Number Of Prior Treatment Lines Research Articles

Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients.

CAR T-cell therapy is a potent immunotherapy for hematologic malignancies, but patients can develop long-term adverse events including second primary malignancies (SPMs) that impact morbidity and mortality. To delineate the frequency and subtypes of SPMs following CAR-T in lymphoma and myeloma, we performed a systematic review and meta-analysis. A literature search was conducted in the MEDLINE, Embase, and CENTRAL (Cochrane) databases. Following extraction of SPM cases and assignment of malignant origin, we analyzed SPM point estimates using random effect models. We identified 326 SPMs across 5,517 patients from 18 clinical trials (CT) and 7 real-world studies (RWS). With a median follow-up of 21.7 months, the overall SPM point estimate was 5.8% (95%CI 4.7-7.2). SPM estimates were associated with treatment setting (CT>RWS), duration of follow-up, and number of prior treatment lines, which were each confirmed as independent study-level risk factors of SPM in a meta-regression model. A subgroup meta-analysis of the four trials that randomized CAR-T versus standard-of-care revealed a similar risk of SPM with either treatment strategy (p=0.92). In a distribution analysis of SPM subtypes, hematologic malignancies were the most common (37%), followed by solid tumors (27%) and non-melanoma skin cancers (16%). T-cell malignancies represented a small minority of events (1.5%). We noted disease- and product-specific variations in SPM distribution. These data raise awareness of SPM as a clinically relevant long-term adverse event in patients receiving CAR T-cell therapy. However, our findings do not indicate that SPM frequency is higher with CAR-T versus previous standard-of-care strategies.

Biological relapse in multiple myeloma: Outcome and treatment strategies in a Spanish real-world setting.

Recommendations regarding the best time to start treatment in patients with relapsed/refractory multiple myeloma (RRMM) after biological relapse/progression (BR) are unclear. This observational, prospective, multicenter registry aimed to evaluate the impact on time to progression (TTP) of treatment initiation at BR versus at symptomatic clinical relapse (ClinR) based on the Spanish routine practice in adult patients with RRMM. Patients had two or less previous treatment lines and at least one previous partial response. Baseline characteristics and treatment outcomes were recorded, and survival was analyzed. Of 225 patients, 110 were treated at BR (TxBR group) and 115 at ClinR (TxClinR group) according to the investigators'criteria. The proportion of patients with higher ECOG, previous noncomplete remission (CR), and second relapse were significantly higher in the TxBR group compared to the TxClinR group. TheTxClinR group showed improved outcomes, including TTP, compared to the TxBR group. Progression-free survival increased in the TxClinR group (56.2 months) compared to the TxBR group (32.5 months) (p = 0.0137), and median overall survival also increased (p = 0.0897). Median TTP was significantly longer in patients relapsing from a CR (50.4 months) and in their first relapse (38.7 months) compared to those relapsing from a non-CR response (32.9 months) and in their second relapse (25.2 months). Physicians seemed to start treatment earlier in RRMM patients with poor prognosis features. Previous responses to anti-MM treatment and the number of prior treatment lines were identified as prognosis factors, whereby relapse from CR and first relapse were associated with a longer time to progression.

Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study

BackgroundThe prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting.Patients and methodsThe study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5.ResultsThe trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3–4 non-haematological toxicities.Conclusions14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

The interim analysis of a first-in-human phase 1 trial of ET-901, a CRISPR edited allogeneic immune-cloaked anti-CD19 CAR-T cell therapy in patients with r/r B-NHL.

e19010 Background: Allogeneic CAR T-cell therapy faces challenges like limited persistence and host rejection. Current research has improved its viability by modifying genes like B2M, despite new challenges like NK cell targeting have emerged. Through CRISPR screening, we discovered a novel gene, named GeneX, and its role in enhancing T cell persistence against allogeneic attacks and AICD. GeneX influences glycan composition, affecting immune responses and AICD initiation. Engineered GeneXKO/TCRKO/anti-CD19 CAR T cells (ET-901) resisted allogeneic killing and maintained anti-tumor effects without causing GvHD, marking a significant advancement in CAR T-cell therapy. Methods: ET-901 is being tested in a phase 1 trial for r/r B-NHL at a single center, utilizing a 3+3 dose escalation scheme and planning for expansion at the recommended Phase 2 dose. Participants must have an ECOG status of 0–2, without a history of allo-HSCT or CAR-T therapy. The study's main goals are to assess ET-901's safety and establish the optimal Phase 2 dosage. Patients undergo a 3-day lymphodepletion with fludarabine (30-50 mg/m2/d) and cyclophosphamide (500-1000 mg/m2/d), followed by a single-dose infusion of ET-901 at escalating doses (DL1:1*10e6/kg, DL2:3*10e6/kg, and DL3:10*10e6/kg). Pharmacokinetic monitoring occurs during follow-up. Results: From September 2023, a total of six patients were enrolled in the escalation cohort, including 4 patients with LBCL and 2 with FL. In these patients (3 males), the median age was 53 years (range: 46–55 years), and the median number of prior treatment lines was 5. The median SPD was 7,650 mm2 (range: 2,700-43,400 mm2). Notably, two cases in DL2 exhibited unusual lymphoma infiltration sites: patient No.4 in the forearm muscle and patient No.5 in the spleen. Update to February 2024, we have completed the safety evaluation of Dose Level (DL) 1 and DL2. No DLTs were observed. The most common TRAEs of any grade included leukopenia (6/6), granulocytopenia (6/6), anemia (6/6), thrombocytopenia (6/6), CRS (6/6), infection (2/6), ICANS (2/6), and GvH like reaction (1/6). All patients achieved objective responses, with 2 cases of PR and 4 cases of CR (1 in DL1, 3 in DL2). The peak values of CAR+ cells count and VCN in peripheral blood were 36.0/μl (range: 14.0-48.0/μl, median: day 7), and 9.6e4 copies/μg (range: 7.7e4-1.2e5 copies/μg, median: day 7), respectively. In all patients, a second expansion of CAR-T cells was observed alongside B cell recovery. This confirms that GeneX knockout enables allo CAR-T cells to maintain long-term immune privilege while preserving their biological function. Conclusions: The study demonstrated the safety and feasibility of ET-901 in patients with r/r B-NHL. These findings highlight the potential of ET-901 as an effective therapeutic approach for improving outcomes for these patients. Clinical trial information: NCT06014073 .

