Independent Review Committee Assessment Research Articles

Phase 2 Trial of Enfortumab Vedotin in Patients With Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma in China.

Enfortumab vedotin, a fully human monoclonal antibody-drug conjugate (ADC) directed to Nectin-4, prolonged overall survival (OS) versus standard chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma (mUC) previously receiving a programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor and platinum-based chemotherapy in the pivotal, phase 3 EV-301 clinical trial, supporting global approvals of enfortumab vedotin monotherapy. This bridging study was the first to evaluate enfortumab vedotin monotherapy in previously treated Chinese patients with locally advanced or mUC. EV-203 was a multicenter, open-label, phase 2 study (NCT04995419) assessing efficacy, safety/tolerability, pharmacokinetics (PK), and immunogenicity of enfortumab vedotin in 40 Chinese patients (PK analysis set, n = 13) with previously treated locally advanced or mUC. Patients received enfortumab vedotin 1.25 mg/kg (Days 1, 8, and 15). Primary endpoints included confirmed objective response rate (ORR) by the independent review committee (IRC) and PK parameters of ADC, total antibody (TAb), and free monomethyl auristatin E (MMAE). Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; immunogenicity; and safety/tolerability. As of May 13, 2022, the median follow-up was 6.5 months. Confirmed ORR was 37.5% (n/N = 15/40; 95% CI: 22.7%-54.2%) by IRC and 42.5% (n/N = 17/40; 95% CI: 27.0%-59.1%) by investigator assessment. By IRC, DCR was 72.5% (n = 29), median DOR was not reached, and median PFS was 4.7 months. Median OS was not reached. Endpoints assessed by investigators were consistent with IRC assessments. Two patients discontinued treatment for treatment-related adverse events. No new safety signals were identified. ADC, TAb, and free MMAE were characterized in Chinese patients and consistent with previously characterized populations. The incidence of positive antitherapeutic antibodies postbaseline was 0%. Enfortumab vedotin demonstrated meaningful clinical activity with a manageable safety profile in Chinese patients with previously treated locally advanced or mUC. ClinicalTrials.gov identifier: NCT04995419.

A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study.

8513 Background: A multinational pivotal study WU-KONG1 (NCT03974022) has been conducted to assess sunvozertinib (DZD9008) in pre-treated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (exon20ins). Here we report the results of primary analysis. Methods: WU-KONG1 Part B is a phase 2, multinational pivotal study to assess the antitumor efficacy of sunvozertinib at two dose levels, 200 mg and 300 mg, in platinum pre-treated NSCLC patients with EGFR exon20ins. Eligible patients were randomized at the ratio of 1:1 to receive 200 mg or 300 mg sunvozertinib once daily until discontinuation criteria were met. Randomization was stratified by brain metastasis at baseline and number of regimens of prior systemic anti-cancer therapy. The primary endpoint was Independent Review Committee (IRC) assessed objective response rate (ORR) (per RECIST v1.1) and key secondary endpoint included IRC assessed duration of response (DoR). Results: As of January 4, 2024, a total of 184 patients were randomized to receive sunvozertinib treatment at 200 mg or 300 mg. Patients who met the predefined criteria for efficacy analysis were included in the primary analysis. The majority of patients (96.0%) had metastatic diseases, 60.7% had ECOG PS of 1, and 23.7% had baseline brain metastasis. All patients received prior platinum-based chemotherapy for advanced NSCLC, and 43.4% and 13.3% had prior onco-immunotherapy or amivantamab treatment. Per IRC assessment, the best ORR was 54.3% (41.0% confirmed and 5.8% pending confirmation). Confirmed complete response (CR) was achieved in 2.9% patients. The disease control rate (including CR, PR and stable disease) was 90.8%. The primary endpoint met its predefined target, with statistical significance. Tumor response was observed in patients with baseline brain metastasis, different demographics and EGFR exon20ins subtypes. With median follow-up time of 5.5 months for responders, the duration of response has not been reached, with 74.6% responders still responding. The PFS data are not mature with approximately 6-month follow-up. Safety findings were similar to previously reported results of sunvozertinib in other clinical studies. The most common drug-related TEAEs included diarrhea, skin rash and CPK increase. The majority of the TEAEs were CTCAE grade 1 or 2 and clinically manageable. Conclusions: In this primary analysis of WU-KONG1 multinational pivotal study, sunvozertinib demonstrated promising antitumor efficacy in platinum pre-treated NSCLC with EGFR exon20ins, with a tolerable safety profile. The updated data will be presented at the meeting. Clinical trial information: NCT03974022 .

A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom’s macroglobulinemia

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer

BackgroundBintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell...

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. Dizal Pharmaceutical.

