R CLL/SLL that progressed on BTKi and failed venetoclax (ven)-based regimens, achieving CR with current treatment is uncommon. New therapies that achieve deep and durable responses are needed. We report the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study evaluating liso-cel in pts with R/R CLL/SLL. Methods: Pts must have received at least 2 prior lines of therapy, including a BTKi. Eligible pts received liso-cel at a target dose of either 50 (DL1) or 100 (DL2) × 106 CAR+ T cells. The primary endpoint was rate of CR and CR with incomplete marrow recovery (CRi) by IRC per 2018 iwCLL criteria in the prespecified subset of efficacy-evaluable pts with disease progression on BTKi and ven failure (primary efficacy analysis set [PEAS]) at DL2 (null hypothesis [H0]: ≤ 5%). Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed pts, 117 received liso-cel (safety set), 96 (DL1 = 9; DL2 = 87) were efficacy evaluable, and 53 (DL1 = 4; DL2 = 49) were in the PEAS. In the safety set, median (range) age was 65 y (49–82), 83% had high-risk features, median (range) lines of prior therapy was 5 (2–12), and all pts had prior BTKi. Median (range) on-study follow-up was 21.1 mo (0.4–55.6) for the safety set. In the PEAS at DL2, the primary endpoint of CR/CRi rate was met at 18.4% (95% CI, 8.8–32.0; 1-sided P = 0.0006; Table). ORR was 42.9% and was not statistically significant (95% CI, 28.8–57.8; 1-sided P = 0.3931). The uMRD rate was 63.3% in blood and 59.2% in marrow. Median (95% CI) DOR was 35.3 mo (11.01–not reached [NR]) with a median follow-up of 19.7 mo. Median duration of CR/CRi was NR. In the safety set, rate of any-grade CRS was 84.6% (gr 3, 8.5%; no gr 4/5) and neurological events (NE) was 45.3% (gr 3, 17.9%; gr 4, 0.9%; no gr 5); 69.2% received tocilizumab and/or corticosteroids for CRS/NEs. Rate of gr ≥ 3 infections, hypogammaglobulinemia, and prolonged cytopenia was 17.1%, 15.4%, and 53.8%, respectively. One death related to liso-cel was due to hemophagocytic lymphohistiocytosis. Liso-cel exhibited rapid in vivo expansion and was detected by qPCR in blood up to 36 mo after infusion. Conclusions: Liso-cel demonstrated durable CR/CRi, high uMRD rates, and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL and high unmet need. Clinical trial information: NCT03331198 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Axi-cel was approved by NMPA to treat R/R LBCL adult patients who had received 2 or more prior treatments in 2021 June. For better understanding the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in real world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is median OS. Here we made an interim analysis and reported clinical outcomes of Chinese patients treated by commercial CAR-T products in real world for the first time. Methods: R/R NHL patients treated with commercial Axi-cel in 17 authorized treatment centers from 11/2021 to 02/2023 were included. All patients signed written informed consents. We reported best objective response rate (bORR), best complete response (bCR) rate and adverse events. Results: A total of 101 R/R NHL patients were efficacy-evaluable. The median age was 56.8 years old, and 25 (24.8%) patients were ≥65 years. Fifty-nine patients were male. Baseline characteristics, including 80 (79.2%) with DLBCL, 4 (4.0%) with PMBCL, and 6 (5.9%) with high grade B-cell lymphoma. Forty-two (44.2%) patients had IPI ≥3 and 18 (24.3%) patients ECOG PS were ≥2. The median prior lines of therapy was 2, including 36 (35.6%) patients got ≥3 previous treatments and 10 patients had history of ASCT. Eighty-four patients were resistant to previous therapy, and the primary refractory subgroup reached 47 (46.5%). Bridging therapy was given in 56 (55.4%) patients, while combination therapy in 29 (28.7%) patients. The median follow-up was 9.2 months. The bORR and bCR was 83.2% (95% CI, 74.4 to 89.9) and 58.4% (95% CI, 48.2 to 68.1) respectively (Figure 1A). Response rates were consistent across key covariates, including disease type, disease stage, IPI score, cell-of-origin subtype, etc. Patients ≥65 years had favorable ORR [92.0% (95% CI, 74.0–99.0)] and CR rate [80.0% (95% CI, 59.3–93.2)]. Median PFS was 12.0 months (95% CI, 7.3 to NA). The median DOR and OS were not reached. No new safety signal was observed in Chinese patients. The most common ≥ grade 3AE were white-cell count decreased (in 87.6% of the patients), neutropenia (in 82.9%), pyrexia (in 73.3%). Eighty-one patients experienced cytokine release syndrome (CRS) of any grade, and 16 (15.2%) patients occurred grade 3 or higher. Any grade of neurologic events (NE) occurred in 17 (16.2%) patients, and only 1 (1.0%) patients were grade 4. No grade 5 CRS or NE appeared (Figure 1B-C). Fifty-five percent received tocilizumab and 52% received glucocorticoids to manage CRS and/or NE. The median cumulative cortisone-equivalent corticosteroid dose was 2000 mg, which was similar to ZUMA-1 cohort6 and much smaller than ZUMA-1 cohort1+2. The research was funded by: The research was funded by Fosun Kite Biotechnology Co., Ltd., Shanghai, China. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies No conflicts of interests pertinent to the abstract.