An open-label phase I study to evaluate the safety, tolerability and preliminary efficacy of YY001 in patients with advanced solid tumors.

e15104 Background: Prostaglandin E2 (PGE2) receptor 4 (EP4) is the master regulator of immunosuppressive myeloid cells (IMCs), one of the major drivers of resistance to immune checkpoint blockade therapy. YY001, a novel and selective EP4 antagonist, effectively blocked the function of IMCs and enhanced cytotoxic T-cell mediated tumor elimination in preclinical studies. Here we report the preliminary data of YY001 in Chinese patients with advanced solid tumors from a phase I study approaching completion. Methods: The key eligibility criteria include: patients aged 18 to 75 years with histologically or pathologically confirmed advanced or metastatic solid tumors; refractory to or intolerant of standard treatment; at least one measurable lesion per RECIST v1.1; ECOG PS 0-1. Accelerated titration and classic 3+3 design were applied for dose escalation. The first dose was administrated once orally within 1 hour after a meal. After 3-days observation, patients took YY001 QD orally continuously in each 21-day treatment cycle. Results: 16 eligible patients were enrolled, including 100mg (n = 1)、200mg (n = 1)、300mg (n = 4)、400mg (n = 3)、500mg (n = 7), and no dose limiting toxicity (DLT) occurred. All patients have received multiple prior treatments before enrolling and the median number of prior treatment lines was five. As of the cut-off date (December 18, 2023), the median of treatment duration is 44 days and the longest is 194 days. No treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported. The most common TRAEs were gastrointestinal disorders, alanine aminotransferase increased, fibrin D-dimer increased, alkaline phosphatase increased and hypoalbuminemia. No patients have DLT or AE leading death. 14 patients were evaluated and 2 patients withdrew from the study before tumor assessment. 6 of 14 patients (42.9%) achieved stable disease and 1 patient achieved Non-CR/Non-PD. The disease control rate was 46.2% (95% Cl 19.2, 74.9). The median progression-free survival and median overall survival were 2.38 (95% Cl 1.93, 4.00) and 10.12 (95% Cl 4.01, -) months, respectively. By the cut-off date, 11 patients were still alive, 1 patient was lost to follow-up and 1 patient is still under treatment. PK analysis concluded YY001 exposure increased in human plasma with increasing dose gradients from 100mg to 300mg. From 300mg to 500mg, the drug exposure in human plasma remained essentially the same, suggesting the PK value peak has been reached. The recommended phase II dose would be 300mg to 500mg. In addition, a median t1/2 of 8.7h was derived from 100mg to 500mg dose groups. Conclusions: The preliminary results suggest that YY001 had a manageable safety/tolerability profile and promising efficacy in patients with advanced solid tumors. YY001 will be combined with immune checkpoint inhibitor in a phase II study subsequently. Clinical trial information: NCT06228846 .

Phase I summary of the HB0025 efficacy and safety to the heavily pretreated non-small cell lung cancer (NSCLC) population.

e14600 Background: HB0025 is a recombinant humanized bispecific molecule built on IgG1 that targets the human programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF, VEGF-A, VEGF165). Here we present the NSCLC results in Phase 1 study. Methods: This ongoing, open-label, multicenter, dose escalation and dose expansion, phase 1 trial to evaluate the safety and efficacy of HB0025 for pts with advanced solid tumors. HB0025 is administered intravenously every 14 days (Q2W). Response was evaluated by RECIST v.1.1 every 8 weeks. Results: As of Dec 25, 2023, 12 (7M/5F) NSCLC pts have received HB0025 at doses of 3mg/kg (n=1), 6mg/kg (n=2), 10mg/kg (n=2), 12mg/kg (n=1), 20mg/kg (n=5), 30mg/kg (n=1). Overall, the median age was 61.5 years, the median number of prior treatment lines was 4. The histologic types include squamous cell (Sq)-NSCLC (2 pts) without EGFR/ALK mutation and non- squamous cell (Nonsq)-NSCLC (10 pts), among of Nonsq-NSCLC 9 pts carrying EGFR/ALK mutation. The 3 pts with EGFR/ALK wild-type gene fail to prior anti-PD-1 treatment, 9 pts with EGFR/ALK gene mutation fail to prior TKI therapy. Among the 12 pts having imaging tumor assessment, the ORR was 25% and DCR was 66.7%, which included 3 partial responses (PR) ,5 stable disease (SD), and 4 progressive disease (PD) according to RECIST v1.1.For the 2 Sq-NSCLC pts, one pt achieved PR with 3mg/kg HB0025 treatment, the other pt achieved SD. For the10 Nonsq-NSCLC pts, there were 2 PR (20mg/kg and 30mg/kg treatment, respectively), 4 SD and 4 PD. Till the report date, the PR status and HB0025 treatment are ongoing to 3 PR pts, which includes 1 Sq-NSCLC pt, and 2 Nonsq-NSCLC pts which one pt doesn’t carry EGFR/ALK mutation. The Sq-NSCLC pt whose maximum tumor regression is 60% achieves PR after 4 cycles of treatment, and the duration of response (DOR) is more than 22 months. The one Nonsq-NSCLC pt whose maximum tumor regression is 74% achieves PR after 2 cycles of treatment, and the DOR is more than 11 months. The other Nonsq-NSCLC pt whose tumor regression is 32% achieves PR after 4 cycles of treatment, and the DOR is more than 2 months. Among the 5 SD pts, 1 Sq-NSCLC pt’s progression-free survival (PFS) is more than 14 months and continusous, 2 Nonsq-NSCLC pts’ PFS is more than 6 months and ongoing. For the 12 pts, 11 pts (91.7%) experienced a treatment related adverse events (TRAEs). The most common TRAEs included proteinuria (50%, 6/12), lymphocyte count decrease (50%, 6/12), blood bilirubin increased (33.3%, 4/12), and blood pressure increased (33.3%, 4/12). TRAEs ≥ grade 3 occurred in 2 (16.7%) pts. No TRAE leading to discontinuation and death. Conclusions: HB0025 monotherapy showed an acceptable safety profile and promising anti-tumor activity for prior heavily treated NSCLC, no matter in TKI-resistant population with EGFR/ALK mutation or population failed to anti-PD-1 treatment. Now Phase II studies of combination chemotherapy are ongoing. Clinical trial information: NCT04678908 .

Selinexor combined with tislelizumab in patients with relapsed or refractory extranodal NK/T-cell lymphoma (R/R ENKTL): Results of dose escalation of cohort C, from a multicenter, single-arm, phase I/II study (TOUCH).