Kinetics of Complete Remission (CR) and CR Duration and Its Impact on Overall Survival (OS) and Event-Free Survival (EFS) in Quantum-First

Background Results from the phase 3 QuANTUM-First study (NCT02668653) showed that in patients (pts) with newly diagnosed (nd) acute myeloid leukemia (AML) and positive for FMS-like tyrosine kinase 3-internal tandem duplication ( FLT3-ITD+), the addition of the oral, highly potent, and selective, type 2 FLT3 inhibitor quizartinib (Quiz) to standard chemotherapy ± allogeneic hematopoietic cell transplantation (allo-HCT), followed by continuation monotherapy for up to 3 years, decreased the relative risk of death by 22.4% vs placebo (PBO) (PMID: 37116523). We assessed 1) the impact of CR duration on OS and EFS and 2) the kinetics of CR achievement over time after induction. Methods QuANTUM-First enrolled pts aged 18-75 years with FLT3-ITD+ nd AML, randomized to receive standard induction chemotherapy with either Quiz (40 mg/d) or PBO, and stratified by region (Europe, North America, or Asia/Australia/South America), age (&amp;lt;60 years, ≥60 years), and white blood cell count (WBC; &amp;lt;40×10 9/L, ≥40×10 9/L) at diagnosis. Pts who achieved CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine combined with Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years (36 cycles) of continuation therapy with Quiz (30-60 mg/d) or PBO. OS was the primary endpoint, EFS and rates of CR and composite complete remission (CRc) were secondary endpoints; CR duration was an exploratory endpoint. The impact of CR duration on OS was analyzed by extended Cox regression model stratified by region, age, and WBC count at diagnosis and included treatment group and CR duration status (time-dependent covariate). CR duration status was 0 for pts who did not achieve CR, 1 for CR pts throughout the duration of sustained CR, and 0 for CR pts after they relapsed. Results Of the 539 randomized pts enrolled in QuANTUM-First (Quiz, n=268; PBO, n=271), there were 297 CR pts (Quiz, n=147; PBO, n=150) based on independent review committee assessment after 1 to 2 courses of induction. Among 533 treated pts, 20% had 2 induction cycles. Baseline characteristics in CR pts were well balanced between arms: median age in years (range), 56.0 (23-75) vs 55.5 (20-74); females, 55.8% vs 60.0%; ECOG ≥1, 64.6% vs 63.3%; mutated NPM1 / CEBPA,66.7% vs 64.7% / 25.9% vs 23.3%; variant allele frequency (VAF) &amp;gt;25%, 68.7% vs 66.7%; and WBC count at diagnosis ≥40×10 9/L, 55.8% vs 49.3%. Median OS in CR pts was not reached (95% CI 48.6 months-NE) in the Quiz arm vs 35.4 (95% CI 15.1-NE) months in the PBO arm (HR 0.572, 95% CI 0.400-0.816; Figure 1). Although CR rates were similar between arms (55% in both), median CR duration was longer with Quiz vs PBO (38.6 months, 95% CI 21.9-NE vs 12.4 months, 95% CI 8.8-22.7; HR 0.621, 95% CI 0.451-0.857). Based on the extended Cox model, CR duration status covariate was strongly predictive for OS (HR 0.156, 95% CI 0.113-0.216; nominal P&amp;lt;0.0001; Figure 2). Importantly, the HR for Quiz vs PBO effect on OS in the model with the time-dependent covariate CR duration status was higher (HR 0.851, 95% CI 0.672-1.076) vs the HR of the primary OS analysis (HR 0.776, 95% CI 0.615-0.979), implying that a substantial fraction of OS benefit was mediated through its effects on achieving a durable CR (Figure 2). EFS favored Quiz over PBO when induction treatment failure (ITF) was defined as not achieving CRc or CR, by the end of induction up to day 56 from the last induction cycle, with HR 0.729 (95% CI 0.592-0.897; nominal P=0.0031) and 0.818 (95% CI 0.669-0.999; nominal P=0.032), respectively. EFS was similar between arms when ITF was defined, according to FDA guidance, as not achieving CR by day 42 from the start of the last induction cycle (HR 0.916, 95% CI 0.754-1.114; P=0.24; primary EFS analysis). Between day 42 and the end of the induction phase, there were 51 pts who achieved CR (Quiz, n=33; PBO, n=18), and they were considered as ITF with EFS event on day 1 in the primary analysis of EFS. Among these 51 pts, 9 (Quiz, n=5; PBO, n=4) had CRi by day 42 and became CR after day 42 in the induction phase. Conclusions These analyses demonstrated that in QuANTUM-First: 1) a substantial fraction of the estimated effect of Quiz on OS was mediated through its effect on achieving a durable CR and 2) more pts in the Quiz arm vs the PBO arm achieved CR after day 42 of the last induction cycle, suggesting that there was a delay in CR achievement with Quiz. Longer EFS was observed in Quiz over PBO based on the EFS definition including CRs between day 42 and end of induction.