KontRASt-01 update: Safety and efficacy of JDQ443 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC).

9007 Background: KRAS G12C oncogenic mutations occur in ~13% of NSCLCs and up to 4% of other solid tumors. JDQ443 is a selective, covalent, orally bioavailable KRASG12C inhibitor that irreversibly traps KRASG12C in the inactive, GDP-bound state. Clinical activity was seen in initial cohorts of patients (pts) treated with JDQ443 monotherapy, and 200 mg twice daily (BID) was selected as the recommended dose (RD) for expansion (Tan DS, et al. AACR 2022; Abstract CT033). Methods: KontRASt-01 (NCT04699188) is a Phase Ib/II, open-label, multicenter, dose-escalation (DEs), and dose-expansion (DEx) trial of JDQ443 as a monotherapy or in combination with TNO155 (SHP2 inhibitor) and/or tislelizumab (anti–PD-1 monoclonal antibody). Primary objectives of DEs are to assess safety/tolerability and identify the RD and regimens for future studies. The primary objective of DEx is to assess efficacy. Key inclusion criteria: advanced, KRAS G12C-mutated solid tumors; previous standard-of-care treatment; age ≥18 years; and ECOG PS 0–1. Prior KRASG12C inhibitor treatment is not permitted for the JDQ443 monotherapy arm and is allowed for the JDQ443 + TNO155 and JDQ443 + tislelizumab DEs arms. Results: As of Oct 28, 2022, 84 pts were treated with JDQ443 monotherapy, orally, continuously, in DEs, DEx, and food effect (FE) cohorts at 200 mg once daily (QD; n=10), 400 mg QD (n=11), 200 mg BID (n=56), and 300 mg BID (n=7). Median age was 61 years (range 26–83); median prior lines of therapy was 3 (range 1–7); and indications included NSCLC (n=38), colorectal cancer (n=42), and others (n=4). Median duration of exposure was 14.6 weeks (range 0.1–68.4) for all pts and 15.1 weeks (0.1–68.1) for pts treated at 200 mg BID. Among pts treated at 200 mg BID, 40 (71.4%) and 4 (7.1%) experienced treatment-related adverse events (TRAEs) of any grade (Gr) and of Gr 3, respectively. There were no Gr 4–5 TRAEs at any dose level. The most common TRAEs (any Gr, occurring in ≥10% of pts) at 200 mg BID were fatigue (17.9%), edema (14.3%), diarrhea (16.1%), nausea (16.1%), vomiting (10.7%), and peripheral neuropathy (10.7%). Gr 3 TRAEs were neutropenia in 2 pts, ALT and AST increase in 1 pt, and myalgia in 1 pt. One pt receiving 200 mg BID required a dose reduction due to a TRAE of Gr 2 peripheral neuropathy. Among response evaluable pts with NSCLC treated in DEs and FE cohorts, the confirmed overall response rate was 41.7% (10/24 pts) across dose levels and 54.5% (6/11 pts) at the RD of 200 mg BID. Combination JDQ443 + TNO155 and JDQ443 + tislelizumab arms are enrolling. Additional data will be available at the time of presentation. Conclusions: JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in pts with NSCLC. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443 + TNO155 and JDQ443 + tislelizumab combination arms. Clinical trial information: NCT04699188 .

