Treatment-naive Pts Research Articles

Phase 3 study of disitamab vedotin with pembrolizumab vs chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (DV-001).

TPS4616 Background: Platinum-based chemotherapy (chemo) has been the standard first-line (1L) therapy for locally advanced or metastatic urothelial carcinoma (la/mUC). Recently, enfortumab vedotin, a nectin-4-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload, plus pembrolizumab (pembro) showed improved survival over chemo. Human epidermal growth factor receptor 2 (HER2) expression (immunohistochemistry [IHC] 1+-3+) has been reported in approximately half of all patients (pts) across tumor types, including UC, and is a biomarker that may be associated with poor outcomes. Disitamab vedotin (DV; RC48-ADC) is an investigational ADC comprising a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to MMAE via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action, including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. DV has shown encouraging activity with a manageable safety profile in pts with la/mUC—as a single agent in a HER2-expressing post-platinum setting (IHC 3+/2+; ORR, 50.5%; median [m]PFS, 5.9 months; mOS, 14.2 months) and in combination with a programmed cell death protein 1 (PD-1) inhibitor in all comers (ORR, 76.0% in treatment-naive pts; 83.3%, 64.3%, and 33.3% in HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, respectively). Improved outcomes observed with an MMAE payload plus PD-1 inhibition across the ADC landscape, along with DV data, provide a robust rationale for this phase 3 trial of DV with pembro in the 1L setting for HER2-expressing la/mUC. Methods: DV-001 (NCT05911295) is an open-label, randomized, multicenter, controlled phase 3 trial evaluating DV with pembro vs chemo in pts with previously untreated HER2-expressing la/mUC. Pts will be randomized 1:1 to Arm A or B. Pts in Arm A will receive DV IV every 2 weeks and pembro IV every 6 weeks. Treatment will continue until disease progression or intolerable toxicity; pembro will be administered for a maximum of 18 6-weekly infusions (approximately 2 years). Pts in Arm B will receive platinum-based chemo with gemcitabine IV on Days 1 and 8 of every 3-week cycle, and either cisplatin or carboplatin on Day 1 of every 3-week cycle for 4-6 cycles. Maintenance therapy with avelumab after completion of chemo may be given to eligible pts where approved and available. Pts must have previously untreated la/mUC, measurable disease per RECIST v1.1, ECOG PS of 0-2 and must be eligible for platinum-based chemo. HER2 expression must be determined using the VENTANA 4B5 HER2 IHC Assay centrally and using the most recent archival or fresh tumor sample. Primary endpoints include PFS per blinded independent central review and OS. Enrollment is ongoing in the US, Canada, and Australia and is planned globally. Clinical trial information: NCT05911295 .

Real-World Analysis of Obinutuzumab-Based Immunochemotherapy in Follicular Lymphoma in Chinese Population

Background Obinutuzumab is a first-in-class glycoengineered humanized type II anti-CD20 antibody. Immunochemotherapy based on obinutuzumab has demonstrated an advantage in prolonging progression-free survival (PFS) in pts with follicular lymphoma(FL) in a number of clinical trials(Marcus R, et al. N Engl J Med. 2017; Cheson BD, et al. J Clin Oncol. 2018). In Jun, 2021, obinutuzumab came into the market of China. However, few studies have investigated the efficacy and safety of obinutuzumab-based immunochemotherapy aiming at Chinese population. Therefore, we retrospectively analyzed the data of Chinese pts with treatment-naïve(TN) or relapsed/refractory(R/R) follicular lymphoma who received obinutuzumab-based immunochemotherapy in our center, hoping to provide treatment reference for Chinese pts. Methods Eligible pts were age ≥18 years with histologically documented, CD20-positive follicular lymphoma (grade 1 to 3a, stage III/IV or stage II with tumor ≥7 cm in the greatest dimension), and at least 2 cycles of obinutuzumab-based treatment. Efficacy was assessed by objective response rate (ORR) and best of response (BOR), with toxicity evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) (The 5th Edition). In addition, we recorded the incidence and severity of corona virus disease 2019 (COVID-19) infection according to Scheme for Diagnosis and Treatment of COVID-19 (The 10th Trial Edition). Results Between Nov 1, 2021 and Apr 1, 2023, the data of 27 pts with TN FL who received G-CHOP (obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen and 7 R/R pts treated with GB (Obinutuzumab, bendamustine) regimen was collected. The demographic and clinical characteristics at baseline were shown in Table 1. The median age of TN pts was 52 years, and 63.0% were female. The efficacy evaluation of TN pts was displayed in Figure 1. All of 27 pts achieved partial response (PR) after 2 cycles of GCHOP regimen. Eventually, 21 patiens completed 6 cycles of treatment, with 95.5% (21/22) assessed as complete response (CR) and 4.5% (1/21) maintaining PR. Three pts discontinued treatment due to COVID-19 infection and 2 for severe infections of other reasons. The end of treatment (EOT) ORR was 100% and the BOR of 96.3% (26/27) pts was assessed as CR. In 7 R/R pts, 5, 1 and 1 pts received 1, 2 and 3 lines of previous treatment regimens, respectively. The median age of this subgroup was 56 years. Totally, 6 pts achieved CR with an ORR of 85.7%, except for one pt who was evaluated as SD after 2 cycles of GB regimen and switched to another regimen. Two pts continued with maintenance therapy of obinutuzumab, and the rest 5 pts went on with autologous hematopoietic stem cell transplantation. By the end of follow-up, no pts showed progressive disease (PD) except for one who died of COVID-19 infection. All these pts in this study were infected with COVID-19 during the pandemic in China. For TN pts, mild, ordinary, severe and critical cases accounted for 14.8%, 44.4%, 29.6% and 11.1% respectively, and no pt died of COVID-19 infection. The median duration of COVID-19 infection was 23 (14-68) days, and over half of them were tested positive for more than 3 weeks. Of the R/R pts, 57.1% (4/7) presented severe, 14.3% (1/7) was critical and finally died of respiratory failure. The median duration of positive was 26 (21-95) days. Among pts treated wih GCHOP regimen, common grade 3-5 adverse events included infection (excluding COVID-19 infection) (25.9%) and hematological adverse events consisting of neutropenia (51.8%), thrombocytopenia (22.2%). Grade 3 infection, neutropenia and thrombocytopenia were observed in 14.3% (1/7) R/R pt each. The median follow-up time of TN pts and R/R pts was 8.9 (12.1-13.7) months and 11.7 (11.2-14.0) months, respectively. The median PFS of both was not achieved, 1-year PFS rate was 100% and 85.7% in TN and RR pts, respectively. Conclusions This real-world analysis with small sample size indicates that similar efficacy and toxicity was observed in Chinese patients with FL who were treated with obinutuzumab-based immunochemotherapy to that reported in literature. However, it is noteworthy that long-lasting immunosuppression may result in higher incidence and severity of COVID-19 infection in these patients compared to the general population.