7065 Background: ENKTL is a rare subtype of mature T and NK/T cell lymphoma presenting features of highly aggressive clinical course and association with EBV infection.The prognosis remains poor for R/R ENKTL patients (pts) with treatment failure of L-Aspariginase (L-Asp) based regimens, highlighting the need for novel approaches. Monotherapy of tislelizumab (Tis) showed preliminary clinical activity in R/R ENKTL. Selinexor (Sel), a novel XPO1 inhibitor, has demonstrated preclinical synergistic effects when combined with PD-1 antibody. The TOUCH study (NCT04425070) includes three cohorts investigating the combination of Sel with chemotherapy (ICE or GEMOX) or Tis in R/R ENKTL. Methods: Cohort C was designed to evaluate the safety, tolerability, preliminary efficacy of Sel plus Tis in R/R ENKTL. Pts who received at least one prior treatment containing L-Asp were enrolled. In the escalation stage, a 3+3 design was implemented to determine the RP2D of Sel. The starting dose of Sel was 40 mg QW, followed by 60 mg QW (dose level 2), administered orally on Days 1, 8, and 15 of each 21-day cycle. Tis was administered at a fixed dose of 200 mg every 3 weeks on Day 1. DLTs were assessed during the first cycle. Efficacy was evaluated per Lyric 2016. Results: As of 25 Dec 2023, 12 R/R ENKTL pts were enrolled in the escalation stage [Sel 40mg (n=3); Sel 60mg (n=9)]. At study entry, the median age was 52 years (range 32-65); Five males and 7 females; 6 (50.0%) had stage III/IV disease; Seven (58.3%) pts had PINK score ≥2 and 6 (50.0%) pts were circular EBV-DNA positive. The median number of prior treatment lines was 2.5 (range 1-5); Ten (83.3%) pts were refractory to their last-line therapy. Eleven pts had prior exposure to PD-1/PD-L1 antibodies, including 7 pts who had received prior Tis. No DLT was observed and MTD was not reached. The most common TEAEs were asthenia (83.3%), neutropenia (83.3%), nausea/vomiting (58.3%), decreased appetite, weight loss, anemia, thrombocytopenia (50.0%, respectively), lymphocytopenia (41.7%), pneumonia, AST increased and proteinuria (33.3%, respectively). Only 1 pt experienced an irAE with thyroiditis. Seven pts (58.3%) had Grade≥3 TEAEs. TESAEs occurred in 3 pts (25%) with only 1 (sepsis) considered treatment related. No pt discontinued or died due to TEAEs. Among 11 efficacy evaluable patients, ORR was 72.7% (8/11), and CR rate was 36.4% (4/11). Of 7 Tis exposed pts, 2 achieved CR and 3 achieved PR. At a median follow-up of 6.8 months (range 5.5-12.6), the median PFS, DOR and OS were 6.1 months, 4.7 months, and not reached (6-month OS rate 90.9%), respectively. The RP2D of Sel in Cohort C was determined to be 60mg QW. Conclusions: Selinexor plus tislelizumab showed tolerable safety profile and encouraging response rate in R/R ENKTL. Expansion stage of Cohort C is ongoing. Clinical trial information: NCT04425070 .

Abstract PO3-18-12: Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269

Abstract Background: Topoisomerase I inhibitors (Topo I) have been shown to be highly effective across a broad range of tumors including breast cancer. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been shown to be effective in BRCAm breast cancers. The combination of Topo I plus PARPi is known to be synergistic beyond the BRCAm subtype but overlapping myelotoxicities have prohibited successful clinical combinations. DAN-222 is a novel therapeutic HDC (High-capacity drug conjugate) whose payload is the topoisomerase 1 inhibitor camptothecin (CPT). Our previously published preclinical data demonstrates synergy of DAN-222 plus a PARPi regardless of BRCA or HRD status. Furthermore, DAN-222 demonstrates reduced bone marrow exposure enabling clinical combinations. Herein we present data for the first-in-human study of DAN-222 as mono- and combination therapy with a PARPi. The expectation is clinical benefit with this complimentary combination for patients with HRD+ and HRD- tumors, and not restricted to BRCAm, while minimizing overlapping myelotoxicities. Methods: A phase 1 study of DAN-222 as monotherapy and in combination with niraparib is being conducted in heavily pretreated patients with metastatic breast cancer. The objectives are to evaluate the safety, tolerability, and pharmacokinetics of DAN-222, and initial clinical activity based on RECIST v1.1 criteria to determine the recommended phase 2 dose. PK will be characterized for the total conjugated and the unconjugated CPT. Adults (≥18 years) with HER2-negative metastatic breast cancer that progressed on standard therapies were enrolled, without restriction on BRCA or HRD status. Results: As of June 2023, 30 patients had enrolled in dose escalation of monotherapy (2-16 mg/m2) or combination therapy with niraparib (100 mg). The median age was 61.5 years old (range, 36-75). The median number of prior treatment lines was 6. All patients were PARPi naïve and BRCAwt. In the monotherapy cohorts, the hematological adverse events (AEs) were neutropenia (28%; grade [Gr] ≥3: 17%), thrombocytopenia (22%; Gr ≥3: 6%) anemia (17%; Gr ≥3: 0%), and lymphopenia (11%; Gr ≥3: 0%), the non-hematologic adverse events Gr ≥3 was one case of cystitis. In the combination cohorts, the hematological AEs were anemia (25%; Gr ≥3: 17%), thrombocytopenia (17%; Gr ≥3: 8%), neutropenia (8%; grade Gr ≥3: 8%), and lymphopenia 8%; Gr ≥3: 0%) and there was no Gr ≥3 non-hematologic adverse events. The exposure of DAN-222 was linear and increased in a dose-proportional manner. The mean half-life ranged from 25.2 to 33.5 hours across all cohorts. Clinical activity during dose escalation was demonstrated with stable disease in 28% of patients with monotherapy and 67% of patients with combination therapy across all dose levels. Conclusions: No DLTs were observed in monotherapy or combination therapy in the dose escalation phase of this study. This study demonstrates the feasibility for DAN-222 to be combined with a PARPi at clinically relevant doses. The reduced myelotoxicity of DAN-222 will also enable combination with other therapies to treat patients with other types of cancer. The promising antitumor activity seen with DAN-222 in combination with PARPi in BRCAwt, supports continued clinical development. Citation Format: Sara Hurvitz, Erika Hamilton, Timothy Pluard, Aki Morikawa, Hatem Soliman, Kay Yeung, Adam Brufsky, Amy Tiersten, Wajeeha Razaq, Kristen Foye, Timothy Hagerty. Results from a first-in-human study of DAN-222, a novel high-capacity drug conjugate in metastatic breast cancer as monotherapy and in combination with a PARPi [NCT05261269] [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 PO3-18-12.

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer

Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

A Compilation of Experiences in Utilizing CAR-T Cell Therapy for Richter's Transformation