Luveltamab tazevibulin (STRO-002), an anti-folate receptor alpha (FolRα) antibody drug conjugate (ADC), safety and efficacy in a broad distribution of FolRα expression in patients with recurrent epithelial ovarian cancer (OC): Update of STRO-002-GM1 phase 1 dose expansion cohort.

5508 Background: Luveltamab tazevibulin (luvelta) is a novel FolRα-targeting ADC with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR of 4) that induces cytotoxic and immunologic cell death. Using site-specific conjugation technology, luvelta is designed to target a broad range of FolRα expressing OC. STRO-002-GM1 is a global phase 1 study evaluating luvelta in patients with relapsed OC. We provide updated data from the initial ovarian expansion cohort. Methods: The study enrolled advanced OC pts who had progressive platinum resistant (PROC) after 1-3 prior lines or platinum sensitive disease after 2-3 prior lines of platinum chemotherapy. Pts were randomized 1:1 to received luveltamab at 4.3 or 5.2 mg/kg given IV every 3 weeks until disease progression. Prophylactic corticosteroid eyedrops were not required/administered. FolRα expression was not required for study entry but was analyzed retrospectively in archival tissue using the FOLR1 IHC assay (Ventana Medical Systems). The scoring paradigm assessed percentage of cells with any intensity expression (TPS). TPS >25% was selected for further analysis. Results: 44 pts were enrolled (23 pts at 4.3 mg/kg and 21 pts at 5.2 mg/kg). For pts with a TPS >25% (n=35), the median prior lines of therapy was 2.5 (range 1-3), 69% had prior bevacizumab treatment, and 83% prior PARP inhibitor treatment. Investigator assessed efficacy data for pts with a TPS >25% are presented in the table. The most common grade ≥ 3 treatment emergent adverse events (TEAEs) included neutropenia (70.5%), arthralgia (18.2%), and anemia (13.6%). G3/4 neutropenia had a higher incidence at 5.2 mg/kg than 4.3 mg/kg (76% vs 65%); most notable for G4 neutropenia (52% vs 22%). 1 pt at each dose level had febrile neutropenia. TEAEs led to dose delay in 80% of pts with a higher incidence at 5.2 mg/kg (95% vs. 65%). TEAEs led to dose reduction in 61% of pts with a higher incidence at 5.2 mg/kg (76% vs. 48%). 1 pt had a G5 sepsis with G4 neutropenia. Neutropenia, arthralgia and anemia were managed with standard medical treatment and dose reductions. Conclusions: These dose expansion data confirm activity of luvelta at starting doses ranging from 4.3-5.2 mg/kg in recurrent OC with FolRα expression as low as TPS>25% and supports further clinical study in this population. The global phase 2/3 REFRaME registration study will evaluate luvelta in PROC pts with TPS >25%. Clinical trial information: NCT03748186 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Relapsed/refractory (r/r) peripheral T cell lymphomas (PTCL) are highly aggressive tumors associated with very poor prognosis. We recently described a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2) (Maciocia, PM. et al. Nat Med, 2017) which can spare a proportion of the normal T cell compartment. Here we describe first in human clinical findings of AUTO4, a TRBC1 directed autologous CAR T cell therapy for patients with TRBC1-positive PTCL. Methods: NCT03590574 is an ongoing, multi-centre, single-arm phase 1/2 study of AUTO4 in r/r TRBC1-positive PTCL. Here we report the findings of the dose escalation. Four dose levels were explored: 25 × 106, 75 × 106, 225 × 106, and 450 × 106 CAR T cells were administered as a single dose. CAR T-cell products were generated using a semi-automated closed process. The initial AUTO4 manufacturing process A was optimized and is now being used in process B to define the recommended phase 2 dose. Primary endpoints in phase 1 are incidence of ≥Grade 3 toxicity occurring within 60 days of AUTO4 infusion and the frequency of dose limiting toxicities (DLT) within 28 days of AUTO4 infusion. Overall response (CR + PR) rate by Lugano PET-CT criteria is a secondary endpoint. Results: As of 8 February 2023, 12 patients (10 process A, 2 process B) have been treated with AUTO4. The median age was 57 years (range 34–72) with a median prior lines of 2 (range 1–5). 7 patients were diagnosed with PTCL-NOS, 4 with AITL (Angioimmunoblastic T-cell lymphoma) and 1 with ALCL (Anaplastic large cell lymphoma). Chemotherapy bridging was given to 70% of patients and 4/8 CD30+ patients recieved brentuximab as bridging or as prior line therapy. 