A Phase (Ph) 2 Study of TL-895, a Highly Selective, Novel Covalent BTK Inhibitor (BTKi), in Patients (pts) with Treatment-Naïve (TN) and Relapsed/Refractory (R/R) BTKi-Naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Background: Covalent BTKi have become the backbone of CLL/SLL therapy. Through improved target kinase selectivity, second generation BTKi offer improved safety with potentially better efficacy, yet compartmental clearance leading to complete remission (CR) remains elusive. TL-895 is a potent, second generation, irreversible, oral BTKi with best-in-class selectivity (Gulrajani 2023) over other second generation BTKi; which may lead to improved safety and clearance of leukemic disease to induce deeper and more durable responses. Methods: This multicenter Ph 2 study (NCT02825836) enrolled symptomatic, BTKi-naïve CLL/SLL pts ≥18 years with ECOG PS 0-2. The R/R and TN arms enrolled sequentially and pts were randomly assigned to receive TL-895 at 100 mg (Arm 1 [R/R] and Arm 4 [TN]) or 150 mg (Arm 2 [R/R] and Arm 3 [TN]) twice a day continuously until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR: partial remission [PR], nodular PR [nPR], or CR) per iwCLL 2018 criteria and key secondary were CR rate, safety and BTK occupancy. Results: As of 11 July 2023, 84 pts were enrolled at 12 sites throughout the US and Europe. In TN Arms 3 and 4 (n=21 each), 57% of pts were IGHVUNMUT, 14% had del17p/ TP53MUT and 29% bulky (≥5 cm) adenopathy. Median baseline ALC was 77x10 9/L (range 2-444) in Arm 3 and 46x10 9/L (range 3-215) in Arm 4. In R/R Arms 1 and 2 (n=21 each), pts received a median of 2 prior therapies (range 1-5), 69% of pts were IGHVUNMUT, 48% had del17p/ TP53MUT and 52% bulky adenopathy. Median baseline ALC was 21x10 9/L (range 1-235) in Arm 1 and 34x10 9/L (range 2-178) in Arm 2. In TN Arms 3 and 4, at a median follow-up of 8 months ([mo] range 1-10), the ORR was 86%. In the R/R Arms 1 and 2, at a median follow-up of 23 mo (range 1-26), the ORR was 86% and 81%, respectively. At the 100 mg dose, two unconfirmed CRs (uCR) pending bone marrow (BM) biopsy were reported in R/R Arm 1. At the 150 mg dose, one CR, one uCR pending BM biopsy and two nPRs were reported, two each in R/R Arm 2 and TN Arm 3. All CRs/uCRs and nPRs occurred by week 48. In TN Arm 3 150 mg dose, a faster time to response was observed compared to TN Arm 4 100 mg dose ( Figure 1), with a median ALC reduction of 50% by 3 mo compared to 6 mo, respectively (Figure 2). Additionally, at a median of only 5 mo (range 0.3-8.3), 62% (13/21) of pts in Arm 3 compared with 20% (4/21) of pts in Arm 4 had complete resolution of lymphocytosis in their blood (<4 x10 9/L). Full trough target occupancy (median ≥95%) was achieved in both TN and R/R pts, with low intrapatient variability and near complete inhibition of signaling proteins downstream of BTK by FACS analysis. In the TN arms, treatment-emergent adverse events (TEAEs) regardless of causality were reported in 88% of pts (36% grade [Gr] 3, 0% Gr 4). Most common TEAEs (>10%), were anemia (21%), neutropenia (14%), COVID-19 and upper respiratory tract infection (URTI; 12% each). Most common Gr 3/4 TEAEs (>10%) were anemia and neutropenia (12% each). In the R/R arms, TEAEs were reported in 98% of pts (31% Gr 3, 14% Gr 4). Most common TEAEs were neutropenia (31%) and COVID-19 (21%), thrombocytopenia (19%), diarrhea (17%), anemia, hypertension (HTN) and URTI (14% each), sinusitis and pneumonia (12% each). Most common Gr 3/4 TEAE was neutropenia (26%). In the TN arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (2%; 0%), HTN (5%; 2%), and headache (2%; 0%) with no events of atrial fibrillation (AFib) or major hemorrhage. In the R/R arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (5%; 0%), HTN (14%; 5%), headache (5%; 0%), AFib (5%; 5%) and major hemorrhage (2%, 2%). Gr 5 TEAEs occurred in six R/R pts (three in each arm) and one TN Arm 4 pt, including three COVID-related deaths; none were considered related to TL-895. Excluding COVID-related deaths, median progression free survival (PFS) was not reached with an estimated 8 mos PFS rate of 93% (95% CI, 79-95) in TN pts and 84% (95% CI, 69-93) at 22 mos in R/R pts. Treatment discontinuations included 2 Richter's transformations, one each in TN Arms 3 and 4. Conclusion: Treatment with TL-895 resulted in rapid clearance of leukemic compartments, particularly in TN pts, leading to earlier and deeper responses than expected with monotherapy BTKi. In R/R pts with a very high frequency of del17p/ TP53MUT, remissions have been durable. With a very low incidence of AEs typical of less selective BTKi (e.g., AFib, major hemorrhage, rash and headache), TL-895 has the potential to be a best-in-class backbone BTKi.

Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib

Background: Covalent Bruton tyrosine kinase inhibitor (cBTKi) is a standard treatment for chronic lymphocytic leukemia (CLL). Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib. Mutations in BTK C481 and to a lesser extent PLCG2 are frequently detected in ibrutinib-treated pts at the time of progressive disease (PD). In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib. A recent study identified 3 pts with BTK C481 mutations and no pts with PLCG2 mutations among 8 acalabrutinib-treated pts with progressive disease (PD) (Black, et al. Blood 2022). A second study found a kinase-dead BTK L528W mutation in 7/13 zanubrutinib-treated pts (Blombery, et al. Blood Adv 2022). Although cBTKi share the same mechanism of action by binding to BTK C481, the latter report discloses differences in clonal selection and underscores the need for further investigation in pts treated with next generation cBTKi. In a phase 2 study of acalabrutinib in pts with treatment naïve (TN) CLL or small lymphocytic lymphoma (SLL) with 17p deletion, or TP53 or NOTCH1 mutation, or relapsed/refractory (R/R) CLL/SLL regardless of cytogenetics or somatic mutations (Sun, et al. Blood 2020), we sought to understand clonal evolution during treatment. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 48 pts at baseline, after 6 months, then annually on treatment until PD. Current analysis includes 14 PD pts [excluding 3 Richter transformation (RT) pts] comprising 10 R/R and 4 TN CLL pts. Additionally, paired baseline and PD bone marrow (BM) from 6 pts and lymph node (LN) samples from 2 pts were included. Targeted next-generation sequencing of ~700 recurrently mutated genes in hematological malignancies (Collins, et al. Leuk Lymphoma. 2021) was performed using DNA isolated from CD19 + enriched cryopreserved PBMCs and BM aspirates, as well as fresh-frozen core LN biopsies. Filtered variants in putative CLL driver genes (Knisbacher, et al. Nat Genet. 2022) with variant allele frequencies (VAF) ≥1% for BTK and PLCG2, ≥5% for variants with known oncological significance, and ≥7.5% for all other variants were included in downstream analysis. Results: After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years. Best response was complete remission in 2/20 (10%) pts and partial remission in 18/20 (90%) pts with CLL PD. IGHV was unmutated in all but one PD patient. At baseline, 34 CLL driver genes were mutated in 41/45 pts (91%; excluding 3 RT pts) with most mutations in NOTCH1, TP53, ATM, SF3B1, BIRC3, and NFKBIE. During acalabrutinib treatment but before PD, 14/45 pts (31%; 8 R/R and 6 TN) acquired mutations in 11 driver genes, most commonly in BRAF (n=4), CREBBP (n=4), and KMT2D (n=2). At the time of PD, 11/14 pts (79%) had newly acquired mutations in 4 genes, predominantly BTK (n=6) and PLCG2 (n=4). BTK C481 mutations (VAF 2-42%) were detected in 6/14 (43%; 4 R/R and 2 TN) pts and T474I mutation (VAF 4-46%) in 3/14 (21%; 1 R/R and 2 TN) pts. Paired BM samples in 2 pts and LN samples in 2 pts showed the same BTK mutations as PBMCs with similar VAFs. PLCG2 mutations (VAF 1-8%) were found in 4/14 (29%; 2 R/R and 2 TN) pts. BTK C481 co-occurred with BTK T474I in 3 pts, but on different sequencing reads suggesting independent subclones, and with a PLCG2 mutation in 1 pt. There have been no pts with BTK L528 mutations. In conclusion, mutations in BTK and PLCG2 are the predominant resistance mechanism to acalabrutinib. Among BTK mutations, C481 was the most common. All T474I mutations co-occurred with C481.

Molecular Measurable Residual Disease (MRD) Clearance (≤1%) Is Associated with Improved Clinical Outcomes in Patients with Higher-Risk Myelodysplastic Neoplasms (HR-MDS): An Exploratory Analysis of Stimulus-MDS1 in Patients Receiving Sabatolimab or Placebo + Hypomethylating Agent (HMA)

Background: Sabatolimab (MBG453) is a novel immunotherapy targeting TIM-3, an immuno-myeloid regulator expressed on both immune and leukemic stem cells. In the randomized, double-blind, placebo-controlled, Phase (Ph) II STIMULUS-MDS1 study (NCT03946670) in patients (pts) with HR-MDS, although improvements in complete remission (CR) and progression-free survival (PFS) were not statistically significant, sabatolimab + HMA was associated with longer duration of response (DoR), and the data suggest a delayed-onset benefit in the sabatolimab arm, as well as a potential treatment effect in pts with lower disease burden (Zeidan AM, et al. ASH 2022). The clinical significance of MRD in HR-MDS is not well established. We report an exploratory analysis of mutational clearance and MRD by next-generation sequencing (NGS) to evaluate the association with clinical outcomes. Methods: Treatment-naive pts aged ≥18 years with intermediate (+ ≥5% bone marrow [BM] blasts), high or very high risk MDS by Revised International Prognostic Scoring System were randomized to sabatolimab or placebo added to azacitidine/decitabine (Zeidan AM, et al. ASH 2022). Peripheral blood (PBMC) and/or BM mononuclear cell (BMMC) samples were collected and NGS performed on genomic DNA extracted from baseline (BL) and on-treatment samples using a 38-gene NGS-error-corrected panel with sensitivity of 2% and 0.2% variant allelic frequency (VAF), respectively. Concordance and correlation between PBMC and BMMC were assessed. The prognostic value of clonal clearance at different VAF cut-offs (0.2%, 0.5% or 1%) was assessed. MRD-x status was defined as any mutation call above VAF cut-off x, excluding mutations in DNMT3A, TET2 and ASXL1 ( DTA). Association between MRD status and clinical outcomes was analyzed regardless of treatment to increase sample and used best overall response, 6-month landmark analysis, and a time-dependent Cox model to rule out immortal bias. Results: NGS was run on 332 BMMC samples from 112 pts and 439 PBMC samples from 123 pts (127 pts randomized). 112 pts had ≥1 qualifying BL mutation (NGS cohort) and 106 pts (sabatolimab + HMA, N=56; placebo + HMA, N=50) had ≥1 at follow-up (MRD cohort). BL characteristics were balanced between NGS/MRD cohorts and between treatments in the MRD cohort. Overall agreement in mutation calling at variant level between BMMC and PBMC was >97% (8312/8566 total mutation calls), with >88% positive (817/926) and >98% negative agreement (7495/7640). Across reported mutated variants (N=817), there was good correlation (pearson cor=0.88) in VAF between BMMC and PBMC. When considering all paired samples, concordance of best MRD status using PBMC or BMMC results at the pt level (N=95) was: MRD-0.2, 97%; MRD-0.5, 89%; MRD-1, 90%. Given good PBMC and BMMC agreement, results were combined (higher VAF used if both) for outcomes analysis. In the MRD cohort, 11% (N=12), 18% (N=19) and 27% (N=29) of pts achieved MRD-0.2, MRD-0.5 and MRD-1 negativity, respectively. Most pts with MRD-0.2, -0.5 and -1 clearance had documented response of CR/marrow CR [mCR] (>80%) or CR/partial remission [PR]/hematologic improvement [HI] (>75%). Best overall response of MRD-1 negativity achieved anytime on treatment was associated with improved PFS and overall survival (OS) in the overall population and for responding pts (CR/mCR or CR/PR/HI). Similar results were obtained in a landmark analysis at 6 months ( Fig 1). This was supported by a time-dependent Cox-model indicating that MRD-x negativity was associated with a lower hazard ratio for PFS and OS vs MRD-x positivity ( Fig 2). A consistently higher proportion of pts in the sabatolimab (N=56) vs placebo (N=50) arms had on-treatment mutation clearance at different cut-offs: MRD-0.2, 16.1% vs 6.0%; MRD-0.5, 25.0% vs 10.0%; MRD-1, 35.7% vs 18.0%, respectively. Conclusions: We present the first results from a prospective, controlled, randomized study demonstrating the potential prognostic value of MRD for PFS and OS in HR-MDS. Our results demonstrate high NGS concordance between PBMC and BMMC on-treatment samples, indicating that PBMC could represent an alternative for clonal monitoring. Interestingly, more pts treated with sabatolimab + HMA reached MRD negativity while in remission, potentially explaining the longer DoR in pts receiving sabatolimab + HMA vs placebo + HMA. These findings will be further explored in the ongoing Ph III STIMULUS-MDS2 study (NCT04266301).