Objective:Even with Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, the prognosis for Richter's Transformation (RT) remains dismal, with a median overall survival (OS) of only 9-12 months from initial diagnosis. Although there are reports on CAR-T therapy for RT, the sample size is small and the conclusions vary greatly. Methods: We conducted a retrospective investigation of the efficacy of CAR-T cell therapy in treating RT at our center. Each participant provided their informed consent to partake in the “Phase II Clinical Trial of Sequential CAR-T Cell Therapy Targeting Different B-Cell Epitopes for Recurrent, Refractory Aggressive B-Cell Lymphoma”(Protocol number: BR-XG-CART-II, ChiCTR2100055062, Ethical Approval Number 20191225-PJ-003). Before lymphocyte collection, chemotherapy regimen without fludarabine/ Bendamustine is first used to reduce peripheral blood tumor load if peripheral blood tumor cells are higher than 10%. Patients with extramedullary tumor loads of 5cm or larger were treated with tumor reduction chemotherapy between lymphocyte collection and CART cell transfusion. The pretreatment scheme based on Bendamustine or FC scheme was adopted before CAR-T cells were infused. The efficacy and safety of CART cells were observed. Results: Between Feb 1, 2020 and Feb 28, 2023, our center administered CAR-T cell therapy to 16 patients diagnosed with RT, all of whom developed into diffuse large B-cell lymphoma. The patient population had a median age of 59 years (range: 42-69 years), consisting of 62.5% (10/16) males and 37.5% (6/16) females. The ECOG scores varied between 0 and 3. The median number of prior treatment lines was 5 (2-7). 93.8% failed previous BTKis treatment and 75% failed BCL2 inhibitor treatment; 93.8% had undergone chemotherapy (median 6 courses). 1 patient had previously failed universal CAR-T cell therapy, and another relapsed after autologous transplantation. 90% had at least one TP53 abnormality detected by either FISH or second-generation gene sequencing. Extramedullary masses were found in 87.5% (14/16) of patients, with a median maximum diameter of 42.5mm (18-144mm). Masses larger than 5cm were found in 25% (4/16) of cases, marrow involvement was noted in 62.5% (10/16), and cerebrospinal fluid was affected in 18.75% (3/16). None of the patients had central masses observed in their MRIs. During lymphocyte collection, 58.3% of patients showed positivity for peripheral blood tumor cells, with a maximum tumor cell proportion of 5.69%. The median infused CAR-T cell dose was 1.37×10 6/kg. 12 of them were injected with mouse CD19CAR-T, 2 with human CD20CART, and 2 with human CD19CART. CRS occurred in 81.3%of patients, of which, 68.8%were grade 1-2 and 12.5%were grade 3. Central CRS occurred in 6.3% (1/16) of patients. The complete response (CR) rate at the 3-month mark stood at 56.3% (9/16), with an overall response rate (ORR) of 68.8% (11/16). As of July 6, 2023, the median follow-up time was 10.6 months (4.4-33.6m), the 1-year OS was 73.4%, and the 1-year PFS was 68.8%. Median OS and PFS were not reached. One of the five patients who did not respond later underwent allogeneic hematopoietic stem cell transplantation and is still alive. The other four, despite attempts at salvage treatment including second CAR-T cell therapy, all died, with a median OS of only 5.6 months (4.4-8.9m). None of the four patients with extramedullary masses larger than 5cm achieved ORR despite tumor-reducing chemotherapy prior to CAR-T infusion. Only 1 of 3 patients with central involvement achieved CR and experienced grade 3 CRS along the way, while the other 2 did not respond to CAR-T therapy. Among all patients, only one experienced central CRS, and his cerebrospinal fluid showed no signs of tumor cells prior to the administration of CAR-T treatment. A patient who was in CR succumbed to an acute coronary event 19 months following infusion, despite remaining in CR. Conclusion: Even in the presence of TP53 gene abnormalities, resistance to BTK/BCL2 inhibitors, and unsuccessful previous chemotherapy regiments, A single CAR T cell therapy can result in CR in more than half of RT patients. Nonetheless, the prognosis remains bleak for patients presenting with large tumor masses and central nervous system involvement, despite having received chemotherapy aimed at reducing tumor size. The outlook is particularly dismal for those patients who fail to respond to CAR-T cell therapy.

Evaluation of the Impact of Tocilizumab Use in Recipients of CAR T Cells for Non-Hodgkin Lymphoma

Introduction: CAR T has revolutionized the treatment of patients with relapsed or refractory (R/R) Non-Hodgkin lymphoma (NHL). Treatment of the major toxicity of cytokine release syndrome (CRS) is tocilizumab (toci) and corticosteroids based on the ASTCT grade. Real-world experiences in the United States and Europe have reported a higher rate of tocilizumab use than in pivotal trials; however, the impact of single or multiple administrations on clinical outcomes is not clear. Methods: Patients diagnosed with diffuse (DLBCL), high grade (HGBCL) and primary mediastinal B cell lymphoma (PMBL) treated at our institution with commercial CAR T were retrospectively identified. The association between the number of doses received with best overall response by day 100, PFS, and OS was investigated through a Cox regression model using a 14-day landmark analysis. Late neutropenia was defined as an ANC <1000/mmc for two consecutive counts beyond day 30 post CAR-T infusion and a 30-day landmark analysis was performed in this case. Results: 230 patients with R/R DLBCL (80%), HGBCL (17%) and PMBL (3%) were included in the analysis. Axicabtagene ciloleucel (Axi-cel), tisagenlecleucel (Tisa-cel), and lisocabtagene maraleucel (Liso-cel) were administered in 62%, 29% and 9% of cases, respectively. Median age at time of CAR-T infusion was 65 years (range 20-86), with a male predominance (63%). The median number of prior treatment lines was 3 (range 1-12), and 21% underwent a prior autologous hematopoietic cell transplant. Disease burden prior to CAR-T infusion can be inferred by the following: bridging therapy was deemed necessary in 77% of patients, pre-lymphodepletion LDH was elevated in 40%, and bulky disease with largest mass diameter was > 10 cm in 10%. CRS and ICANS were grade 2 in 107 patients (46%) and 46 patients (20%), respectively. Median time to first administration of toci was 4 days (range 1-16) with patients receiving 0 (51%), 1 (27%), 2 (14%), or 3-4 (8%) doses. Best response by day 100 for the whole cohort was CR in 138 (60%) and PR in 36 (16%) patients. In univariable analysis, factors associated with a lower likelihood of response were the administration of Tisa-cel (p=0.014), bulky disease (p<0.001), administration of bridging therapy (p=0.009), and being refractory to the last treatment line (p=0.006). Number of doses of tocilizumab did not impact the likelihood of response (p=0.72). In a Cox regression model for survival, number of doses of tocilizumab was not associated with worse PFS (p=0.38, Figure 1) or OS (p=0.64), while other known negative predictors of response had impact on survival, such as bulky and refractory disease. By univariable analysis, tocilizumab administration was significantly associated with prolonged neutropenia (p<0.001). The likelihood to observe an ANC<1000/mmc beyond day 30 increased accordingly to the number of doses received (Figure 2). Other factors associated with late neutropenia were bulky disease (P=0.013), need of bridging therapy (p=0.004), and corticosteroids administration (p<0.001). Conclusion: The number of tocilizumab infusions did not impact CAR T efficacy in terms of overall response and long-term survival, a finding that is concordant with other real-world experiences. The cumulative incidence of late neutropenia events was impacted by the number of doses received. We speculate that a severe CRS driven systemic inflammatory response, requiring several tocilizumab and corticosteroids administrations, may hinder the bone marrow function and recovery.