PI3Kδ Inhibitor Linperlisib As a ≥ 3-Line Treatment for Relapsed or Refractory Follicular Lymphoma: A Subgroup Analysis of a Phase II, Single-Arm, Open-Label Trial

Introduction Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL), originating in follicular central B cells, and accounts for approximately 22% of all newly diagnosed cases of NHL. Chemo-immunotherapy is the standard treatment option for FL. Unfortunately, the progression of the disease to relapsed or refractory FL (r/r FL) is still inevitable, which raised concern about subsequent effective treatments. Several δ isoform of phosphatidylinositol 3-kinase (PI3K-δ) inhibitors have ever been approved for r/r FL after ≥2 lines of prior therapies. However, most of their indications for r/r FL were withdrawal for increased risk of death and serious side effects. The latest data from the Chinese phase II clinical trial of linperlisib (Trial registration ID: NCT04370405), a novel oral PI3Kδ-selective inhibitor, in patients with r/r FL who had received at least two systemic therapies were presented. In this trial, linperlisib demonstrated compelling efficacy and was generally well-tolerated in the treatment of r/r FL patients after ≥2 prior systemic therapies. Linperlisib was approved by China National Medical Products Administration (NMPA) for adult r/r FL previously treated with at least two system therapies in November 2022. The ≥3 lines of treatment options are still unmet for the r/r FL. In this setting, this subgroup analysis of the linperlisib phase II trial aimed to evaluate outcomes of linperlisib in later-line treatment of r/r FL. Methods This study included all the patients with r/r FL who had received at least two systemic therapies previously enrolled in the open-label, single-arm, phase II trial (linperlisib, 80mg, po, q.d., in a 28-day cycle), with overall response rate (ORR) as the primary endpoint. In this subgroup analysis, the patients were divided into two groups according to the treatment lines they received: &amp;gt;3 prior lines of treatment and ≤3 prior lines of treatment. All of the statistical analyses were descriptive. Results A total of 84 r/r FL patients from 25 sites in China from April 2019 to September 2020 were enrolled in this trial, with a cutoff date of September 30, 2021. The ORR was 79.8%, with statistical significance in a heavily pretreated FL patient population with a median of 4 prior therapies, with a well-tolerated safety profile. A total of 43 patients received &amp;gt;3 prior lines of treatment, while 41 patients received ≤3 prior lines of treatment. The median age between the two groups was similar (range: 29.0 - 78.0, 52.0 years for &amp;gt;3 prior lines vs. 48.0 years for ≤3 prior lines). The majority of patients had Ann Arbor staging III-IV (40 for &amp;gt;3 prior lines vs. 34 for ≤3 prior lines). The median number of prior regimens was 4 for &amp;gt;3 prior lines and 3 for ≤3 prior lines. Overall, there were 67 patients achieved responses, with ORR of 83.7% (36, 95%CI:69.3, 93.2) for &amp;gt;3 prior lines vs. 75.6% (31, 95% CI: 59.7, 87.6) for ≤3 prior lines based on independent review committee assessment. Compared with patients who received ≤3 prior lines, patients received ≤3 prior lines achieved higher disease control rate (41[95.3] vs. 37 [90.2%]). The median DOR was 12 months (95% CI: 7.3, 15.9) for &amp;gt;3 prior lines vs. 13 months (95% CI: 9.2, NE). The median PFS was 11.9 months (95% CI: 9.1,19.4) for &amp;gt;3 prior lines vs. 13.3 months (95% CI: 8.2, NE) for ≤3 prior lines. The OS of both groups was not reached. The most common treatment-related adverse events (≥20%, TRAEs) were neutropenia (21 [48.8%] for &amp;gt;3 prior lines vs. 18 [43.9%] for ≤3 prior lines), leukocyte count decreased (15 [34.9%] vs. 15 [36.6%]), alanine aminotransferase increased (10 [23.3%] vs. 9 [22.0%]), lymphocyte count decreased (9 [20.9%] vs. 5 [12.2%]), hypertriglyceridemia (9 [20.9%] vs. 11 [26.8%]), and hypercholesteremia (6 [24.0%] vs. 7 [11.9%]). The most common grade ≥3 TRAEs (≥10%) were neutropenia (9 [20.9%] vs. 4 [9.8%]), pulmonary inflammation (3 [7.0%] vs. 6 [14.6%]), infectious pneumonia (2 [4.7%] vs. 5 [12.2%]). Conclusions This subgroup analysis revealed that linperlisib could achieve benefit in r/r FL patients who received at least 2 prior system therapies regardless of treatment lines. The AEs were well-tolerated. Further trials with large-scale samples were warranted.

Subgroup Analysis from a Phase 2, Single-Arm Trial of the Oral PI3Kδ Inhibitor Linperlisib in Patients with Relapsed or Refractory Follicular Lymphoma