A Long-Term Analysis of Lenalidomide and Rituximab (R 2) for the Treatment of Chronic Lymphocytic Leukemia

Background:Lenalidomide (len) is an immunomodulator that binds cereblon and alters protein degradation of Ikaros and Alios via E3 ligase. The R 2 regimen (len paired with Rituximab (R)) is an effective treatment (tx) for lymphoid malignancies, and its promise in patients (pts) with chronic lymphocytic leukemia (CLL) has been previously reported (James et al, JCO 2014). We performed a long-term, single-center follow-up (f/u) analysis of pts previously enrolled in two phase 2 open-label studies evaluating R 2 in both treatment naïve (TN) and relapsed-refractory (R/R) CLL pts. Methods: The CLL Research Consortium (CRC)-014 trial enrolled TN pts. Pts initiated 2.5 mg of len daily for 21 days (D) out of a 35-day cycle (C) for C1, then 28d cycles for C2-C7. Len was escalated to 10 mg daily as tolerated. R was initiated in a dose-intensive manner: 50 mg/m 2 on C1D29; 325 mg/m 2 on C1D31 and C1D33; 375 mg/m 2 weekly for C2; then 375 mg/m 2 on D1 for C3-C7. R 2 was stopped after 7C. The CRC-022 trial enrolled R/R pts. Pts initiated 5 mg of len daily for 21 days of each 28d cycle, with escalation to 25 mg daily as tolerated. R was initiated weekly at 375 mg/m2 for C1, then 375 mg/m2 on D1 for C2-C6. R/R pts could continue len for up to 6 consolidative cycles after completion of 6C of R 2. Response assessment was performed using iwCLL criteria and minimal residual disease (MRD) was assessed by multi-parametric flow cytometry of the bone marrow with a sensitivity of 10 -4. Time-to-event analyses were performed with the Kaplan-Meier method. Results: We identified 43 TN pts and 25 R/R pts. Notably, 6 pts enrolled in both studies sequentially. The median age for all pts was 62.5 years (range 45-82). Rai staging at time of tx initiation was: 2 38.7%; 3 24.2%; 4: 37.1%. The profile of cytogenetic abnormalities was: 54.8% del(13q); 17.7% del(11q); 16.1% trisomy 12; 9.7% del(17p); 19.4% normal; and 1.6% complex karyotype. 69.4% of pts had unmutated immunoglobulin heavy chain. The median number of prior tx for R/R pts was 2 (range:1-6). The overall response profile was: CR 13.2%; PR 69.1%; SD 2.9%, PD 1.5%. No pts had undetectable MRD. At median f/u time of 129 months (mo), median progression-free survival (PFS) was 15.7 mo in the TN pts and 25.4 mo in the R/R pts (p = 0.11, Figure 1A). The trend towards improvement may reflect len consolidation available to the R/R pts. Median time to next treatment (TTNT) was also not significantly different between the TN pts and the R/R pts (29.5 mo vs. 29.0 mo, p = 0.56). Median OS was significantly higher for the TN pts than the R/R pts (164.8 mo vs. 108.0 mo, p = 0.0001, Figure 1B). This likely reflects heavy pre-treatment in the R/R pts. Across both TN and R/R groups, 21 pts died: 8 deaths (38.1%) were related to CLL, none were related to R 2 treatment, and 13 (61.9%) were related to other causes or unknown. Adverse events included: 30.9% of pts with Grade (Gr) 3-4 neutropenia, 58.8% of pts with Gr ≥2 thrombocytopenia, and 30.9% of pts with Gr ≥2 anemia. During the extended f/u period, 16.2% of pts developed pneumonia and 13.2% developed viral infections. Through the extended f/u, venous thromboembolism (VTE) developed in 9 (14.5%) pts. Only 2 pts developed VTE during active R 2 and both were not taking prophylactic aspirin. Five other pts developed VTE >6 mo after stopping R 2 and had other provoking factors. Four pts (6.5%) developed Richter transformation lymphoma. 43.5% of pts developed cutaneous neoplasms and 12.9% of pts developed non-cutaneous solid neoplasms. No pts developed secondary myeloid neoplasms. Conclusions: In this long-term pooled f/u analysis of CLL pts, we found that R 2 provided high ORR, modest PFS and OS benefit, and tolerable long-term toxicities. The ORR of R 2 in this study (82.3%) compares favorably to ORR of R monotherapy in previous studies (51%, Hainsworth et al, JCO 2003). The absence of secondary myeloid neoplasms suggests that len may not substantially increase cumulative secondary malignancy risk-the cumulative cutaneous neoplasm incidence may reflect elevated baseline risk in CLL pts. Importantly, we found no increased risk in deaths attributed to therapy. The demonstrated activity of R 2 in CLL warrants further investigation of len in combination with other agents. Currently, new immunotherapeutic approaches-such as bispecific antibodies and CAR-T cell therapy-are being investigated in CLL. Given len's immunomodulatory properties, combination approaches with these treatments should be explored in future trials.

#4033 RAPID COMPLEMENT INHIBITION WITH THE C5 INHIBITOR CROVALIMAB: A TIMING ANALYSIS USING ANIMAL MODEL AND COMPOSER TRIAL DATA

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS) is a life-threatening disease, characterised by acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia due to complement dysregulation. Currently approved treatments for aHUS include the anti-complement C5 monoclonal antibodies eculizumab and ravulizumab. Although currently approved therapeutic options are effective at both inhibiting complement-mediated thrombotic microangiopathy (TMA) and improving renal function, the regular intravenous (IV) infusion dosing regimens impose a significant treatment burden, particularly in paediatric patients (pts) with aHUS, who may need dialysis in the future due to chronic kidney injury and would benefit from preservation of vascular access. Crovalimab is a novel monoclonal antibody developed against complement C5, engineered to allow for small volume subcutaneous (SC) self-injection every 4 weeks, in a weight-based dosing regimen [1]. In the adaptive Phase I/II COMPOSER trial (NCT03157635) evaluating crovalimab in pts with paroxysmal nocturnal haemoglobinuria (PNH), that, like aHUS, is a complement disorder characterised by uncontrolled complement activation, crovalimab has shown maintained disease control and was well tolerated after a median exposure of 3 years. Further, a Phase III study evaluating crovalimab in previously untreated pts met its primary efficacy endpoints [2]. The efficacy and safety of crovalimab are currently being evaluated in adult and paediatric pts with aHUS, either treatment-naive or switching from another complement inhibitor, in the ongoing Phase III single-arm COMMUTE-a and COMMUTE-p trials [3]. Due to the rapidly progressing nature of aHUS, pts experiencing a TMA require rapid suppression of complement activation upon diagnosis to shut down the complement cascade and avoid further kidney deterioration and organ damage. Here, data from in vivo models and the COMPOSER trial were used to determine the time to complete complement inhibition after first crovalimab IV dose. Method Crovalimab's ability to suppress C5 function and complement activity rapidly was initially studied in in vivo models of cynomolgus monkeys. This study assessed the pharmacokinetics and pharmacodynamics of crovalimab in these monkeys after a single IV or SC dose. As part of this study, four animals per group were evaluated with single 4 mg/kg IV and 20 mg/kg IV doses. Crovalimab was also evaluated in the four-part, Phase I/II COMPOSER trial. Part 2 (n = 10) and Part 4A (n = 8) enrolled pts with PNH who were naive to complement inhibition. Pts in Part 2 received crovalimab 375 mg IV on Day 1, 500 mg IV on Day 8, 1000 mg IV on Day 22 and 170 mg SC weekly from Day 36 for 20 weeks. Pts in Part 4A received an optimised crovalimab dosing regimen of 1000 mg IV on Day 1, 340 mg SC on Days 2, 8, 15, and 22 and 680 mg SC Q4W from Day 29 onwards for 20 weeks. Crovalimab concentration, free C5 and complement activity were measured using validated assays in cynomolgus monkeys and in pts with PNH. Results Compared with baseline values in cynomolgus monkeys, a single crovalimab IV dose of 4 mg/kg reduced mean free C5 concentration by 99.6% and terminal complement activity by 81.4%, within 5 minutes after administration. In treatment-naive pts from COMPOSER Parts 2 and 4, mean free C5 concentration dropped to below 1 μg/mL, indicating a high level of target engagement within 1–6 hours from the first IV dose (Figure 1). Correspondingly, inhibition of terminal complement activity was reached within 1 hour, with values near or below the lower limit of quantification (10 U/mL; Figure 2). Complete complement blockade was generally maintained long-term, up to Week 20, in both Parts 2 and 4, regardless of dose. Conclusion Crovalimab induced a complete, rapid, and sustained blockade of terminal complement activity in both non-human primates and pts with PNH, within hours from first dose. The dosing schedule of crovalimab included an initial IV loading dose, allowing for a rapid onset of action, followed by a convenient long-term SC maintenance regimen.