French Early Nationwide Idecabtagene Vicleucel (Ide-Cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy Experience in Patients with Relapsed/Refractory Multiple Myeloma (FENIX): Update of the IFM Study from the Descar-T Registry

Introduction Prognosis of patients with relapsed/refractory multiple myeloma (RRMM) is poor, particularly in triple-class refractory patients (refractory to a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody). Idecabtagene vicleucel (Ide-Cel) is the first chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) approved by both the European Medicines Agency and the US FDA and the only one available in France through the Early Access Program for treatment (≥ 3 lines) of RRMM. Here we present an update of characteristics and outcome of patients enrolled in this program. Methods We conducted a multicenter, retrospective, observational study that included all consecutive patients with RRMM registered in the DESCAR-T database of patients treated with CAR T therapy, who underwent apheresis up to November 2022 to be treated by commercial Ide-Cel in France. The main objective was to analyze efficacy in terms of response rates, progression free survival (PFS) and overall survival (OS). Secondary objectives included evaluation of safety in terms of cytokine release syndrome (CRS), neurotoxicity, cytopenia, infections and management of relapse including subsequent anti myeloma therapies (sAMT). Results From June 2021 to November 2022, 207 patients were registered in DESCAR-T and underwent leukapheresis to be treated with Ide-cel, 164 (79%) were infused; 43 were not infused: 13 due to rapidly progressive disease or death and 5 due to manufacturing failure. Fifty seven (28%) patients did not meet KarMMa inclusion criteria: cytopenia (n=23), kidney failure (n=13), performance score (PS) >1 (n=15), prior anti BCMA drug conjugate antibody (n=8), prior allograft (n=5). Median age of the 164 patients was 60.5 years (range 34-82), 59% were male, median number of prior treatment lines was 4 (range 2-12) including prior autologous stem cell transplantation in 147 (90%); 130 (80%) were triple-refractory, 47 (29%) were penta-refractory. At diagnosis, 12 (16%) patients had R-ISS stage III disease (89 missing). High tumor burden (> 30% BMPCs) was present in 71 patients (54%) (33 missing). High risk cytogenetic abnormalities defined by del(17p) or t(4;14) were present in 63 patients (58%) (56 missing) and 15 (23%) had extramedullary disease (EMD) (98 missing). One hundred and forty-two (87%) received bridging therapy of which 39 (27%) responded: 25 had partial response (PR); 8 very good partial response (VGPR); 6 complete response (CR). Median time from apheresis to infusion was 62 days. Median follow-up after infusion was 6.2 months. In the first 3 months, overall response rate was 82% (n=134), best achieved response was CR, VGPR and PR in 60 (38%), 36 (23%) and 38 (24%) respectively. Median PFS was 11.6 months (95% CI (7.1; NA)). The 12-month OS was 73% (95% CI (64; 84)). In the first 6 months post-infusion, MRD was analyzed for 45 patients and reached negativity rate in 77%. In univariate analysis, only EMD had a significant impact on PFS: median PFS was 6.3 months (95% CI (3; NA)) for patients with EMD (p = 0.003; HR 3.5, 95% CI (1.55; 7.9)). CRS occurred in 146 (89%) patients, with only 3 cases (2%) of grade ≥ 3. Neurotoxicity occurred in 19 (12%) patients (5 with grade ≥ 3). Ninety-eight (60%) patients received tocilizumab, and 37 (23%) received steroids. Persistent grade ≥ 3 thrombocytopenia, anemia and neutropenia at M1 were observed in 55 (34%), 20 (12%) and 90 (55%) patients, respectively. Forty (24%) patients presented infections grade ≥ 3 in the first six months after infusion. Fifty-two patients progressed during follow-up. 34/52 patients (65%) received a sAMT. Median time from relapse to first administration of sAMT was 0.6 months. Eighteen received bispecific antibodies including 12 anti-BCMA and 6 anti-GPRC5D. Among these 34 patients, a total of 13 (38%) died. Overall, at data cut-off, 26 patients had died, including 9 after disease progression, 4 of acute toxicity and 2 of sepsis. Conclusion This updated study confirms safety and efficacy of Ide-cel in patients with RRMM in real world settings. Response rates and safety were comparable to those reported in the registration trial (Munshi et al., 2021) and American real world study (Hansen et al., 2023). Importantly, patients with EMD had a significant lower PFS. Prognosis data at relapse following ide-cel require a longer follow up and will be presented at ASH.

Efficacy and Tolerance of Brexucabtagene Autoleucel in Adults with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia : A Graall Study from the Descar-T Registry

Background : Brexucabtagene autoleucel (brexu-cel) was recently approved for adult patients with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) based on the results of the ZUMA-3 phase 2 study. After a median follow-up of 39 months, brexu-cel showed a complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 71% and a median overall survival of 26 months (Shah B, et al. ASCO 2023). In the present study, we aimed at investigating the efficacy and safety of brexu-cel in a real-life cohort of adult BCP-ALL patients included in the French early access program. Methods : In this Group for Research on Adult Acute Lymphoblastic leukemia (GRAALL) study, we performed an analysis of the DESCAR-T registry which collects real-life data of patients treated with CAR T-cells since July 2018 in France. All patients who underwent a leukapheresis with an intent to manufacture brexu-cel were included (N=80). Efficacy and safety analyses were performed in the 64/66 infused patients with available response assessment after infusion. The data cut-off was June 2023. The present study reports on best overall response, overall survival (OS), relapse-free survival (RFS), as well as immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (according to ASTCT Consensus). Results : Between May 2019 and February 2023, 80 adults with R/R BCP-ALL from 22 French centers had a leukapheresis for brexu-cel. Among them, 14 patients (18%) were not infused because of death (8 pts), progression (1 pt), manufacturing failure (2 pts), or other causes (3 pts). Among the 64 infused patients with available response assessment, median age was 43.5 yrs (range, 22-69). A Philadelphia(Ph)-chromosome was found in 20/64 (31%). Patients had received a median of 3 (range, 1-6) prior lines of treatment including blinatumomab, inotuzumab ozogamicin and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 67%, 19% and 70% of patients respectively. Twelve patients (19%) had an active CNS disease (CNS2/3) prior to apheresis and 18/40 (45%) had bone marrow blasts ≥ 25% before lymphodepletion (LD). ECOG before infusion was ≥2 in 6/64 (9%) patients. All patients received fludarabine and cyclophosphamide as LD. Median time from apheresis to infusion was 40 days (range, 27-99). CRS and ICANS occurred in 48/64 (77%, grade 3+ in 6%) and 28/64 (45%, grade 3+ in 8%) of patients respectively and were reversible. A CR was achieved in 49/64 patients (77%) of whom 23/25 (92%) were MRD-negative. An older age, a prior allo-HSCT, and the occurrence of CRS were associated with significantly higher CR rates. The median follow-up was 13 months. Three patients were bridged to an allo-HSCT in continuous complete remission (second allo-HSCT for 2 of them). The median RFS and OS were 12.9 months and 15.6 months respectively (Figure). In patients who achieved a CR, median OS was 25.8 months (Figure). Patients with CNS involvement before leukapheresis had a significantly shorter RFS (HR 5.4, 95%CI 1.9-15.8, p=0.002) and OS (HR 3.3, 95%CI 1.4-8.2, p=0.008). Number of prior treatment lines, prior inotuzumab, prior blinatumomab, or pre-LD BM blast% were not associated with outcome. A better OS was observed in patients with prior allo-HSCT (HR .4, 95%CI 0.2-0.9, p=0.04). Conclusion : This multicenter real-life study confirms the efficacy and acceptable safety profile of brexu-cel in adult patients with R/R BCP-ALL. It also suggests that patients with CNS involvement, that were not eligible to ZUMA-3 study, have a limited benefit of brexu-cel when compared to other patients.