Background In our previous phase 2 trial (NCT04370405), linperlisib, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, demonstrated encouraging activity and manageable safety in adult patients with relapsed/refractory (R/R) follicular lymphoma (FL) who had received at least 2 prior systemic therapies. It's crucial to note that FL patients with bone marrow involvement (BMI) generally present more unfavorable prognosis. Here, we present a subgroup analysis from this phase 2 study, which is specifically focused on BMI at baseline. Methods Details of the trial design and study population have been previously reported. In brief, eligible patients (age &amp;gt; 18 years; histologically confirmed relapsed or refractory FL; disease progression post at least 2 prior systemic therapies) received 80 mg linperlisib tablets daily in a 28-day cycle, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC); secondary endpoints included the duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety profile. For this subgroup analysis, patients were grouped based on the presence or absence of BMI at baseline. For those with baseline BMI, biopsies were evaluated to confirm complete responses. Evaluations of antitumor response were conducted every 2 treatment cycles, following the guidelines of the International Research Working Group. Results As previously reported, 84 patients included in the full analysis set (FAS). By subgroup, 25 had baseline BMI and 59 did not. Baseline characteristics by subgroup are shown in Table 1. In this subgroup analysis, a trend toward higher response rate was seen in R/R FL patients with BMI compared to those without such involvement: ORR based on IRC assessment was 88.0% vs 76.3%; best overall response (BOR) of CR was 24.0% vs 11.9%; BOR of PR was 64.0% vs 64.4%. Patients with BMI had DCR that was consistent with those without BMI (92.0% vs 93.2%). The median DOR and PFS were similar across this subgroup (DOR: 11.7 months vs 13.0 months; PFS: 13.3 months vs 13.7 months) (Table 2). Although the median OS was not reached, 12-month OS rates for patients with and without BMI was 91.7% and 91.5%, respectively (Table 2). Safety was evaluated in all R/R FL patients who had received ≥1 dose of linperlisib. Rates of any-grade treatment-related adverse events (TRAEs) were similar across this subgroup and comparable with the overall population (Table 2). When compared to the overall population, patients without BMI experienced fewer grade ≥3 TRAEs, while a marginally higher incidence of grade ≥3 TRAEs was observed in patients with BMI (Table 2). Conclusions This subgroup analysis indicated that linperlisib is an effective and well-tolerated treatment option for patients with R/R FL, irrespective of BMI. Although minor differences were observed in this subgroup, their significance is limited due to the small sample sizes and probably do not alter the overall clinical benefit of linperlisib. Nevertheless, these findings warrant further investigation.

Matching-Adjusted Indirect Comparison (MAIC) of Efficacy and Safety of Lisocabtagene Maraleucel (liso-cel) and Mosunetuzumab for the Treatment (Tx) of Third Line or Later (3L+) Relapsed or Refractory (R/R) Follicular Lymphoma (FL)

Background:The tx landscape of R/R FL is evolving with the availability of anti-CD19 chimeric antigen receptor (CAR) T cell therapies and CD20xCD3 bispecific T-cell-engaging monoclonal antibodies (mAb). Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell therapy which recently reported a positive benefit-risk tx profile for the 3L+ tx of patients with R/R FL (Morschhauser F, et al. ICML 2023; LBA4). Mosunetuzumab, a CD20xCD3 bispecific T-cell-engaging mAb, is approved for the tx of R/R FL after 2 or more lines of therapy (LOT). In the absence of head-to-head data, we conducted an unanchored MAIC to compare the efficacy and safety of liso-cel and mosunetuzumab for the 3L+ tx of patients with R/R FL. Methods: Unanchored MAICs were used to estimate population-adjusted relative tx effects between individual patient-level data from TRANSCEND FL (NCT04245839; data as of January 27, 2023; median follow-up of 19.3 months) and aggregate data from GO29781 (NCT02500407; data as of August 27, 2021; median follow-up of 18.3 months; N = 90). For TRANSCEND FL, the leukapheresed (intention to treat [ITT]) set (N = 114) was used for primary comparisons of efficacy endpoints: Progression-free survival (PFS), objective response rate, and complete response rate (all per independent review committee assessment). Overall survival was not analyzed due to the low rate of events. The treated efficacy set (n = 101) was used for a sensitivity analysis of efficacy comparisons. The treated set (n = 107) was used for comparisons of safety endpoints: cytokine release syndrome (CRS), neurological events (NEs), serious infections, and use of corticosteroids or tocilizumab for CRS. Baseline characteristics and outcome measures in TRANSCEND FL were redefined to align with those reported in GO29781. Data from TRANSCEND FL were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among patients from GO29781. A panel of expert clinicians selected and ranked tx effect modifiers separately for efficacy and safety endpoints. For efficacy, factors adjusted for included number of prior systemic LOTs, progression of disease ≤ 24 months from initiation of immunochemotherapy, bulky disease at screening, FL International Prognostic Index risk factor, refractory to last therapy, double refractory to an anti-CD20 antibody and alkylating agent, ECOG PS at screening, sex, and prior autologous HSCT. For safety, factors adjusted for included age, bulky disease at screening, refractory to last therapy, number of prior systemic LOTs, ECOG PS at screening, Ann Arbor stage, and sex. Hazard ratios (HR) were used to compare PFS, and odds ratios (OR) were used for response rates and safety outcomes. Results: After adjusting for all available factors, when compared with mosunetuzumab, liso-cel was associated with higher objective response rate (OR, 3.78 [95% CI, 1.48‒9.67]), and complete response rate (OR, 6.46 [2.85‒14.65]), and improved PFS (HR, 0.28 [0.16‒0.49]) based on an effective sample size (ESS) of 71.4 (Figure). Results were consistent across all scenario analyses, including unadjusted comparisons and sensitivity analyses using the treated efficacy set for TRANSCEND FL. Although liso-cel was associated with higher incidence of any-grade CRS (OR, 1.86 [1.01‒3.43]) and any-grade NEs (OR, 2.16 [0.72‒6.44]), it demonstrated a lower incidence of grade ≥ 3 CRS (OR, 0.45 [0.04‒5.13]) and grade 3-4 serious infections (OR, 0.35 [0.12‒1.03]) based on an ESS of 81.9 compared with mosunetuzumab. Furthermore, liso-cel was associated with reduced use of corticosteroids for CRS management (OR, 0.14 [0.03‒0.65]), while the use of tocilizumab was higher in patients treated with liso-cel (OR, 2.27 [0.86‒5.99]). Conclusions: In this MAIC, liso-cel was associated with improved efficacy compared with mosunetuzumab. Liso-cel had a lower incidence of grade ≥ 3 CRS, grade 3-4 serious infections, and steroid use for management of CRS; however, liso-cel exhibited higher incidence of any-grade CRS, any-grade NEs, and tocilizumab use for CRS management. Safety comparisons were confounded by preventative use of corticosteroids in all patients in GO29781 and definition differences, most notably for NEs. These findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ tx option for R/R FL.