Safety and efficacy of ABR in pts with TN or R/R MCL: Ph Ib trial.

7546 Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Bendamustine (B) + rituximab (R) is used for treatment-naive (TN) and R/R MCL. We present updated data on safety and efficacy of ABR in patients (pts) with TN or R/R MCL. Methods: Eligible adults received ABR in this phase 1b study (NCT02717624) as follows: ABR for 6 28-d cycles, maintenance A+R for up to 2 y (TN cohort responders), then oral A continuously until progressive disease (PD) or treatment discontinuation due to toxicity (both cohorts). The primary endpoint was safety. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), all per Lugano. Results: Overall, 38 pts were enrolled (TN, n=18; R/R, n=20) with median age 66 y (range, 47–86). Baseline characteristics were (TN and R/R cohorts, respectively): stage IV disease in 88.9% and 95.0%, high-risk simplified MIPI score in 11.1% and 15.0%, bulky disease >5 cm in 16.7% and 30.0% or ≥10 cm in 5.6% and 10.0%, and blastoid morphology in 5.6% and 15.0%; R/R pts had a median of 2 prior lines of therapy. As of the data cutoff date (6/15/22), 6 (33.3%) TN pts and 4 (20.0%) R/R pts were receiving A monotherapy (Table). Most common any-grade AEs were nausea (n=14, 77.8%; TN) and neutropenia (n=11, 55.0%; R/R). Grade 3–4 AEs occurred in 13 (72.2%) TN pts and 17 (85.0%) R/R pts, most commonly neutropenia in both cohorts (n=7, 38.9% [TN]; n=10, 50.0% [R/R]). Serious AEs occurred in 11 (61.1%) TN pts and 13 (65.0%) R/R pts. There were no reports of ventricular tachyarrhythmia. Grade 3 atrial fibrillation occurred in 1 pt outside the safety reporting period and was not related to study treatment. Grade ≥3 major hemorrhage was reported in 2 (11.1%) TN pts and 3 (15.0%) R/R pts. Grade ≥3 hypertension was reported in 3 (16.7%) TN pts and 2 (10.0%) R/R pts. Five TN pts died (AE: pneumonitis, n=1; unknown, n=4) and 6 R/R pts died (AE: COVID and cerebrospinal meningitis, n=2; PD, n=2; unknown, n=2). ORR was 94.4% (n=17) in the TN cohort and 85.0% (n=17) in the R/R cohort, with CR rates of 77.8% (n=14) and 70.0% (n=14), respectively. Median DOR was not estimable (NE) in the TN cohort and 43.5 mo in the R/R cohort. Median PFS and overall survival were NE in the TN cohort (median follow-up 47.6 mo) and 28.6 mo and NE, respectively, in the R/R cohort (median follow-up 20.4 mo). Conclusions: Triple-combination ABR was tolerable and effective in pts with TN or R/R MCL. Clinical trial information: NCT02717624 . [Table: see text]

Nivolumab (Nivo) plus ipilimumab (Ipi) 6-month treatment versus continuation in patients with advanced non-small-cell-lung cancer (aNSCLC): 3-year results of the IFCT-1701 DICIPLE phase 3 trial.

9068 Background: 1st-line immunotherapy (io) is a standard treatment for patients (pts) with advanced NSCLC devoid of targetable mutation. Classical 2-year io duration does not rely on indubitable evidence. We aimed to assess whether 6-month nivo/ipi was equivalent to continuation until progression or unacceptable toxicity in pts with disease control (DC). Methods: In this multicenter non-inferiority randomized phase 3 trial, eligible treatment-naive pts, age>18, PS 0-1, had stage IV NSCLC and measurable disease. They received Nivo 3 mg/kg q2w plus Ipi 1 mg/kg q6w, until progression or unacceptable toxicity for a maximum of 6-month induction treatment. At 6 months, pts with DC and no severe TRAEs were randomized (1:1) into io continuation (arm A), and observation (arm B). At progression, arm A pts received an investigator's choice 2nd line platinum-based chemo, while arm B pts resumed double io. Primary endpoint was progression-free survival (PFS). 450 pts x 2 were to be randomized, to achieve 80% power, with 0.025 one-sided a error. Observing that European filing for the io combo was not submitted, the trial's steering committee recommended to stop the accrual on Jan. 2021. Results: From May. 2018 to Jan. 2021, 265 pts (70.6% male, 62.7yr median age, 59% stage IVB, 22.3% SCC, 9.9% PDL1≥50%, 12.2% PDL1<1%) were accrued. 138 (72.6%) pts had disease progression before 6 months, 11 died (5.8%), 30 (15.8%) experienced TRAEs contra-indicating continuation, 11 (5.8%) were deemed ineligible for randomization. 71 pts with DC were randomized. With a median follow-up from randomization of 29.9 months, median PFS was 20.5 (7.4-36.7) months in arm A, 35.2 (21.4-NR) in arm B. 12-month PFS was 55.6% (38.0-69.9) and 81.2% (62.9-91.1), respectively (p=0.08). Adj.HR (arm B vs. arm A) was 0.66, 95%CI (0.28-1.31), p=0.23. OS data, yet immature, did not show any significant difference between both arms (adj.HR arm B vs. A: 0.54 95%CI (0.20-1.49), p=0.23). From randomization, 28.6% G3-5 TRAEs in arm A were observed vs. 2.9% in arm B (p=0.005). Conclusions: The 6-month i.o. interruption for NSCLC patients with DC did not yield significant PFS or OS differences in this prematurely halted trial. Updated OS with a 3-year follow-up, quality of life and biomarker data, will be presented at the meeting. Clinical trial information: NCT03469960 .

Fruquintinib plus sintilimab in patients with either treatment-naive or previously first line treated metastatic clear-cell renal cell carcinoma (ccRCC): Results from a multicenter, single-arm phase 2 study.

e16514 Background: Antiangiogenic therapy combined with immunotherapy significantly improved the progression-free survival (PFS) and preliminary survival benefit for advanced clear-cell renal cell carcinoma (ccRCC). However, no combined immune therapies are currently approved for ccRCC in China. Fruquintinib (F, a highly selective VEGFR inhibitor) combined with sintilimab (S, an anti-PD-1 monoclonal antibody) showed encouraging antitumor activity in multiple solid tumors. Here, we reported the results of F plus S in metastatic ccRCC cohort from an open-label, single-arm phase 2 study (NCT03903705). Methods: Patients (pts) with pathologically confirmed metastatic ccRCC who were treatment-naive or had failed previously first-line treatment were eligible. They received F (5 mg, 2 weeks on/1 week off, orally, QD) plus S (200 mg, IV, Q3W) in 21-day cycles until disease progression or unacceptable toxicity; treatment of S was allowed for up to 24 months. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: As of cutoff (November 30, 2022), a total of 42 pts (22 treatment-naïve pts, and 20 previously first-line treated pts) were enrolled and received the combination treatment. Median (range) age was 59.0 (34.2-72.4) years; 34 (81.0%) pts were male. Among previously treated pts, 19 (19/20, 95.0%) pts had received VEGFR therapy as prior first-line treatment, including sunitinib (3/20, 15.0%), pazopanib (7/20, 35.0%), axitinib (2/20, 10.0%) and others (7/20, 35.0%). International Metastatic RCC Database Consortium (IMDC) risk included: favorable in 15 (35.7%) pts, intermediate in 22 (52.4%) pts, and poor in 5 (11.9%) pts. The median follow-up duration was 14.8 months (m) and 23.3 m for treatment-naive and previously treated pts, respectively. All pts had at least 1 post-baseline tumor assessment. Confirmed ORR was 68.2% and 60.0%, median duration of response was not reached (NR) and 13.9 m, and disease control rate was 95.5% and 85.0% for treatment-naive and previously treated pts, respectively. Median PFS (mPFS) was NR and 12m-PFS rate was 64.8% in treatment-naive pts; mPFS was 15.9 m in previously treated pts. The median treatment duration of F and S was both 14.7 m. All pts experienced at least 1 treatment-emergent adverse event (TEAE). Common (≥5%) grade ≥3 TEAEs were hypertension (21.4%), hypertriglyceridaemia (9.5%), amylase increased (7.1%), cerebral infarction (7.1%) and proteinuria (7.1%). No new safety signals were observed. Conclusions: F plus S demonstrated a favorable efficacy with manageable toxicity for treatment-naive and previously first-line treated metastatic ccRCC. A phase 2/3 study is being conducted to confirm this combination efficacy in the second-line treatment of ccRCC (NCT05522231). Clinical trial information: NCT03903705 .