3/12 patients had prior autoSCT. The most common treatment adverse events were transient Grade1–4 neutropenia, thrombocytopenia. Lymphopenia was observed with CD3+ lymphocytes recovering to baseline levels after pre-conditioning. No ≥Grade 3 infections were observed. Any grade CRS was observed in 6/12 patients (5 at 450 × 106, 1 at 250 × 106) and one patient developed Grade 3 CRS which resolved within 3 days. No ICANS or DLTs were observed. Response at month 1 was evaluable in 9/10 patients using process A. Five patients were in complete metabolic response (CMR) (1/5 was in CMR at the time of lymphodepletion), 1 patient achieved a partial response (PR) and 3 patients had no response. At the 450x106 dose level, 3/4 patients achieved CMR at month 1, and 2 of them are in ongoing remission at 12 and 15 months, respectively. The efficacy non-evaluable patient at month 1, due to COVID19 infection, showed no response at month 3 but achieved a delayed PR by month 9 without any further treatment. Conclusions: AUTO4 was well tolerated with no DLT. Ongoing CMR at months 12 and 15 are encouraging. Updated data and longer follow up using the improved manufacturing process B will be presented. The research was funded by: Autolus Ltd Keywords: aggressive T-cell non-Hodgkin lymphoma, cellular therapies, ongoing trials Conflicts of interests pertinent to the abstract J. Shang Employment or leadership position: Autolus Therapeutics E. Xue Employment or leadership position: Autolus Therapeutics M. Zhang Employment or leadership position: Autolus Therapeutics S. Basilico Employment or leadership position: Autolus Therapeutics M. Raymond Employment or leadership position: Autolus Therapeutics P. Lao-Sirieix Employment or leadership position: Autolus Therapeutics K. Lilova Employment or leadership position: Autolus Therapeutics W. Brugger Employment or leadership position: Autolus Therapeutics M. Pule Employment or leadership position: Autolus Therapeutics

Sunvozertinib for the treatment of NSCLC with EGFR Exon20 insertion mutations: The first pivotal study results.

9002 Background: Sunvozertinib(DZD9008) is a rationally designed selective, irreversible EGFR exon20 insertion (exon20ins) inhibitor with wild-type EGFR selectivity. Here we reported the results of WU-KONG6, the first pivotal study of sunvozertinib in previously treated NSCLC patients with EGFR exon20ins. Methods: WU-KONG6 (NCT05712902 and CTR20211009) is a phase II, multi-center pivotal study in NSCLC patients with EGFR exon20ins, whose diseases had progressed on or were after platinum-based chemotherapy. Tumor tissue EGFR exon20ins status was tested by local or central laboratory. The primary and key secondary endpoint were objective response rate (ORR) and duration of response (DoR), respectively, assessed by Blinded Independent Central Review (BICR). Patients received 300 mg sunvozertinib once daily until discontinuation criteria were met. Results: Between July 19, 2021, and May 6, 2022, a total of 104 Chinese patients were enrolled into WU-KONG6 study. The efficacy analysis set included 97 patients, whose EGFR exon20ins status was retrospectively confirmed by a central laboratory. A total of 30 different exon20ins subtypes were enrolled. The median age was 58 years; 59.8% (58/97) were female; 95.9% (93/97) were adenocarcinoma; 95.9% (93/97) had metastatic diseases at study entry; 32% (31/97) had baseline brain metastasis; the median prior lines of therapy were 2. By the data cutoff date (October 17, 2022), the BICR assessed confirmed ORR (cORR) was 60.8% (59/97). In patients with baseline brain metastasis, the cORR was 48.5% (15/31). Anti-tumor efficacy was observed irrespective of age, gender, smoking status, prior lines of therapies, prior onco-immunotherapies, mutation subtypes, and baseline brain metastasis. By the data cut-off date, median follow-up time for responders was 7.1 months, and 64.4% (38/59) of responders were still responding. The longest DoR was > 11 months, and the median DoR has not been reached. The safety analysis set included all enrolled 104 patients. The most common treatment emergent adverse events (TEAEs) were similar as what have been previously reported for sunvozertinib, and also similar as that of other EGFR inhibitors. Majority of the TEAEs were grade 1 or 2, and clinically manageable. Conclusions: The first pivotal study results confirmed sunvozertinib’s superior anti-tumor efficacy than the current available therapy for NSCLC with EGFR exon20ins. The safety profile from WU-KONG6 study was consistent with previously reported findings. The updated data will be presented at the meeting. A multinational phase II pivotal study (WU-KONG1, NCT03974022) with the same study design is ongoing in the USA, Australia, and countries/regions in Asia, Europe and South America. Clinical trial information: NCT05712902 .