Clinical Outcomes of Patients with Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 Elara 3-Year Follow-up

Background: Tisagenlecleucel is approved in the United States and Europe for adults with relapsed/refractory follicular lymphoma (r/r FL) after ≥2 lines of prior therapy. The primary analysis of the Phase II ELARA trial (median follow-up: 17 months) reported high response rates and a favorable safety profile in heavily pretreated patients with r/r FL. Here we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after a median follow-up of more than 3 years. Methods: Eligible patients with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody [mAb] and alkylating agent) received a single tisagenlecleucel infusion (0.6-6×10 8 CAR+ viable T cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with clinical response. Cellular kinetics were assessed using quantitative polymerase chain reaction. Results: As of March 29, 2023, 97 patients were infused and had a median follow-up of 41 months (range, 34.2-49.7). At baseline, 68% of patients were double refractory to anti-CD20 mAb and alkylating agent, 65% had bulky disease (&amp;gt;7 cm or 3 lesions &amp;gt;3 cm), and 63% had progression of disease within 2 years of frontline systemic therapy (POD24). Comorbidities included cardiac disorders (9%), diabetes (9%), and renal insufficiency (5%). Among 94 patients evaluable for efficacy, best overall response (BOR) of complete response (CR) rate by independent review committee assessment was 68% (95% CI, 57.7%-77.3%) and overall response rate (CR + partial response) 86% (95% CI, 77.5%-92.4%). Median progression-free survival (PFS) was 37 months; 36-month PFS was 53% in all patients and 69% in patients with a BOR of CR. In the POD24 subgroup, 36-month PFS was 50% (n=61) compared with 59% for patients without POD24 (n=33) (Figure). CAR transgene persistence was observed for up to 1290 days. Patients without POD24 had higher median in vivo CAR expansion and longer persistence than patients with POD24. Median duration of response (DOR) was not reached; 64% of responding patients had ongoing response at the time of the 36-month analysis. Among patients with a BOR of CR, 73% had an ongoing response at the time of the 36-month analysis. High baseline levels of circulating CD8+ naive T cells (&amp;gt;2.14% of total T cells) were associated with prolonged PFS and DOR. Median overall survival (OS) and median time to next treatment were not reached. The OS rate at 36 months was 82%, and probability of starting a new treatment at 36 months was 35%. In the POD24 subgroup, 36-month OS rate was 83% compared with 81% in patients without POD24 (Figure). No new safety signals were reported. The most common grade ≥3 adverse events (AEs) were neutropenia (43%) and anemia (19%). The most common serious AEs were cytokine release syndrome (20% [Lee grading]), pneumonia (11%), and febrile neutropenia (8%). To date 18 patients have died during the study (progressive disease, n=8; AE, n=9; euthanasia, n=1). Conclusions: Patients with r/r FL maintained a high rate of durable responses more than 3 years after tisagenlecleucel infusion, including patients in high-risk subgroups such as POD24. Tisagenlecleucel's safety profile remains favorable with no new safety signals during extended follow-up. Correlative analyses suggest higher baseline levels of CD8+ naive T cells (&amp;gt;2.14%) are associated with improved long-term clinical outcomes.

Golidocitinib in Treating Refractory or Relapsed Peripheral T- Cell Lymphoma: Full Analysis of the Multinational Pivotal Study Results (JACKPOT8)