Early efficacy results from atezolizumab (ATZ) with split doses of cisplatin plus gemcitabine in patients with locally advanced or metastatic urothelial carcinoma (SOGUG-AUREA).

502 Background: Urothelial carcinoma (UC) commonly affects patients (pts) who are ineligible for full doses of cisplatin-based chemotherapy (CT) due to bad performance status, advanced age, or renal impairment. The combination of split-dose cisplatin with ATZ might be a feasible treatment for pts with UC who are unfit for full doses of cisplatin. Methods: The phase II SOGUG-AUREA clinical trial recruited treatment-naive pts in advanced or metastatic settings considered unfit for full dose of platinum-based CT. Pts received a split dose of cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) days 1 and 8 (up to 6 cycles) in combination with 3-weekly ATZ 1200 mg in D1 intravenously until progression, unacceptable toxicity, or absence of clinical benefit. Here we present the early results from the confirmed objective response rate (ORR) according to RECIST 1.1, the primary endpoint for efficacy, progression-free survival (PFS), overall survival (OS) and safety. Results: Between Jan 2021 and Mar 2022, 82 pts were screened, 66 pts were enrolled and received at least one dose of study treatment. Baseline characteristics are outlined in the table. The median duration of ATZ treatment was 4.4 months (m) (95%CI: 4.1-4.6). The confirmed ORR was 40.9%, with 5 (7.6%) pts having CR and 22 (33.3%) PR. The median duration of the response was 7 m (95%CI: 4.9-10.4). The clinical benefit rate (CBR) was 53%, and SD (maintained > 6m) was reported in 8 (12.1%) pts. Eight (12.1%) pts were not evaluable for response due to exitus previous to disease evaluation (9.1%), non measurable target lesions (1.5%) or withdrawal (1.5%). With a median follow-up of 9.3 m (range: 0.6-18.1), the median PFS was 6.9 m (95%CI: 6.4-9.2), with a 6-m PFS rate of 67.1% (95% CI: 56.5-79.7). The reasons for platinum ineligibility did not correlate with PFS. The 6-m OS rate was 78.2% (95%CI: 68.6-89). Most frequent grade 3-4 toxicities were neutrophil count decreased (24.2%), anemia (21.5%) and platelet count decreased (13.6%). Conclusions: ATZ with split doses of CT was safely administered in a population of frail pts with mUC who were unfit for CT showing promising preliminary survival outcomes in terms of response. Final survival results are awaited. Clinical trial information: NCT04602078 . [Table: see text]

Chemotherapy-Based Regimes Increase Karyotype Complexity of Del(11q) CLL Cells and Impact the Response to Subsequent Ibrutinib Treatment

The introduction of targeted agents in the treatment strategy of chronic lymphocytic leukemia (CLL) has changed the prognostic implications of some traditional high-risk markers such as del(11q). Recent data has suggested that this alteration might associate with superior progression-free survival (PFS) in patients (pts) treated with the BTK inhibitor ibrutinib (Ibr), especially in treatment-naïve (TN) cases (Kipps et al. 2019). This seems to be in marked contrast to data from chemotherapy (CHT) relapsed/refractory (CHT-R/R) pts treated with Ibr, where del(11q) cases showed inferior PFS than CLLs harboring other cytogenetic abnormalities (CAs) (excluding del(17p)) (Byrd et al. 2020). In this study we aimed to elucidate the mechanism underlying this differential response between TN and CHT-R/R del(11q) CLL pts treated with Ibr. We conducted a retrospective analysis of 211 CLL pts treated with Ibr-based regimes (n=88 TN; n=123 CHT-R/R). Median follow-up was 37 months (mo) [IQR 17-54] and CHT-R/R patients had a median of 3 therapies [1-7] (at least one line of CHT) prior to Ibr start. Thirty pts discontinued treatment due to adverse events. Restricting the analysis to the rest of the pts (n=181), the median PFS was significantly longer in del(11q) TN than del(11q) CHT-R/R cases (not reached (NR) vs 45 mo; P=0.001). TN del(11q) pts showed a 5-year PFS rate of 100% vs 75% of non-del(11q) TN pts (P=0.1). In contrast, the median PFS of del(11q) CHT-R/R pts was 45 vs 54 mo for non-del(11q) CHT-R/R cases (P=0.45). We next investigated whether differences at the genomic level would play a role in the diminished response of del(11q) CHT-R/R pts to Ibr. Targeted next-generation sequencing and miRNA profiling of del(11q) TN and CHT-R/R pts did not reveal substantial changes in the mutational and miRNA profile between both groups. In contrast, the presence of complex karyotype (≥3 CAs; CK) was able to stratify the outcome of del(11q) CHT-R/R pts (median 31 mo vs NR (CK vs non-CK); P=0.014). To validate these findings in an ex vivo setting, we co-cultured primary CLL cells from del(11q) TN and CHT-R/R pts (n=18) with HS5 stromal cells (+CpG and IL2) in the presence of Ibr. Consistent with the clinical findings, cells from del(11q) TN pts were more sensitive to Ibr than those cells from del(11q) CHT-R/R pts (P=0.012). Moreover, del(11q) CK CHT-R/R primary cells were more resistant to Ibr ex vivo than del(11q) non-CK CHT-R/R cells (n=8; P=0.05). To evaluate how CHT could impact the karyotype stability of del(11q) pts, we quantified the number of CAs in 263 CLL samples before (n=85) or after (n=178) treatment with CHT-based regimes and we found that the mean number of CAs was higher in del(11q) cases after treatment (mean 1.7 vs 3.7; P=0.01). Importantly, non-del(11q)/non-del(17p) pts did not show an increased number of CAs after CHT (mean 1.1 vs 1.0; P=0.36). In parallel, in a cohort of 314 CLLs treated with non-CHT agents (n=175 pre- and n=139 post-therapy), the mean number of CAs in del(11q) cases remained stable after treatment (mean 2.4 vs 1.9; P=0.1), suggesting that non-CHT regimes are less prone to induce karyotype instability in del(11q) CLL cells. We further analyzed longitudinal karyotype samples from del(11q) CLL pts before and after treatment with CHT (n=9) or non-CHT (n=19) agents. Notably, CHT induced karyotype changes in 6/9 del(11q) pts (P=0.03), whereas the vast majority (18/19) of del(11q) pts treated with non-CHT agents did not acquire additional CAs after treatment. Karyotype clonal evolution analyses revealed linear (3/6) and branched (3/6) patterns of evolution from the founder del(11q) clone in post-CHT samples, all resulting in del(11q) clones with a higher karyotype complexity, with a particular enrichment of chromosome 8 CAs. Conversely, karyotype clonal evolution was far less frequent (1/19) in del(11q) pts treated with non-CHT agents, even in the presence of multiple lines of therapy. Collectively, this work uncovers previously unknown differential Ibr sensitivity between del(11q) TN and del(11q) CHT-R/R CLLs and shows that such differential sensitivity could be mediated through CHT-induced karyotype complexity in the del(11q) clone of CHT-R/R del(11q) pts. Moreover, treatment with non-CHT agents maintains clonal stability of del(11q) cells, consistent with the prolonged PFS rates of del(11q) TN pts treated with Ibr. Thus, our data support the use of ibrutinib as a first-line therapy in del(11q) CLL.