Phase 2 trial of TRC102 (methoxyamine HCl) with temozolomide (TMZ) in patients with granulosa cell ovarian cancer.

5564 Background: TRC102 is a novel small molecule that binds to reactive aldehyde created in apurinic/apyrimidinic (AP) sites, inhibiting base excision repair (BER), which is implicated as a pathway of resistance to alkylating agents. In preclinical studies, TRC102 demonstrated synergistic anti-tumor activity when TRC102 was combined with the alkylating agent temozolomide (TMZ) and the phase 1 trial of this combination reported 4 patients with partial response, two of which were of granulosa cell ovarian cancer (GCOC) histology. Here we report the phase 2 results of the combination TRC102 and TMZ in the GCOC cohort (NCT01851369). Methods: We conducted an open-label, single center Simon 2-stage trial including patients (pts) with GCOC who received ≥ one line of therapy in the metastatic setting. TRC102 was dosed at 125 mg (100 mg for BSA < 1.6) and TMZ was dosed at 150 mg/m2 orally on day (D) 1-5 in 28-day cycle (C). Restaging CT scans every 2 Cs were evaluated by RECIST v1.1. Mandatory paired biopsies (C1D1 pretreatment and C1D4 3-4 hours after drug administration) and optional blood samples for circulating tumor cells (CTC) were collected at set time points for pharmacodynamic analyses. Results: Nine pts with GCOC (7 adult, 2 juvenile histology) were enrolled as of 12/23/2022. Median age was 53 years (range 21-79) and median prior lines of therapy was 6 (range 3-9). Most common grade (G) 1 and G2 treatment-related adverse events (trAE) were fatigue, myelosuppression, nausea, and vomiting. One pt had G3 trAE of vomiting. No toxicity-related treatment discontinuations and no treatment-related deaths were reported. The median PFS for the 8 evaluable pts was 3.7 months. One pt exited the study after one C per pt’s choice with no restaging available. Four pts had stable disease (SD) as their best response. Of those who had SD, one pt completed 26 Cs prior to progression, one pt completed 11 Cs as of data cut-off but continues on study, two pts completed 6 Cs (one pt went off study for PD and one by pt choice). MGMT analysis was performed for 3 pts, including the pt still on study after 11 Cs with SD. MGMT immunohistochemistry (IHC) of pretreatment biopsies were positive for protein expression, consistent with unmethylated MGMT status. No significant induction in the levels of the DNA damage response markers γH2AX, pNbs1, and RAD51 was detected in 5 evaluable post-treatment biopsy samples as compared to the pre-treatment timepoint. Conclusions: TRC102 combined with TMZ was well-tolerated and demonstrated durable disease control in 4 pts, which is promising in this heavily pretreated GCOC cohort. MGMT analysis suggests that unmethylated MGMT status and protein expression does not preclude response to TRC102/TMZ combination therapy. Analysis of CTCs and biopsy samples are ongoing to further elucidate possible biomarkers of response. Funded by NCI Contract No. HHSN261201500003I. Clinical trial information: NCT01851369 .