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma

Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi). The pivotal ZUMA-2 trial demonstrated very good efficacy of brexu-cel in r/r MCL and tolerable safety including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (Wang et al. J Clin Oncol. 2022). Allogeneic stem cell transplantation (alloSCT) is potentially curative but is associated with high treatment related mortality (TRM) and clinically significant graft-versus-host disease (GvHD). The optimal choice of treatment between brexu-cel and alloHCTs is unclear. We conducted a propensity score matched (PSM) analysis of brexu-cel and alloSCT in patients (pts) with r/r MCL. Methods Pts from ZUMA-2 were matched with alloSCT pts from the EBMT database. Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi. We performed a 1:1 nearest neighbor matching without replacement, balanced for 5 baseline parameters: age, sex, number of prior treatment lines, time from diagnosis to cellular immunotherapy, and prior autologous stem cell transplantation (autoSCT). The primary endpoint was overall survival (OS) from cellular immunotherapy. The following secondary endpoints were analyzed: progression-free survival (PFS), TRM, defined as incidence of deaths which are related to the treatment and occurred in absence of disease progression, and rate of GvHD. Competing risks were defined as relapse, progression or treatment-unrelated death for TRM, and death for GvHD. The EBMT registry includes pts who actually underwent alloSCT. To characterize the dropout rate prior to cellular therapy, we conducted a multicenter intent-to-treat (ITT) analysis and identified 77 pts with r/r MCL for whom an unrelated donor search was initiated and an alloSCT was intended. Results Sixty-four of 68 pts from the ZUMA-2 cohort were included in the study; 4 pts were excluded because of inability to anonymize. A total of 270 pts who had undergone alloSCT and met eligibility criteria were identified in the EBMT registry. Patient characteristics between the brexu-cel and the alloSCT cohorts were imbalanced. Brexu-cel pts were older (p<0.001), had more prior lines of treatment (median 3 vs 2, p<0.001), had less prior autoSCT (41% vs 71%, p<0.001), and had longer time between diagnosis and treatment (53 vs 40 months, p=0.01). After 1:1 PSM matching, criteria were well balanced between cohorts. Median follow-up time was 36.5 and 46.4 months for the brexu-cel and the matched alloSCT cohort, respectively. PFS and long-term OS were similar between both cohorts (Fig. 1A). However, the risk of death within the first 12 months was significantly lower in the brexu-cel cohort vs the alloSCT cohort (logistic regression with inverse probability of censoring weighting, risk ratio=0.5, 95% confidence interval [CI] 0.3-0.9, p=0.02). This was mainly attributable to the significantly higher TRM rate in the alloSCT cohort (alloSCT vs brexu-cel: cause specific hazard ratio=7.7, 95% CI 1.9-31.6, p=0.005, Fig. 1B). The cumulative incidence of acute GvHD grade ≥3 at 3 months and chronic GvHD at 24 months was 17.9% (95% CI 9.1-29.0%) and 44.3% (95% CI 30.6-57.2%), respectively. In our ITT analysis, the dropout rate was significantly higher in the cohort intended to receive alloHCT (23%, [18/77]) vs the cohort intended to receive brexu-cel (8% [6/74]; Fisher test, p=0.01). For alloSCT, failure to proceed to cellular therapy was related to progression in 13%, change of patient's preference in 5% and ineligibility in 4%; in the brexu-cel cohort this was due to manufacturing failures in 4% and progression in 3%. Conclusion Brexu-cel is an effective treatment in pts with r/r MCL post-BTKi with a superior safety profile compared with alloSCT, as indicated by lower 12-month mortality, lower TRM, and absence of chronic GVHD-related morbidity. Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented.

CART-AI-Radiomics: Survival and Neurotoxicity Prediction in B-Cell Lymphoma Patients Treated with CAR-T Cells through an Imaging Features-Based Model

Background: Despite clinical outcome improvements observed in relapsed/refractory (R/R) B-cell lymphoma patients (pts) treated with antigen receptor modified T-cells (CAR-T cells), a sizeable proportion still progress or relapse after infusion. Besides, this procedure is associated with significant morbidity primarily due to the immune effector cell-associated neurotoxicity syndrome (ICANS). The main goal of the CART-AI-Radiomics study is to apply artificial intelligence to develop new imaging-based prognostic and predictive models that integrate molecular and imaging biomarkers towards improved stratification of pts at high risk of R/R. In this sub-study, we retrospectively assessed the ability of imaging features and clinical data to predict survival and neurotoxicity. Methods: Consecutive pts diagnosed of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) treated with anti-CD19 CAR-T cells from 2019-2022 in Valencia Clinic Hospital and La Fe Hospital were included (cut-off date: July 2023). All the pre-infusion flourine18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18F-FDG PET/CT) scans and clinical data were collected. The volume of interest (VOI) was manually contoured for all visible lesions in the PET/CT imaging exams. A subsequent imaging features extraction was performed. Features included PET conventional parameters-maximum standardized uptake value (SUV max), metabolic tumor volume (MTV; defined as the volume of voxels with SUVs higher than the threshold of 41% × SUV max) and total lesion glycolysis (TLG)-and radiomic features. Imaging parameters were calculated for all lesions (total) and for the dominant lesion (DL), whereas clinical variables were measured before lymphodepletion (LD). Univariate and multivariate analyses were carried out using Cox proportional-hazards models for survival prediction and logistic regression for neurotoxicity assessment. Survival analyses were conducted according to MTV total values. Results: A total of 29 pts (median age 63.2 [range 21.8-79.3] years; 18 [62.1%] females) who received CAR-T cell therapy were included. Twenty-six (89.7%) pts had DLBCL and 3 (10.3%) had PMBCL. At the time of pre-LD, 22 (75.9%) pts had increased lactate dehydrogenase (LDH) levels 18 (62.1%), presented with stage IV disease, 16 (55.17%) with an International Prognostic Index (IPI) score of 3-5, 8 (27.6%) had bulky disease. Median number of prior treatment lines was 2 (range 2-6). Twenty-three (79.3%) pts were treated with axicabtagene ciloleucel and 6 (20.7%) with tisagenlecleucel. Bridging therapy before LD was required by 26 (89.6%) pts. For survival analyses, a cut-off MTV total value of 236.03 mL that maximized the Log-Rank statistic was selected to divide pts into high MTV total and low MTV total categories. Median overall survival (OS) was 5.7 [3.2-NA, 95% CI] months and 36.2 [13.9-NA, 95% CI] months for the high and low MTV total, respectively (Fig. 1). In multivariate analyses, a model including MTV total, SUV max and TLG total as imaging feature, and ICANS, C-reactive protein LD (CRP LD), LDH LD, lymphocytes count LD (Li LD) as clinical variables was able to successfully predict OS ( p = 0.019). Median progression-free survival (PFS) was 3 [1.31-NA, 95% CI] months and 11.06 [5.81-NA, 95% CI] months for the high and low MTV total, respectively. In multivariate analysis, a successful prediction of PFS ( p = 0.007) was achieved with a model including the same predictors that were used for OS. For the neurotoxicity assessment, a logistic regression model including six conventional PET parameters-MTV total, MTV DL,TLG total, TLG DL, median SUV DL, SUV max-two radiomic features,-entropy and entropy DL-and four clinical variables-CRP LD, LDH LD, Li LD and type of CAR-T cell treatment-was able to successfully predict the development of ICANS with an area under the curve of 0.971, a sensitivity of 0.813, a specificity of 0.846 and an accuracy of 0.828 (Fig. 2). Conclusions: Imaging features extracted from pre-infusion 18F-FDG PET/CT images in combination with several clinical features could predict survival and neurotoxicity in pts with DLBCL or PMBCL treated with CAR-T cell therapy. Quantitative features extracted from the PET/CT imaging exams may be useful for patient risk stratification and neurotoxicity prediction. Validation of these classifiers in independent datasets is warranted.