Acalabrutinib Plus Rituximab with or without Lenalidomide in Patients with Follicular Lymphoma: A Multipart, Open-Label, Phase 1b Trial

Background: Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) have limited treatment options. FL becomes more aggressive and resistant with subsequent lines of therapy (LOT). Bruton tyrosine kinase (BTK) inhibition increases the anti-tumoral phenotype of tumor-associated macrophages, favoring its combination with rituximab or rituximab + lenalidomide (R2). Due to its specific and potent BTK inhibition and lack of interleukin-2-inducible T-cell kinase inhibition, acalabrutinib (A) is more likely to increase R2 efficacy without increasing T-cell-mediated toxicity. We report the first results from a phase 1b trial (NCT02180711) evaluating A alone and combined with rituximab or R2 in FL. Methods: The study enrolled pts with FL grade 1-3a who were R/R to ≥1 prior therapy or who were treatment naive (TN). In part 1, R/R pts received A alone (arm A) or A + rituximab (arm A+rituximab-R/R); TN pts received A + rituximab (arm A+rituximab-TN). A was dosed at 100 mg twice daily. Part 3 was a dose-finding study for lenalidomide and enrolled R/R FL pts; these pts received A + R2 (arm A+R2) as follows: A daily until disease progression or unacceptable toxicity; rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-6, followed by 10 additional maintenance doses every other cycle, and lenalidomide 15 mg or 20 mg on days 1-21 of each 28-day cycle up to cycle 12. Primary objective was to characterize the safety of A alone or in combination with rituximab in pts with R/R FL (part 1) and safety of A+R2 in pts with R/R FL (part 3). Secondary objectives included safety (part 1, TN cohort) and efficacy (all cohorts). Response assessment was based on Lugano criteria. Data cutoff was March 11, 2022. Results: In part 1, 25 pts with R/R FL (arm A, n=12; arm A+rituximab-R/R, n=13) and 13 pts with TN FL (arm A+rituximab-TN) were enrolled. Median age in the R/R and TN cohorts was 67 y and 57 y, respectively. Pts had median 2 (range, 1-5) prior LOT in arm A (25.0% refractory to an anti-CD20 therapy regimen) and median 1 (range, 1-5) prior LOT in arm A+rituximab-R/R (38.5% refractory to an anti-CD20 therapy regimen). In the TN cohort, 46.2% had high tumor burden per Groupe d'Etude des Lymphomes Folliculaires criteria. Median follow-up was 8.1 mo (arm A), 8.8 mo (arm A+rituximab-R/R), and 49.5 mo (arm A+rituximab-TN). Median duration of exposure was 7.0 mo (arm A), 6.0 mo (arm A+rituximab-R/R), and 27.6 mo (arm A+rituximab-TN). The safety profile is summarized in the Table. Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥2 patients were hypertension (HTN; 16.7%; also present at baseline) in arm A and diarrhea, increased alanine aminotransferase, and increased aspartate aminotransferase (15.4% each) in the A+rituximab-TN arm. AEs led to discontinuation of A in 25.0% (arm A), 46.2% (arm A+rituximab-R/R), and 7.7% (arm A+rituximab-TN). Among events of clinical interest (ECIs), atrial fibrillation (grade 2) was reported in 1 pt in the A+rituximab-R/R arm. Any-grade hemorrhage was reported in 33.3% (arm A), 46.2% (arm A+rituximab-R/R), and 53.8% (arm A+rituximab-TN), with highest severity grade 2; no major hemorrhage events were reported. All except 1 pt (A+rituximab-R/R arm) were evaluable for response. Overall, 1 pt died due to progressive disease (A+rituximab-R/R arm; best response: partial response). Efficacy results are provided in the Table. In part 3, 29 patients with R/R FL received A+R2 (lenalidomide dose: 15 mg, n=7; 20 mg [recommended dose], n=22). Median age was 64 y. Median time on study was 16.9 mo and median duration of exposure was 16.6 mo. Grade 3/4 TEAEs occurring in ≥2 patients were neutropenia (34.5%), and rash, thrombocytopenia, COVID-19, COVID-19 pneumonia, and febrile neutropenia (6.9% each). Five patients discontinued ≥1 study drug due to an AE. Among ECIs, atrial fibrillation (grade 2) was reported in 1 patient (3.4%), and any-grade hemorrhage was reported in 13 (44.8%) pts; no major hemorrhage events were reported. Three pts died due to AEs (septicemia, tumor lysis syndrome, aortic aneurysm). Efficacy results are provided in the Table. Of the evaluable pts, all but 1 had tumor reduction (Figure); overall response rate was 81%. Conclusions: The combination of A+rituximab was well tolerated in TN FL and R/R FL. The addition of lenalidomide 20 mg suggests improved overall response rate in R/R FL compared with A alone; further studies of this regimen in FL are needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sintilimab Plus P-Gemox (Pegaspargase, Gemcitabine and Oxaliplatin) Regimen for Newly-Diagnosed Advanced, Extranodal Natural Killer/T Cell Lymphoma, Nasal Type: A Multicenter, Phase 2 Cohort of the Open-Label Spirit Study

Background: Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma with a high incidence in Asian and south American populations. Pegaspargase, oxaliplatin plus gemcitabine are considered as the standard first-line therapy for advanced ENKTL, but the prognosis remains poor. In ENKTL, most patients overexpress PD-L1 protein, which is associated with a poor prognosis, and suggests that ENKTL should be sensitive to PD-1/PD-L1 axis blockade. In a phase II trial, the PD-1 mAb sintilimab showed promising efficacy as monotherapy in r/r ENKTL (Tao, Signal Transduct Target Ther, 2022). Additionally, we previously conducted a retrospective study of PD-1 mAb combined P-GEMOX for the treatment of advanced ENKTL patients (pts), which showing favorable antitumor activity with a non-overlapping toxicity profile (Cai, Signal Transduct Target Ther, 2020). Therefore, we conducted this prospective phase II trial to evaluate the efficacy and safety of sintilimab plus P-GEMOX as first-line therapy in pts with advanced ENKTL. Methods: This is a prospective, single-arm, open-label, multi-center, phase II clinical trial. Adult treatment-naive pts with histologically confirmed ENKTL nasal type had at least one measurable or evaluable lesion were enrolled to receive six cycles of sintilimab 200 mg plus pegaspargase 2000 U/m2 (day 1), gemcitabine 1g/m2 (days 1 and 8), and oxaliplatin 130 mg/m2 (day 1) (induction phase), followed by sintilimab 200 mg maintenance every 3 weeks (maintenance phase) for up to 2 years or until disease progression or unacceptable toxicities. Involved field radiotherapy (IFRT) is allowed for residual lesions after induction therapy. The primary endpoint was the proportion of pts who achieved complete response rate (CR) in response evaluable population. Secondary endpoints included overall response rate (ORR), response at the end of induction therapy (EoT), duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Treatment related adverse events (TRAE) were rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 5.0. This trial is registered with ClinicalTrials.gov, number NCT04127227. Results: From November 2019 to April 2022, 27 eligible pts were enrolled. Median age was 38 years (range, 25-72), 19 (70.4%) were male, 14 (22.2%) pts had PINK-E score ≥ 3 points (Table 1). Of 24 response evaluable pts, the ORR was 100% (24/24), and the CR rate reached 87.5% (21/24, figure 1, 2). At data cut-off, 18 pts completed 6 cycles of induction therapy and entered the maintenance phase, 1 patient experienced disease progression after 4 cycles of the treatment, and the EoT CR rate of induction phase is 13/19 (68.4%). The median time to response (TTR) was 1.6 (1.4-3.8) months. During the maintenance phase, 5 more pts achieved CR and at the time of analysis, The median follow-up time was 16.7 (3.0-32.0) months. The mOS and mPFS were not reached, estimated 1-year OS rate was 100%, 1-year PFS rate was 95%.All (100%) pts experienced TRAE at any grade. The most common toxicity was neutropenia (96.3%) and the majority of TRAEs were reported during the first two cycles of the induction therapy. Grade 3-4 TRAE reported in ≥5% of pts included neutropenia (48.1%), triglycerides increased (37.0%), leukopenia (29.5%), anemia (25.9%), thrombocytopenia (25.9%), albumin decreased (7.4%), and lipase increased (7.4%). Immune-related AEs (irAEs) were reported in 16 pts, including a grade 3 hypothyroidism which led to permanent treatment discontinuation in 1 (3.7%) patient, and the remaining irAEs were all grade 1-2. All TRAEs were manageable and only 1 patient discontinued treatment due to TRAEs during maintenance phase. Conclusions: Combination of sintilimab plus P-GEMOX Regimen yielded promising clinical activity with a manageable safety profile, supporting immunochemotherapy as a new first-line treatment option for pts with advanced ENKTL. Treatment and follow-up are currently ongoing and further studies have been initiated to explore biomarkers to better predict response and long-term survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Proton Therapy for Uveal Melanoma: A Single-Institution Experience

<h3>Purpose/Objective(s)</h3> Uveal melanoma (UM) is the most common intraocular malignancy in adults. Eye-preserving approaches like episcleral plaque brachytherapy are common but limited in patients (pts) with large tumors or those adjacent to the optic nerve. Proton therapy (PT) offers an alternative eye-preserving treatment option. We report a single-institution experience utilizing PT to treat UM. We hypothesized that PT would provide excellent local control (LC) and eye preservation (EP) with acceptable toxicity and visual outcomes across all patients, including those with large tumors in adverse locations. <h3>Materials/Methods</h3> We reviewed the records of treatment-naive pts who received PT for non-metastatic UM between June 2012 and December 2020. All pts had ≥ 6 months of follow-up. Treatment planning was performed in EyePlan (Clatterbridge, UK) based on eye/tumor measurements and 3-4 implanted scleral fiducial markers, registered fundus photographs, and confirmed by CT/MRI. Pts were set-up in a seated position with gaze fixation and real-time image guidance using a single en face beam to a total 50-60 Gy RBE in 4-5 consecutive daily fractions. We estimated disease control and survival, including LC, EP, distant metastasis-free survival (DMFS), cause-specific survival (CSS), overall survival (OS), and grade 3+ toxicity as defined by CTCAEv5 using the cumulative incidence method. Regression of multiple variables simultaneously was accomplished with competing-risks Cox regression. <h3>Results</h3> 120 pts met inclusion criteria; 33 had a biopsy of their lesion; 9.2% were class 2. Moreover, 47.5% had COMS medium while 35.8% had large tumors. Median tumor thickness was 5.0 mm (0.5 – 13.0) and median basal dimension was 13.0 mm (4.0 – 25.0). Median distance to the fovea and optic disc was 3.5 mm. 38% had retinal detachment with 47% having significantly impaired visual acuity at baseline (worse than Snellen 20/40). 98.3% received 60 Gy RBE over 4 daily fractions. Median follow-up was 31 months (6 – 104). The 2-year estimates (95% CI) for LC, EP, DMFS, CSS, and OS were 94% (88-97%), 95% (90-98%), 88% (81-93%), 94% (88-97%), and 90% (83-95%), respectively. 9 pts underwent enucleation following PT (5 for recurrent/persistent disease). Retinopathy (5%), neovascular glaucoma (3.3%), and optic nerve disorder (2.5%) were the most common severe toxicities. 60% of toxicity resolved during follow-up. 38% had functional vision (20/40 or better) at last follow-up. Pretreatment visual acuity had a substantial impact on post-treatment vision. Tumor size was an independent prognostic factor for OS (p=0.01), CSS (p<0.01), EP (p=0.02), and DMFS (p<0.01). No prognostic factor was associated with LC. <h3>Conclusion</h3> Our experience using PT for UM is consistent with previously reported outcomes demonstrating high rates of LC and EP with acceptable toxicity despite a significant percentage of patients with large tumors and/or adverse location near the optic nerve.