Introduction: Golidocitinib is the first JAK1 selective inhibitor to enter into pivotal clinical development for the treatment of relapsed/refractory peripheral T cell lymphoma (r/r PTCL). Preliminary analysis of the JACKPOT8 study (NCT04105010) has shown promising antitumor efficacy and a manageable safety profile of golidocitinib. Here we reported the full analysis of the phase 2 multinational pivotal study JACKPOT8 Part B. Methods: This study enrolled r/r PTCL patients who had undergone at least one line of systemic therapies. All patients received golidocitinib at 150 mg once daily (QD) until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was a CT-based objective response rate (ORR) assessed by an independent review committee (IRC) per Lugano 2014 criteria. Other efficacy endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The efficacy analysis set included patients whose pathological diagnosis of PTCL has been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at the baseline assessed by IRC. The safety analysis set included all dosed patients. Results: A total of 88 efficacy evaluable patients with r/r PTCL were included in the analysis. The median age was 57.5 years, and the majority (64.8%) were male. The major pathological subtypes included PTCL NOS (56.8%), AITL (18.2%), and ALCL (11.4%). At the baseline, 54.5% of patients had ECOG PS of 1, 52.3% had elevated LDH levels, and 21.6% had bone marrow involvement. The median prior lines of therapies were two. All patients had been treated with chemotherapies, 50% had been treated with histone deacetylase inhibitors, and 10.2% had received CD30 targeted therapy. Per IRC assessment based on CT imaging, 39 patients achieved tumor response, with an ORR of 44.3% (95% CI: 33.7%, 55.3%), and 26 patients (29.5%) achieved complete response. The primary endpoint met the pre-defined target with statistical significance ( p &amp;lt; 0.0001). Tumor response was observed in various subtypes, irrespective of age, gender, baseline bone marrow involvement, and ECOG PS. With a median follow-up time of 10.4 months for DoR, 59% of responders were still event-free. The median DoR has not been reached, with an estimated 12-month DoR rate of 70.2%. With a median follow-up time of 9.6 months for PFS, the median PFS was 5.6 months. The longest PFS was 20 months, and the patient was still responding. Per investigator assessment, 34 patients achieved tumor response (ORR: 38.6%). The DoR and PFS by investigator assessment were similar to that of IRC assessed results. With a median follow-up time of 15.1 months for OS, approximately 60% of patients were still alive, with an estimated median OS of 19.2 months. A total of 112 patients were included in the safety analysis set. The median relative dose intensity was 100%. A total of 62 patients (55.4%) reported ≥ grade 3 treatment-emergent adverse events (TEAEs). The most common drug-related ≥ grade 3 TEAEs were hematological adverse events in nature, including neutropenia (25%), leukopenia (23.2%), and lymphopenia (18.8%). The majority of TEAEs were reversible and clinically manageable. Treatment-related AEs leading to dose interruption, reduction, and discontinuation were reported in 36.6%, 7.1%, and 8% of patients, respectively. Conclusions: This pivotal study met its primary objective, suggesting golidocitinib can be an effective treatment option with a manageable safety profile for patients with r/r PTCL. The updated data will be presented at the conference.

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study

Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, brain metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. No treatment-related deaths occurred. Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. F Hoffmann-La Roche.

MAHOGANY: A phase 3 trial of zanubrutinib plus anti-CD20 antibodies vs lenalidomide plus rituximab in patients with relapsed or refractory follicular or marginal zone lymphoma.

TPS7590 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in &gt;15 countries, including the United States and European Union, for pts with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab (ZO) vs obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, ZO in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody vs lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1-3A) or MZL, previously treated with ≥1 anti-CD20–based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to ZO (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 years vs &lt; 60 years), number of prior lines of therapy (1-2 vs &gt; 2) and rituximab-refractory status (yes vs no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC), according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 years vs &lt; 60 years) and number of prior lines of therapy (1-2 vs &gt; 2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Clinical trial information: NCT05100862 .

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

Introduction: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, zanubrutinib plus obinutuzumab in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody versus lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1–3A) or MZL, previously treated with ≥1 anti-CD20-based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to zanubrutinib plus obinutuzumab (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 vs. <60 years), number of prior lines of therapy (1–2 vs. >2), and rituximab-refractory status (yes vs. no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC) according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 vs. <60 years) and number of prior lines of therapy (1–2 vs. >2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract L. Sehn Consultant or advisory role AbbVie, Seattle Genetics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Kite, a Gilead Company, Merck, Teva, TG Therapeutics, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Honoraria: Amgen, AbbVie, Gilead Sciences, Janssen-ORtho, Kite, a Gilead Company, Merck, Roche/Genentech, Seattle Genetics, Teva, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Research funding: Roche/Genentech, Teva C. Sarkozy Consultant or advisory role Janssen, GSK, Incyte, BMS Honoraria: AbbVie Research funding: Roche Educational grants: Roche, Incyte Other remuneration: Incyte A. Salar Consultant or advisory role BeiGene, Roche Research funding: Roche, AbbVie Other remuneration: Kite, a Gilead Company, Janssen J. Trotman Consultant or advisory role BeiGene WM Advisory Board 2022 (uncompensated) Research funding: BeiGene, Janssen, Pharmacyclics, Roche, Celgene/BMS, Selectar P. L. Zinzani Consultant or advisory role Celltrion, Gilead Sciences, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Roche, EUSA Pharma, Kyowa Kirin, Takeda, Secura Bio, TG Therapeutics, Novartis, ADC Therapeutics, Incyte, BeiGene, Novartis J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene P. Fustier Employment or leadership position: BeiGene Stock ownership: BeiGene R. Delarue Employment or leadership position: Celgene/BMS, BeiGene Stock ownership: Celgene/BMS, BeiGene L. Nastoupil Consultant or advisory role Sirpant, Iterus Bios Honoraria: Gilead Sciences, Novartis, Janssen Oncology, TG Therapeutics, BMS, ADC Therapeutics, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche, Caribou Biosciences Research funding: Janssen Biotech, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda, BMS/Celgene Educational grants: Genentech/Roche

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

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 .

Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9056 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated rapid, deep, and durable responses in patients (pts) with TRK fusion lung cancer (Drilon et al. ASCO 2022) and is considered a preferred first-line therapy option for these pts (Owen et al. J Clin Oncol 2022). We report updated data from a larger cohort with longer follow-up. Methods: Pts with TRK fusion lung cancer enrolled in 2 larotrectinib clinical trials (NCT02576431 and NCT02122913) were included in this analysis. Larotrectinib was administered at 100 mg twice daily, and response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2022, 30 pts with a median age of 55.5 years (range 25–81) with TRK fusion lung cancer enrolled, including 12 pts with CNS metastases at baseline. The gene fusions involved NTRK1 (n = 24; 80%) or NTRK3 (n = 6; 20%). Pts received a median of 2 prior lines of systemic therapies, with 20 pts (67%) receiving ≥2. Among 27 pts eligible for IRC assessment, the objective response rate (ORR) was 74% (95% CI 54–89): 3 complete responses, 17 partial responses (PR), 4 stable disease (SD), 2 progressive disease (PD), and 1 not evaluable. Among the 12 pts with baseline CNS metastases, the ORR was 67% (95% CI 35–90): 8 PR, 2 SD, and 2 PD. The median time to response for all responders was 1.8 months. Median duration of response (DoR) was 33.9 months (95% CI 9.5–not estimable [NE]); median follow-up was 22.9 months. Median progression-free survival (PFS) was 33.0 months (95% CI 11.3–NE); median follow-up was 24.7 months. Median overall survival (OS) was 39.3 months (95% CI 17.2–NE); median follow-up was 23.1 months. For the 12 pts with CNS metastases, the medians for DoR, PFS, and OS were 9.5, 9.9, and 19.4 months, with median follow-ups of 17.4, 19.3, and 22.2 months, respectively. Duration of treatment for all pts evaluable per IRC ranged from 0.3+ to 75.2+ months. At data cut-off, 10 pts had progressed, with 6 continuing treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in 5 pts (2 each increased aspartate aminotransferase, increased weight; 1 each increased alanine aminotransferase, myalgia, hypersensitivity). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset with longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival, and favorable long-term safety in pts with advanced TRK fusion lung cancer, including those with CNS metastases. These results support the wider adoption of next-generation sequencing testing for NTRK1–3 gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 , NCT02122913 .

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

Introduction: Anbal-cel is a novel autologous anti-CD19 CAR-T cell therapy which has been knocked-down for PD-1 and TIGIT expression using OVIS platform. It demonstrated superior T-cell functionality compared to other marketed CD19 CAR-T cells at preclinical studies. Phase 1 dose escalation study confirmed anbal-cel is safe and potentially effective. Methods: Patients with relapsed or refractory LBCL were enrolled from six Korean investigator sites to receive anbal-cel at a dose of 2 × 106 CAR-T cells/kg. Primary endpoint is objective response rate (ORR) assessed by Independent Review Committee (IRC). Secondary endpoints are progression-free survival (PFS), duration of response (DOR), pharmacokinetics (PK) and safety profiles. Results: As of 28 February 2023, a total of 41 patients were infused and 34 patients completed at least one tumor response evaluation at day 28. With the median age of 63 (range 37–82), 66% of the patients (27/41) were double expressor. Non-GCB type was 76% (31/41) and 42% (17/41) were primary refractory patients. Median follow-up period was 4.6 months. ORR (CR/PR) assessed by investigators was 85.3% and CR rate at day 28 & month 3 were 73.5% (25/34) and 71.4% (22/31) respectively. IRC assessment result was similar and will be presented at the meeting. Among the 41 patients, grade 3 CRS and ICANS were reported from 6 patients (14.6%) and 2 patients (4.9%) respectively. No grade 4 CRS and ICANS was observed. Prolonged neutropenia was observed in 11 patients (26.8%) and thrombocytopenia was observed in 12 patients (29.3%). Three (7.3%) serious infections (1 bacteria and 2 COVID-19 infections) were reported during primary follow-up period. Responder group (CR) reported higher incidence and severity of CRS compared to non-responder group (Non-CR), but it was insignificant. Incidence rate, severity of ICANS and prolonged cytopenia were comparable between the two groups. Among CAR+ T-cells in the anbal-cel product, median CD4:CD8 ratio was 3.6 and CCR7+ memory phenotype CAR T-cells account for 65.8% of CAR-T cells. Median knock-down rates of PD-1 and TIGIT were 65% and 96% respectively. The responder group showed a significantly increased level of CCR7+ memory phenotype (68.6% vs. 44.9%) and PD-1 knock-down rate (71.8% vs. 59.3%) compared to the non-responder group, which showed correlation with increased levels of AUC0-28days and Cmax. Anbal-cel expansion was not correlated to tumor volume measured by SPD and TMTV. In addition, the responder group had notable changes in cytokine levels of IL-2, IL-10, IFN-γ, granzyme, GM-CSF and peak levels of various cytokines were proportional to severity of CRS. Patients with higher levels of IL-15 and MCP-1 at baseline had tendency to experience ICANS. Conclusions: Anbal-cel demonstrated unique characteristics in product profile which demonstrated potential to correlate with treatment outcomes and warrant to confirm with more data. The research was funded by: Curocell Inc. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, immunotherapy No conflicts of interests pertinent to the abstract.

Abstract CT228: Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials

Abstract Background: NTRK gene fusions are oncogenic drivers in various tumor types. Laro, a highly selective and central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, is approved for the treatment of patients (pts) with TRK fusion cancer. Laro demonstrated an objective response rate (ORR) of 69% in 244 pts with solid (non-primary CNS) tumors (Drilon et al. ASCO 2022). Here, we report on the concordance between baseline local tissue-based testing with central tissue-based and liquid biopsy-based ctDNA testing to identify NTRK gene fusions. Methods: Pts with non-primary CNS TRK fusion cancer who underwent independent review committee assessments by July 15, 2019, in three laro clinical trials (NCT02122913, NCT02576431, and NCT02637687) were included. Tumor NTRK gene fusion status was determined locally by a variety of methods, and centrally by next-generation sequencing in both tissue (using Illumina TruSight™ Oncology Comprehensive) and ctDNA (using Guardant360® or GuardantOMNI®) at baseline. Data cut-off: July 20, 2021. Results: Of the 164 pts with NTRK fusions identified by local testing, 117 had evaluable tissue samples for central testing, and 99 had evaluable liquid biopsy samples. In total, 81.2% (95/117) of tumors had the fusion confirmed by central tissue testing. ctDNA testing detected NTRK gene fusions in 33.3% (33/99) of patients. Positive predictive values for each NTRK gene fusion are shown in the Table. The ORR for pts with NTRK gene fusions determined by local and central testing will be presented. Conclusions: A high proportion of tumors with locally identified NTRK gene fusions were confirmed centrally. At present, analysis of ctDNA is significantly less sensitive at detecting NTRK gene fusions. A negative ctDNA result requires next-generation sequencing testing of a tissue biopsy. Further research is needed to improve the sensitivity of ctDNA gene fusion detection. Table NTRK gene fusion Tissue-based LT Tissue-based CT ctDNA-based CT with LB Fusion confirmed, n Fusion confirmed, n Fusion not detected, n Unavailable samples, n† PPV‡: CT vs tissue-based LT, % Fusion confirmed, n Fusion not detected, n Unavailable samples, n† PPV‡: LB vs tissue-based LT, % NTRK1 68 35 14 19 71.4 20 34 14 37.0 NTRK2 4 3 1 0 75.0 0 4 0 0 NTRK3 92§ 57 7 28 89.1 13 28 51 31.7 †Includes no sample available and sample QC failed. ‡Calculated as a percentage of the number of confirmed fusions over the number of available samples. §Includes 9 inferred NTRK3 fusions. CT, central testing; ctDNA, circulating tumor DNA; LB, liquid biopsy; LT, local testing; NTRK, neurotrophic tyrosine receptor kinase; PPV, positive predictive value; QC, quality control. Citation Format: Erin R. Rudzinski, Marc Ladanyi, Lauren L. Ritterhouse, Felix Sahm, Ricarda Norenberg, Hong Zheng, Chi Chen, Vadim Bernard-Gauthier, Nicoletta Brega, Cornelis M. van Tilburg, Jessica J. Lin, Marcia S. Brose, Ulrik N. Lassen, Ray McDermott, Theodore W. Laetsch, David S. Hong, Alexander Drilon, Sinchita Roy-Chowdhuri. Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT228.

Identification of HMGA2 as a predictive biomarker of response to bintrafusp alfa in a phase 1 trial in patients with advanced triple-negative breast cancer.

We report the clinical activity, safety, and identification of a predictive biomarker for bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβRII (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1, in patients with advanced triple-negative breast cancer (TNBC). In this expansion cohort of a global phase 1 study, patients with pretreated, advanced TNBC received bintrafusp alfa 1200 mg every 2 weeks intravenously until disease progression, unacceptable toxicity, or withdrawal. The primary objective was confirmed best overall response by RECIST 1.1 assessed per independent review committee (IRC). As of May 15, 2020, a total of 33 patients had received bintrafusp alfa, for a median of 6.0 (range, 2.0-48.1) weeks. The objective response rate was 9.1% (95% CI, 1.9%-24.3%) by IRC and investigator assessment. The median progression-free survival per IRC was 1.3 (95% CI, 1.2-1.4) months, and median overall survival was 7.7 (95% CI, 2.1-10.9) months. Twenty-five patients (75.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 patients (15.2%); no patients had a grade 4 TRAE. There was 1 treatment-related death (dyspnea, hemolysis, and thrombocytopenia in a patient with extensive disease at trial entry). Responses occurred independently of PD-L1 expression, and tumor RNAseq data identified HMGA2 as a potential biomarker of response. Bintrafusp alfa showed clinical activity and manageable safety in patients with heavily pretreated advanced TNBC. HMGA2 was identified as a potential predictive biomarker of response. NCT02517398.