Efficacy and Safety of Belantamab Mafodotin Monotherapy in Patients with Relapsed or Refractory Light Chain Amyloidosis: A Phase 2 Study By the European Myeloma Network

Introduction Belantamab mafodotin (belamaf) targets B-cell maturation antigen (BCMA) expressing plasma cells (PCs) and is approved for heavily pretreated patients (pts) with relapsed/refractory (RR) multiple myeloma. Clonal PCs in light-chain (AL) amyloidosis also express BCMA; thus, belamaf could be a treatment option for RRAL amyloidosis pts. We present an interim analysis of the prospective EMN27 study assessing efficacy and safety of belamaf monotherapy in RRAL amyloidosis pts. Methods The ongoing prospective, open-label, multinational, phase 2 EMN27 study (NCT04617925) aims to enroll 36 adult pts with RR (defined as ≥2 cycles of therapy directed against PC clone) AL amyloidosis, adequate hematologic, hepatic, renal, and cardiac function, and ECOG ≤2. Pts at Mayo cardiac stage 3B or with previous exposure to anti-BCMA agents are excluded. Monotherapy with belamaf at a starting dose of 2.5 mg/kg (or 1.92 mg/kg for toxicity) is administered by intravenous infusion every 6 weeks for up to 8 cycles. Pre-planned study analyses included an interim safety (after first 6 pts received ≥1 treatment cycle) and an efficacy analysis (after 13 pts were enrolled). Outcomes of both were favorable and study enrollment is ongoing. This descriptive analysis included pts initiating treatment ≥3 months before 31/05/2023 (cutoff date). Results Twenty-eight pts have been included in this analysis (median [range] age: 66 years [46-80]; male: 16 [57%]). At screening, 5 (18%), 15 (54%), and 8 (29%) pts were rated as Mayo stages I, II, and IIIA, respectively. Most pts had cardiac involvement (22, 79%), followed by those with renal (17, 61%) and peripheral nerve (6, 21%) involvement. Most pts (21, 75%) had New York Heart Association class II symptoms and the median N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, and difference in involved and uninvolved free light chain (dFLC) were 1,393 ng/L (90-7,270), 34 ng/L (3-116), and 119 mg/L (38-2,791), respectively. The median number of prior treatment lines was 4 (1-10). Twenty-one (75%) pts had previously received daratumumab (dara) (12 [42.9%] dara refractory pts), while 24 (86%) pts had previously received bortezomib, both with median of 4 (1-10) prior treatment lines. At cutoff, 4 (14%) pts were continuing therapy, 21 (75%) pts discontinued (disease progression/inadequate response: 9 [32%]; adverse events [AE]: 8 [29%]; withdrew consent: 1 [4%]; death 3 [11%]), and 3 (11%) pts completed treatment. Median belamaf cycles administered were 3 (1-8). Ninety-five belamaf doses were given (2.5 mg/kg: 72, 1.92 mg/kg: 23). Eleven (39%) pts had 23 belamaf dose holds due to AE/SAE, with median delay of 21 (7-128) days from planned administration. At a median follow up of 16 months (4-26), the overall hematologic response (≥partial response [PR]) and very good partial response (VGPR) rates were 54% (15 pts) and 32% (9 pts), respectively ( Table). Median times to first hematologic response and VGPR were 15 (7-148) and 43 (15-106) days, respectively ( Table). Median duration of hematologic response (time from first response to hematologic progression or treatment/disease-related death) was not reached either for all pts or for pts pre-treated with dara. At 1 and 3 months, the respective overall hematologic responses were 39% (11 pts) and 50% (14 pts). Respective rates for pts with prior dara exposure were 29% (6 pts) and 43% (9 pts). For all pts, 3-month organ response rate was 14% (4 pts; Table). All pts experienced >1 AE (ocular AEs: 27 [96%] pts; hematologic toxicity: 8 [30%] pts; cardiac disorders: 7 [25%] pts); no new cardiac or renal toxicity observed. Three (11%) pts had a fatal AE, all considered unrelated to belamaf. Twenty-two (79%) pts had visual acuity reduced (grade [Gr]1: 3 (11%); Gr2: 8 [29%]; Gr3: 10 [36%]; Gr4: 1 [4%]), 22 (79%) keratopathy (Gr1: 10 [36%]; Gr2: 8 [29%]; Gr3: 4 [14%]; Gr4: 0 [0%]), and 7 (25%) visual impairment (Gr1: 1 [4%]; Gr2: 4 [14%]; Gr3: 1 [4%]; Gr4: 1 [4%]). Conclusions In heavily pretreated pts with RRAL and limited treatment options, belamaf monotherapy achieved an overall hematologic response of 54% without unexpected toxicity. Results suggest belamaf could be a treatment option for RRAL amyloidosis, a difficult to treat population. Further evaluation of belamaf in combination with other active agents could allow longer intervals (i.e., 8-12 weeks) between belamaf doses, which has shown to reduce ocular toxicity, while maintaining efficacy.

Patient-Reported Outcomes Among Patients with Triple-Class Refractory Multiple Myeloma in Real-World Clinical Practice: A Prospective, Multi-Site Observational Study