61 (PB051) - Capmatinib response in patients with advanced non–small cell lung cancer (NSCLC) harboring focal MET amplifications: Analysis from the phase 2, multicohort GEOMETRY mono-1 study

Background: MET amplifications (METamp) occur in 1–6% of patients (pts) with NSCLC and are associated with a poor prognosis. Capmatinib is a highly selective and potent MET inhibitor (METi) with antitumor activity in pretreated and treatment-naive pts with MET-amplified (gene copy number [GCN] 310) NSCLC. Focal METamp are associated with a relatively high MET GCN and may be a predictor of benefit from METi. In this retrospective analysis from GEOMETRY mono-1 (NCT02414139), we aimed to determine the response to capmatinib according to focality of METamp detected in cell-free DNA (cfDNA) using a blood-based assay. Materials and Methods: Pretreated (1 or 2 prior lines) pts with EGFR wild-type, ALK-negative, MET exon 14 skipping–negative, stage IIIB/IV NSCLC were grouped into cohorts C1a, C1b, C2, and C3 based on different levels of MET GCN amp by FISH on tumor tissue. Pts received capmatinib 400 mg twice daily. cfDNA isolated from blood plasma samples collected at baseline was enriched using RNA-bait–based hybrid capture and analyzed using next-generation sequencing (PanCancer assay 1.0, NGDx, Novartis). Focal METamp were defined using the PureCN pipeline that estimates a gene-level log-ratio relative to normal samples, adjusting for gene probe signal variation. MET was called focally amplified if gene-level P value was <0.001 and gene-level log-ratio reached 90th percentile of all genes. The overall response rate (ORR) by Blinded Independent Review Committee was descriptively compared between pts with focal vs nonfocal METamp (data cutoff, August 2021). Results: 195 pts across the 4 cohorts had METamp by FISH. Of these, baseline cfDNA samples from 113 pts were successfully analyzed (C1a [n = 29], C1b [n = 32], C2 [n = 31], C3 [n = 21]). Baseline characteristics were comparable between pts who were analyzed by cfDNA (n = 113) vs not analyzed (n = 82) and between pts with focal (n = 18) vs nonfocal (n = 95) METamp. Of all pts with focal METamp, most were in high MET-amplified C1a (14 of 18 pts [78%]). In C1a, the distribution of GCN by FISH was similar in pts with focal vs nonfocal METamp but more responders were found in pts with focal vs nonfocal METamp (ORR, 57% vs 13%). In C1b, 3 of 32 pts (9%) had focal METamp; 2 were responders (Table).Tabled 1CohortMET GCN by FISHParameterFocal METampNonfocal METampPts analyzedAll pts in cohortC1a≥10N14152969ORR, n (%)8 (57)2 (13)10 (34)20 (29)C1b≥6 and <10N3293242ORR, n (%)2 (67)1 (3)3 (9)5 (12)C2≥4 and <6N0313154ORR, n (%)-2 (6)2 (6)5 (9)C3<4N1202130ORR, n (%)0 (0)1 (5)1 (5)2 (7) Open table in a new tab Conclusions: METamp status, including focal METamp, was successfully determined using cfDNA isolated from blood. For pts with high MET- amplified NSCLC by FISH, a numerically higher proportion of responders to capmatinib was observed in pts with focal vs nonfocal METamp. Given the small sample size, a larger study is needed to verify this result. Conflict of interest: Ownership: Juergen Wolf: None Markus Riester, Lexiang Ji, Anna Robeva, Aislyn Boran: Novartis stock Advisory Board: Juergen Wolf: Consulting or advisory role for Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Ignyta, Lilly, MSD Oncology, Novartis, Pfizer, Roche, Janssen, Loxo/Lilly, Blueprint Medicines, Amgen, Takeda, Bayer, Daiichi Sankyo Europe GmbH, Seattle Genetics Edward B. Garon: Consultant and/or advisor for Abbvie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio. Daniel S. W. Tan: Consulting/advisory role for Pfizer, Novartis, Takeda, Boehringer Ingelheim, Merck, Amgen, AstraZeneca, DKSH, Roche, C4 Therapeutics, GSK Board of Directors: Juergen Wolf: None Corporate-sponsored Research: Juergen Wolf: Research funding from Bristol-Myers Squibb, Novartis, Pfizer, Janssen Edward B. Garon: Grant/research support from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis Daniel S. W. Tan: Research funding (payments to institution) from AstraZeneca, Pfizer, ACM Biolabs, Amgen Rebecca S. Heist: To institution (not to self) from Agios, Abbvie, Lilly, Novartis, Turning Point, Daichii Sankyo, Mirati, Corvus, Exelixis, Erasca Other Substantive Relationships: Juergen Wolf: Honoraria from Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Roche, Amgen, Bayer, Blueprint Medicines, Chugai Pharma Europe, Daiichi Sankyo Europe GmbH, Ignyta, Janssen, Lilly, Loxo, Loxo/Lilly, Pfizer, Seattle Genetics, Takeda Sylvie Le Mouhaer, Markus Riester, Lexiang Ji, Anna Robeva, Lauren Fairchild, Aislyn Boran: Employment at Novartis Rebecca S. Heist: Consulting for Novartis, Daichii Sankyo, EMD Serono

1447O Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): Cohort 1 of LITESPARK-003

HIF-2α is constitutively activated in RCC and is a transcription factor of multiple oncogenic pathways including TGF-α, GLUT1, cyclin D1, CXCR4, and VEGF. VEGF, and its receptor, are key regulators of angiogenesis and are upregulated in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumor activity and favorable safety in heavily pretreated advanced RCC. Cabozantinib, a multikinase inhibitor that targets VEGF, is approved for advanced RCC. We present the first data of the use of belzutifan plus cabozantinib for treatment-naive pts with advanced RCC (cohort 1) enrolled in the ongoing, open-label, phase 2 LITESPARK-003 study (NCT03634540).

P1237: PRELIMINARY RESULTS OF A PHASE Ⅱ STUDY OF ZANUBRUTINIB COMBINED WITH IMMUNOCHEMOTHERAPY IN PATIENTS WITH CD79A/CD79B-MUTANT DIFFUSE LARGE B-CELL LYMPHOMA

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous hematologic malignancy with highly variable genetic abnormalities and clinical outcomes, highlighting the importance of individualized treatment. Previous studies showed that CD79B mutation was associated with higher risk of relapse and shorter survival after standard treatment (2020 ASH Abstract 2923), and both CD79B- or CD79A-mutant lymphoma cells were sensitive to BTKi in vitro (Nat Med. 2015;21:922-926). Moreover, a recent pooled analysis revealed that CD79B-mutant lymphoma patients (pts) treated with Zanubrutinib alone or in combination with anti-CD20 antibody had better response (2020 EHA Abstract EP1246). Thus, we inferred that BTKi combined with immunochemotherapy might be a favorable option for pts with CD79A/CD79B-mutant DLBCL. Here, we present preliminary data from the phase 2 trial of Zanubrutinib combined with immunochemotherapy in pts with CD79A/CD79B-mutant DLBCL (NCT04668365). Aims: To investigate the efficacy of Zanubrutinib combined with immunochemotherapy in pts with CD79A/CD79B-mutant DLBCL. The primary objective is complete response rate (CRR). Methods: Pts aged 18-80 years with CD79A/CD79B-mutant DLBCL and adequate organ function are being enrolled. This study consisted of treatment naïve (TN) cohort and relapsed/refractory (R/R) cohort. Zanubrutinib (160 mg po bid) plus R-CHOP (ZR-CHOP) was administered in TN cohort, and Zanubrutinib (160 mg po bid) combined with investigator-determined conventional salvage chemotherapy (CSC, including ICE, DHAP, GDP, or GemOx, +/- rituximab) was administered in R/R cohort. A total of 7 cycles of treatment was planned for TN patients. After 5 cycles of induction treatment, responders in R/R cohort undergo autologous stem cell transplantation (ASCT) or Zanubrutinib maintenance for 12 months, based on the patient’s fitness and preference. Results: From July 2020 to 22 February 2022, 91 pts had been screened, including 65 TN pts and 26 R/R pts. CD79A/CD79B mutation was identified in 14 (21.5%) TN pts and in 11 (42.3%) R/R pts, of which 7 TN pts and 8 R/R pts agreed to participate in this trial. Their baseline characteristics are displayed in Table 1. By 22 February 2022, 6 TN pts and 7 R/R pts had been evaluated for response. All of the 6 (100%) TN pts achieved CR. In the R/R cohort, the responses were CR in 4 (51.7%) pts, partial response (PR) in 2 (28.6%) pts, and progression disease (PD) in 1 (14.3%) patient. The median follow-up time was 9.7 (1.2 – 19.2) months for the TN cohort and 3.8 (0.3 – 9.6) months for the R/R cohort. None of the patients had PD in the TN cohort. Two pts (1R/R and 5R/R) in the R/R cohort experienced PD and subsequently succumbed to lymphoma, both of which harbored TP53 mutations. The most common adverse events in both cohorts were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% pts were neutropenia, leukopenia, anemia, and thrombocytopenia. Bleeding events and cardiac events were not observed. Image:Summary/Conclusion:CD79A/CD79B mutation was frequent in DLBCL patients, especially in R/R cases. Zanubrutinib combined with immunochemotherapy showed encouraging activity and acceptable tolerance in pts with CD79A/CD79B-mutant DLBCL. TP53 mutation seems to be a detrimental factor. The study is still ongoing and it is worth looking forward to updating the long-term survival data.

P667: LONG-TERM EFFICACY OF ACALABRUTINIB-BASED REGIMENS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND HIGHER-RISK GENOMIC FEATURES: POOLED ANALYSIS OF CLINICAL TRIAL DATA

Background: Chronic lymphocytic leukemia (CLL) has a highly variable disease course; patients (pts) with higher-risk genomic features typically have poor response to chemoimmunotherapy, and pts with del(17p) also have short, suboptimal response to venetoclax + obinutuzumab. Thus, novel agents such as Bruton tyrosine kinase inhibitors (BTKi), including the highly selective covalent BTKi acalabrutinib (A), are preferred treatments in this higher-risk population based on demonstrated effectiveness in higher-risk subgroups in individual studies. Aims: To assess long-term efficacy of A-based regimens in pts with treatment-naive (TN) or relapsed/refractory (R/R) CLL and higher-risk genomic features. Methods: Data were pooled from CLL pts with higher-risk genomic features treated with A ± obinutuzumab (O) in 3 clinical studies in TN CLL (ELEVATE-TN, CL-001 [TN cohort], CL-003) and 3 in R/R CLL (ASCEND, ELEVATE-RR, CL-001 [R/R cohort]). Higher risk was defined as del(17p) and/or TP53 mutation [del(17p)/TP53m], unmutated IGHV (uIGHV), or complex karyotype (CK, ≥3 chromosomal abnormalities). Efficacy analyses (progression-free survival [PFS], overall survival [OS], response rates) focus on del(17p)/TP53m and uIGHV; safety analyses also include pts with CK. Results: 801 pts (TN 313; R/R 488, median 2 prior therapy lines [range 1–10]) were included; 64 (20%) TN and 219 (45%) R/R pts had del(17p)/TP53m, among whom 44 (69%) and 170 (78%) also had uIGHV. Overall, 288 (92%) TN and 425 (87%) R/R pts had uIGHV and 47 (15%) and 160 (33%) had CK. Median pt age was 68 (TN) and 66 (R/R) y. For A-based regimens combined (A and A+O), overall response rate (ORR) was 91% (n=58/64; complete response [CR]: 20% [n=13/64]) in TN pts with del(17p)/TP53m and 96% (n=276/288; CR 16% [n=47/288) in TN pts with uIGHV. At 47.3 mo median follow-up (range 1.0–82.0), median PFS was not reached (NR) in TN pts with del(17p)/TP53m with A-based regimens; PFS rates at 48 mo suggest similar efficacy with A and A+O in TN pts with del(17p)/TP53m (76% and 77%, respectively) (Fig 1A). Median PFS was NR among TN pts with uIGHV with both A and A+O; PFS rates at 48 mo with A and A+O were 84% and 86%, respectively (Fig 1B). Median OS was NR with A and A+O in TN pts with del(17p)/TP53m or uIGHV; OS rates at 48 mo were similar for A and A+O in pts with del(17p)/TP53m (89% for both) and in pts with uIGHV (92% and 95%). In the R/R cohort (A monotherapy only), ORR was 86% (n=184/214; CR 5% [n=11/214]) in pts with del(17p)/TP53m and 87% (n=356/408; CR 7% [n=29/408]) in pts with uIGHV. At 44.0 mo median follow-up (range 0–88.0), median PFS was 38.6 mo and 46.9 mo and PFS rates at 36 mo were 54% and 65% in pts with del(17p)/TP53m and uIGHV, respectively (Fig 1C). Median OS was 60.6 mo and NR in pts with del(17p)/TP53m and uIGHV, respectively; OS rates at 36 mo were 73% and 82%. Among all higher-risk pts, incidences of grade ≥3 treatment-related AEs were 30% (TN) and 35% (R/R). Discontinuations due to treatment-related AEs occurred in 4% (TN) and 6% (R/R) of pts; 60% and 27%, respectively, remained on treatment at data cutoff. Image:Summary/Conclusion: In this pooled analysis of clinical trial data in 801 CLL pts with higher-risk genomic features, efficacy of A-based regimens led to high PFS and OS rates at a median follow-up of nearly 4 y. The safety profile in this analysis was similar to the overall safety profile of acalabrutinib. Our results demonstrate the long-term benefit of A-based regimens in CLL pts with higher-risk genomic features, regardless of line of therapy.

P830: CROVALIMAB MAINTAINS CLINICAL BENEFIT OVER LONG-TERM TREATMENT IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA: RESULTS FROM THE COMPOSER TRIAL OPEN-LABEL EXTENSION

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired hematopoietic stem-cell disorder, resulting in hematuria, anemia, and acquired thrombophilia. In the Phase I/II COMPOSER trial (NCT03157635), patients (pts) with PNH who were treatment-naive or switched from eculizumab were treated with crovalimab, a novel anti-C5 monoclonal antibody designed with Sequential Monoclonal Antibody Recycling Technology (Röth et al. Blood 2020). Aims: To report the long-term efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) outcomes in pts with PNH treated with crovalimab in the open-label extension (OLE) period of the COMPOSER trial. Methods: COMPOSER consists of four sequential parts followed by an OLE period. Pts with PNH who were treatment-naive or switched from eculizumab in Parts 2, 3, and 4, who completed the primary treatment period through Week 20 and derived benefit from crovalimab treatment, were eligible to enter the OLE (Röth et al. EHA 2019). Long-term efficacy, safety, PK and PD data are presented for the OLE. Efficacy endpoints include change in lactate dehydrogenase (LDH), transfusion avoidance and hemoglobin stabilization (both assessed in 24-week intervals), and breakthrough hemolysis (BTH). PK and PD endpoints include assessment of serum concentrations of crovalimab, complement activity by liposome immunoassay (LIA), and free C5 over time. Results: Overall, 43 of 44 pts entered the OLE and at the clinical cutoff (Nov 1, 2021), 38 pts were ongoing. Mean normalized LDH was maintained at ≤1.5 × upper limit of normal (ULN) during the OLE, and 80% to 100% of evaluable pts achieved LDH ≤1.5 × ULN at each visit (Figure). Transfusion avoidance was achieved in 83% to 92% of pts over each 24-week interval in the OLE. Similarly, hemoglobin stabilization remained relatively stable during the OLE, with 79% to 88% of pts achieving hemoglobin stabilization across 24-week intervals. There was a total of five BTH events during the OLE across all pts (none leading to withdrawal) for an overall BTH rate of 0.05 events per pt-year (95% confidence interval: 0.01, 0.11). The incidence of adverse events (AEs) was reported cumulatively from baseline. Median treatment duration (range) for treatment-naive and switched pts on the study was 3.4 years (0.9-4.4) and 2.9 years (0.4-3.9), respectively. Any grade AEs occurred in 95% (42/44) of pts; none led to withdrawal from treatment. Severe AEs occurred in 17% (3/18) of treatment-naive pts and 19% (5/26) of switched pts. Serious AEs occurred in 32% (14/44) of pts (33% [6/18] in treatment-naive and 31% [8/26] in switched pts), of which 5% (2/44) were assessed as related to study treatment by the investigator. No meningococcal infections or deaths were reported. Crovalimab concentrations were stable and within the expected range over time. Terminal complement activity by LIA was near the lower limit of quantification (10 U/mL) and free C5 levels were maintained at low levels (<0.001 g/L) in most pts. PK/PD relationships between free C5 or LIA with crovalimab confirmed that crovalimab levels of ≈100 μg/mL resulted in complete inhibition of terminal complement activity. Image:Summary/Conclusion: Treatment-naive and switched pts with PNH treated with crovalimab in the COMPOSER trial maintained disease control over long-term follow-up. No new safety signals were identified, and complete terminal complement inhibition was maintained during the OLE. These data support the continued clinical development of crovalimab in PNH.