BACKGROUND Several studies have highlighted the poor outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one PI, one IMiD, and one anti-CD38 mAb) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients in real-world clinical practice who initiate a new line-of-therapy. METHODS A prospective, multi-site observational study of patients with TCR MM was conducted through the Mayo Clinic system. Patients initiating a new post-TCR therapy (defined as the index date) were followed for a 12-month observation period during which PRO surveys were administered for the first 6 months. For patients initiating a CAR-T therapy, a survey assessment was conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and then every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). Patient surveys were supplemented with retrospective chart reviews conducted 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient visit data as of April 2023. RESULTS N=55 patients (60% male, 96% White, mean age 66 years) were included in this interim analysis. The median time interval between becoming TCR and the index date was 3.9 months (interquartile range [IQR]: 1.7, 15.5). Most patients had an ECOG score of 0 or 1 (53% and 38%, respectively) and were R-ISS I or II (36% and 54%, respectively); 53% of patients had high-risk cytogenetics and 20% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4.0, 5.5). N=24 patients initiated a CAR-T therapy as their index therapy (equally split between ide-cel and cilta-cel); the remaining N=31 patients predominantly initiated a treatment regimen containing an IMiD (52%), a PI (55%), an anti-CD38 antibody (13%), or an alkylating agent (36%). Among CAR-T patients, QOL and disease-related symptoms worsened from baseline through Month 2-3 (eg, mean GHS was 65.9 at apheresis, 64.9 at lymphodepletion, and 53.3 at Month 2 [higher scores indicate better QOL]; mean DS domain score from the QLQ-MY20 was 24.1 at apheresis, 23.4 at lymphodepletion, and 33.7 at Month 2 [higher scores indicate more symptoms]; see Table 1). These decrements were followed by improvement back to baseline levels and, in some cases, improvement above baseline levels (eg, GHS was 67.9 and 65.0 at Months 4 and 5, respectively; DS was 18.3 and 17.8 at Months 4 and 5), though few patients had sufficient follow up to analyze QOL at later timepoints. Based on the PGIC, 77.8% of patients reported being “a little better” or “much better” as early as Month 1, though this number declined over time. Among non-CAR-T patients, QOL largely plateaued (GHS was 62.2 at baseline and 58.3 at Month 6), though disease symptoms improved over time (DS was 28.6 at baseline and 24.5 at Month 6; pain was 42.3 at baseline and 29.2 at Month 6). Based on the PGIC, 34.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 50% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, QOL and symptom measures generally worsened over the first few months for CAR-T patients in the real-world though improved to baseline levels and beyond at later time points. Patients did, however, directly report improvement in their disease state as early as Month 1 based on the PGIC. Non-CART patients generally showed a QOL plateau with some modest improvement in disease symptoms which was also reflected in their self-reported assessment of disease state improvement based on the PGIC.

Predictors of survival outcomes in patients (pts) with advanced solid tumors treated with cellular therapies in early clinical trials.

e14532 Background: Treatment strategies utilizing adoptive cell therapies (ACT) have shown promising survival benefits for hematologic malignancies. ACT are also known for the potential high-risk side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Numerous ACT have been tested for solid tumors in phase 1 clinical trials, however no prognostic biomarkers were reported previously. We investigated prognostic markers for toxicities and survival outcomes of pts with solid tumors treated with ACT in a Phase 1 Program. Methods: Pts with advanced or metastatic solid tumors were enrolled in phase 1 ACT trials in the Investigational Cancer Therapeutics Department at The University of Texas MD Anderson Cancer Center. MD Anderson Cancer Center (MDACC) prognosis score was calculated based on the number sites of metastatic sites, lactate dehydrogenase (LDH), albumin, performance status (ECOG) and if gastrointestinal (GI) primary tumors. Clinical and biological characteristics were collected from prospectively maintained electronic medical records and databases. Results: From August 29, 2017 to May 19, 2022, 72 pts received cell therapy in 11 clinical trials. A total of 58% were female (n = 42), 89% white (n = 64) and 26% had GI cancers (n = 19). The median number of prior treatment lines was 3 (interquartile range - IQR = 2) and all pts had received prior chemotherapy. The median baseline MDACC score for all participants was 2 (IQR = 1). The median overall survival (OS) was 7 months (95% CI 5.1-8.8). Day 30+, Day 100+, and Day 365+ mortality rates were 3% (n = 2), 19% (n = 14), and 64% (n = 46), respectively. In total, 64% (n = 46) of pts experienced CRS, with 3 pts having > grade 2, while 13% (n = 9) experienced ICANS, with 1 pt having > grade 2 toxicity. Factors associated with higher rates of mortality at Day 100+ included a diagnosis of GI cancer (37% vs 13%, p = 0.041), more than 2 metastatic sites (37% vs 8.9%, p = 0.003), lung metastasis (29% vs 10.5%, p = 0.043), cardiovascular comorbidity (42% vs 15%, p = 0.048), and MDACC score greater than 1 (33% vs 3%, p = 0.001). Median overall survival (OS) was significantly shorter in pts with GI cancer diagnosis when compared to other cancer types (5 vs 8 months, p = 0.007), no history of prior targeted therapy (7 vs 8 months, p = 0.028), albumin < 3.5 (0 vs 6 months, p < 0.001), hemoglobin < 12 (6 vs 10 months, p = 0.006), and MDACC score > 1 (5 vs 12 months, p = 0.017). Conclusions: MDACC prognosis score of greater than 1 was associated with a reduced OS of pts with advanced solid tumors who received ACT in a phase I clinical trial setting. Further investigation is warranted in larger populations to validate these prognostic factors.

Dose escalation results from a first-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors.

3015 Background: c-Met overexpression is common in non-small cell lung cancer (NSCLC), gastroesophageal adenocarcinoma (GEA), and colorectal cancer (CRC). There is a need for effective therapies that target c-Met–overexpressing tumors, as there are currently no approved options available. The antibody-drug conjugate (ADC) ABBV-400 consists of the c-Met–targeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload. ABBV-400 exhibited sustained antitumor activity in patient-derived xenograft models of c-Met–expressing NSCLC, GEA, and CRC. Herein, we present data from the dose escalation of the first-in-human study of ABBV-400 monotherapy. Methods: A phase 1 dose escalation/expansion study of ABBV-400 has been initiated in patients with advanced solid tumors (NCT05029882). Primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of ABBV-400, to determine the recommended phase 2 dose, and to assess preliminary efficacy. PK will be characterized for the conjugate, total antibody, and free payload. Adults (≥18 years) with an advanced solid tumor that progressed on standard therapies were enrolled during dose escalation, without restrictions on the basis of c-Met overexpression status. Results: As of January 2023, 47 patients had enrolled in dose escalation with a median follow-up of 6.5 months. Median age was 58 years (range, 34–79), 25 (53%) patients were male, and the most common cancer types were CRC (n=21), NSCLC (n=5), and GEA (n=5). The median number of prior treatment lines was 4 (1–13). Most common hematologic adverse events (AEs) were anemia (66%; grade [G]≥3: 38%), neutropenia (62%; G≥3: 43%), thrombocytopenia (43%; G≥3: 26%), and leukopenia (32%; G≥3: 19%). Nausea (60%, all grade 1–2), fatigue (49%; G≥3: 4%), and vomiting (38%, all grade 1–2) were the most frequent non-hematologic AEs. One patient experienced grade 1 interstitial lung disease. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were dose and exposure dependent. Clinical activity was observed with ABBV-400, with an objective response rate of 24.4% (11/45; 95% CI: 12.9, 39.5). All responses were confirmed partial responses (PR). In addition, 23 patients (50.0%) had stable disease (SD) and 7 (15.2%) had progressive disease. Among patients with CRC, 4/21 (19.0%) had a PR and 13/21 (61.9%) had durable SD, with a disease control rate of 81.0% (95% CI: 58.1, 94.6). Outside of CRC, PRs were observed in patients with NSCLC ( EGFR wildtype and mutant), uterine cancer, and acral melanoma. Conclusions: On the basis of DLTs, a maximum tolerated dose of ABBV-400 was identified. At this dose, safety results appear comparable with other Top1i ADCs. Promising antitumor activity was seen with ABBV-400 across tumor types, justifying further evaluation in the ongoing dose expansion in NSCLC, GEA, and CRC. Clinical trial information: NCT05029882 .

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche