Untreated Pts Research Articles

Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: Results from a randomized, open-labeled, phase Ib study.

3505 Background: Immune checkpoint inhibitors have been used in neoadjuvant setting and showed promising clinical benefits in various tumors. Herein, we evaluate IBI310 plus sintilimab as neoadjuvant treatment in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) colorectal cancer (CRC) in a randomized, open-labeled, phase Ib study. Methods: Previously untreated pts with locally advanced (stage IIB-III), resectable, MSI-H/dMMR CRC were enrolled and randomized to receive 1 cycle of IBI310 1mg/kg plus 2 cycles of sintilimab 200 mg Q3W (arm A) or 2 cycles of sintilimab 200 mg Q3W (arm B) as neoadjuvant treatment. The stratification factors were risk evaluation at baseline (high risk: stage T4 or N2 vs low risk: stage T1-3 and N1) and age ( < 55 years vs ≥55 years). Curative resection was scheduled on day 36 to 56 after first dose of neoadjuvant treatment. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included R0 resection rate and safety. Results: As of February 4, 2024, 101 pts were enrolled (males: 55.4%, median age: 56 years, ECOG PS 1: 54.5%, high risk: 76.2%) and randomized into arm A (n = 52) and arm B (n = 49). In arm A, 1 pt had early termination of treatment (withdrawal). In arm B, 4 pts had early termination of treatment (1 withdrawal, 1 died, 2 continued neoadjuvant sintilimab). Scheduled curative resection were performed in 51 (98.1%) pts in arm A and 45 (91.8%) pts in arm B. Postoperative evaluation revealed mismatch repair-proficient (pMMR) in 1 pt each in arm A and arm B. The pCR rates were 80.0% (40/50, 95%CI: 66.3-90.0) in arm A vs 47.7% (21/44, 95%CI: 32.5-63.3) in arm B (p = 0.0007). All pts received surgery had R0 resection. Median time between first dose of neoadjuvant treatment and surgery was 47 days (range: 35-82). Surgery delay occurred in 3 pts including 2 pts in arm A due to grade 2 hypothyroidism (2 days delay) and grade 1 hyperthyroidism (13 days delay), and 1 pt in arm B for other reason (26 days delay). Treatment-emergent adverse events (TEAEs) occurred in 46 pts (88.5%, grade≥3 in 13 pts) in arm A and 39 pts (79.6%, grade≥3 in 9 pts) in arm B. Immune-related adverse events (irAEs) occurred in 22 pts (42.3%) in arm A and 18 pts (36.7%) in arm B. Grade ≥3 irAEs occurred in 3 pts in arm A, including immune-mediated myocarditis, ileus and enteritis, and in 4 pts in arm B, including alanine aminotransferase increased, rash, hypothyroidism and myocarditis. Serious TRAEs occurred in 4 (7.7%) pts in arm A and 3 (6.1%) pts in arm B. TRAE leading to death occurred in 1 pt in arm B (myocarditis). Conclusions: Neoadjuvant IBI310 plus sintilimab significantly improved pCR rate than sintilimab alone in MSI-H/dMMR CRC. The safety profiles were comparable and manageable in both treatment arms. Clinical trial information: NCT05890742 .

A phase II study of tunlametinib in combination with vemurafenib in patients with BRAF V600-mutant advanced melanoma.

e21519 Background: The new MEK inhibitor tunlametinib combined with the BRAF inhibitor vemurafenib showed promising clinical activity in patients (pts) with BRAF V600-mutant solid tumors in a previous Phase I study (NCT03976050). Based on the result, we designed a phase IIa study to evaluate the efficacy and safety of tunlametinib plus vemurafenib in Chinese pts with BRAF V600 mutant melanoma. Methods: This open-label, single arm, multiple-center phase IIa study enrolled Chinese pts with BRAF V600E-mutant advanced melanoma, without restriction on the disease subtype (e.g., acral, mucosal, or cutaneous melanoma). Prior treatment was permitted, excluding BRAF/MEK inhibitors. Pts received oral tunlametinib at a dose of 9 mg twice daily and vemurafenib 720 mg twice daily. The primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: Between October 15, 2021, and June 22nd, 2022, 17 pts were enrolled and included in the analysis. Thirteen (76.5%) pts had received previous systemic antitumor therapy, with 12 (70.6%) receiving immunotherapy. Seven (41.2%) pts had acral melanoma, 8 (47.1%) pts had skin melanoma (non-acral) and 2 (11.8%) pts had mucosal melanoma. All pts had metastatic disease. With a median follow-up of 15.3 months (95%CI: 6.8; NE), 12 (70.6%) pts achieved confirmed partial response (PR), resulting in a confirmed ORR of 70.6% (95% CI: 44.0%-89.7%). The disease control rate was 100% (95% CI: 80.5%, 100.0%). The median progression-free survival (PFS) was 10.0 months (95% CI: 5. 5, NE). the duration of response (DOR) was 20.1 (95% CI: 4.2, NE). The overall survival (OS) was 21.6 months (95% CI: 14.5, NE), with a 12-months OS rate of 87.4% (95% CI: 58.1%, 96.7%). Subgroup analysis revealed that in pre-treated pts, the confirmed ORR was 76.9% (95% CI: 46.2%, 95.0%), the median PFS was 10.0 months (95% CI: 5.5, NE), while in previous untreated pts, the mPFS was 14.0 months (95% CI: 9.9, NE). In pts with skin melanoma, the confirmed ORR was 87.5% (47.3%, 99.7%), the mPFS was 10.0 months (95% CI: 5.5, NE), the mOS was 21.6 months (95% CI: 5.7, NE). In pts with acral melanoma, the ORR was 57.1% (95% CI: 18.4%,90.1%), the mPFS was 18.1 months (95% CI: 2.8, NE), the mOS not reached (12.3, NE). The most common adverse events included rash, pyrexia, and elevated blood creatin phosphokinase, most of which were of grade 1-2 severity. Grade 3 or higher TRAEs occurred in 12 (70.6%) pts, of which 41.2% were rash. Most AEs were manageable with supportive therapy or dose interruption. No treatment-related deaths were reported. Conclusions: The addition of a MEK inhibitor tunlametinib to vemurafenibexhibited promising clinical efficacy in Chinese patients with BRAF V600-mutant advanced melanoma, with a manageable safety profile. Additionally, notable effects were observed in pts with acral melanoma. The efficacy in pre-treated patients was comparable to that of similar agents in previous untreated patients. Clinical trial information: NCT05263453 .

A phase 2/3 study of Bicycle toxin conjugate BT8009 targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC): Duravelo-2.

TPS4619 Background: BT8009 is a Bicycle toxin conjugate (BTC), comprising a highly selective bicyclic peptide targeting nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via a cleavable linker. Nectin-4 is an adhesion molecule commonly expressed in many tumor types, including urothelial cancer (UC), and is a validated therapeutic target (Hoffman-Censits 2021). BT8009 has a low molecular weight and short plasma half-life, with potential to rapidly penetrate solid tumors and reduce toxicity by minimizing exposure to normal tissue (Rigby 2022). Results from the ongoing phase 1/2 clinical trial of BT8009 (NCT04561362) indicate preliminary antitumor activity and a tolerable safety profile in patients (pts) with advanced malignancies including UC (Baldini 2023). This global, open label, phase 2/3 multicenter adaptive study aims to evaluate the safety and efficacy of BT8009 as monotherapy, or combined with pembrolizumab (pembro), vs chemotherapy in pts with locally advanced or metastatic UC (la/mUC) (NCT06225596/BT8009-230; Duravelo-2). Methods: The trial will enroll up to 956 adult pts in 2 cohorts. Cohort 1 will include n≤641 previously untreated pts eligible for platinum-based chemotherapy. Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy. Pts must have la/mUC of the renal pelvis, ureter, bladder, or urethra, ECOG performance status ≤2 (Cohort 1) or ≤1 (Cohort 2), and adequate organ function. Cohort 1 will be randomized 1:1:1 to receive: 1) BT8009 5 mg/m2 on days (D)1, 8, and 15 + pembro 200 mg on D1; 2) BT8009 6 mg/m2 on D1 and 8 + pembro 200 mg on D1; or 3) chemotherapy (gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance). Cohort 2 will be randomized 1:1 to receive: 1) BT8009 5 mg/m2 on D1, 8, and 15 or 2) BT8009 6 mg/m2 on D1 and 8. Cycle lengths will be 21D (28D for avelumab). After 30 pts in each dose arm have 9 weeks follow-up, an interim analysis will determine the optimal dose of BT8009 + pembro (Cohort 1) or BT8009 monotherapy (Cohort 2) to be used for the rest of the study. An additional Cohort 2 arm, optimal dose of BT8009 + pembro, will open after completion of the interim analysis. Discontinuation criteria include planned completion of therapy, progressive disease, and intolerable toxicity. Primary endpoints are progression-free survival (PFS; Cohort 1) and objective response rate (ORR; Cohort 2) assessed by blinded independent central review. Secondary endpoints are ORR (Cohort 1), PFS (Cohort 2), and overall survival, duration of response, disease control rate, safety/tolerability, and health-related quality of life (Cohorts 1 and 2). Pharmacokinetics, incidence/titers of antidrug antibodies, and tumor/peripheral biomarkers are exploratory endpoints. Efficacy endpoints will be assessed per RECIST v1.1. This study is actively recruiting. Clinical trial information: NCT06225596 .

Abstract 4669: Differential preclinical activity of Bruton tyrosine kinase inhibitors (BTKis) against BTK resistance-associated mutations

Abstract Background: Differences in profiles of acquired mutations of resistance to BTKis might have implications for treatment sequencing. We evaluated preclinical activity of BTKis (ibrutinib [Ibr], acalabrutinib [Acala], zanubrutinib [Zanu], and pirtobrutinib [Pirto]) against multiple clinically relevant BTK mutations and report on the clinical impact of BTK C481S in patients (pts) treated with Ibr. Methods: Inhibition of kinase activity by BTKis was evaluated in a cell-free kinase activity assay (Nanosyn). Cell-killing activity on CRISPR-generated BTK mutant knock-in TMD8 cells was assessed after 3 days of BTKi treatment. Time from first detection of C481S mutation to progressive disease (PD) was evaluated in pts treated with Ibr with previously untreated (n=247) or relapsed/refractory (R/R; n=172) CLL using pooled data from 5 clinical trials. Results: In vitro kinase activity was highest for Ibr compared with Acala or Zanu against C481S (Ibr IC50: 26.3 nM; Zanu: 84.8 nM; Acala: 338 nM) and T474I (Ibr: 1.2 nM; Zanu: 4.4 nM; Acala: 43.6 nM). Ibr maintained cell-killing activity against all tested BTK mutants, whereas limited activity was seen with Acala against C481S and A428D; with Zanu against C481S, L528W, and A428D; and with Pirto against T474I, L528W, V416L, and A428D (Table). In pts treated with Ibr, C481S was detected prior to clinical PD in 3 previously untreated pts and in 26 pts with R/R CLL; median (range) time from first detection of C481S to PD in these pts was 17.0 mo (11.2-34.3) and 10.0 mo (2.6-35.7), respectively. Conclusion: This study demonstrates activity of Ibr against all evaluated BTK variants, which are associated with resistance to covalent and noncovalent BTKis. Clinical data shows that pts who develop C481S mutations continue to derive benefit from Ibr for several months before PD. Together, these data suggest a role for Ibr in the treatment of pts with a broad spectrum of BTK variants. Table. Cell-killing activity of BTKis against wild type and mutant BTK EC50 (nM) BTK Wild type C481S T474I L528W V416L A428D Ibr 0.6 414.0 1.9 181.4 0.5 205.3 Acala 3.9 2973.8 43.3 3.5 106.3 3000.0 Zanu 0.7 2322.0 11.7 3000.0 0.6 1726.0 Pirto 8.2 12.6 2727.5 3000.0 1898.0 3000.0 Citation Format: Matthew S. Davids, Inhye E. Ahn, Jacob J. Riehm, Melih Acar, Vincent Girardi, Sima Patel, Tarikere Gururaja, Jennifer Woyach, Lloyd T. Lam, Edith Szafer-Glusman. Differential preclinical activity of Bruton tyrosine kinase inhibitors (BTKis) against BTK resistance-associated mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4669.

Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study.

LBA768 Background: Patients (pts) with MSI-H/dMMR mCRC have poor outcomes with standard chemo ± targeted therapies. NIVO ± IPI are approved in previously treated pts with MSI-H/dMMR mCRC in many countries, based on the phase 2 CheckMate 142 study. CheckMate 8HW (NCT04008030) is a randomized phase 3 study comparing NIVO + IPI with NIVO or chemo in pts with MSI-H/dMMR mCRC. We report progression-free survival (PFS) by blinded independent central review (BICR) at a prespecified interim analysis for NIVO + IPI vs chemo in the 1L setting. Methods: Pts ≥ 18 years with recurrent or mCRC not amenable to surgery and MSI-H/dMMR status per local testing were enrolled across different lines of therapy. Previously untreated pts were randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). For pts with BICR-documented progression with chemo, optional crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. Results: In the 1L setting, 303 pts were randomized to NIVO + IPI (n = 202) or chemo (n = 101); of these pts, 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32]; P < 0.0001) (Table). No new safety signals were identified (Table). Conclusions: NIVO + IPI demonstrated superior PFS vs chemo in previously untreated pts with MSI-H/dMMR mCRC. NIVO + IPI had a different safety profile compared to chemo, with fewer grade 3–4 treatment-related adverse events (TRAEs). These results support 1L NIVO + IPI as a standard-of-care option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]

Real-world performance and clinical outcome of comprehensive genomic profiling of gastrointestinal tumors: High-volume, single-center experience.

727 Background: In order to identify targetable mutations, the Comprehensive Genomic Profiling (CGP) is an important tool. Technologies like extensive genomic NGS panels analyze multiple genes and biomarkers in a single assay. With multi-omics analysis, clinicians could increase the possibility to provide a tailored therapy. In literature, evidence about clinical applicability and performance of NGS are mainly derived from clinical trials and real-world experiences are lacking. Methods: On these bases, we performed a retrospective analysis of CGP data from a cohort comprising 1450 patients (pts) with a diagnosis of gastrointestinal tumor. The primary objective was to estimate adequacy and quality of CGP. As secondary objective, we identified mutations with an available but not already standard of care targeted treatment (TT), defined as gain, and we collected clinical data in those pts. The genomic analysis was performed using the FoundationOne CDx panel. Clinical impact of treated vs not-treated pts with TT was evaluated using 1:1 propensity score matching, according to tumor type, treatment line and gain gene mutation. Survival outcomes were estimated with Kaplan-Meier method and compared with Hazard Ratio (HR), univariate Cox regression. Results: In our population, 1310/1450 samples (90.3%) were adequate for NGS analysis. Failure rates were higher in biopsy samples compared to resections (p < 0.0001); the first cause was insufficient tumor DNA (p = 0.0020) especially for hepato-biliary-pancreatic neoplasms. Low-quality reports observed in 252/1310 (19.2%) were mainly due to inadequate DNA quality or extraction, regardless samples type. Gain molecular alterations were identified in 355/1450 pts (24.5%), corresponding to 28.1% of cases with informative reports and metastatic disease. Among them, based on the presence of gain alteration, 15.2% of pts received TT. Overall survival did not significantly differ in pts with and without gain mutations (HR 1.10, 95% CI: 0.93-1.30). An exploratory analysis of 17 matched treated vs untreated pts showed better overall survival (HR 0.26, 95% CI: 0.08-0.79) for the treated ones. More than 50% of pts with gain mutation did not received TT due to drug unavailability (lack of trials, expanded access programs or off-label use) or decreasing of general conditions (38.1%). Conclusions: The selection of appropriate samples and a bidirectional pathologist-clinician collaboration is crucial to enhance the feasibility of CGP. In our wide population, a relevant proportion of metastatic gastrointestinal pts presented a druggable gene alteration with a potential improvement of outcomes in case of availability of TT. Moreover, the time of testing is important to do not lose the right window of opportunity, especially in the metastatic setting.

Real-world (RW) effectiveness of nivolumab plus chemotherapy (NIVO+chemo) in patients (pts) with advanced or metastatic gastric carcinoma, gastroesophageal junction carcinoma, or esophageal adenocarcinoma (GC/GEJC/EAC).

295 Background: In the CheckMate 649 trial, NIVO+chemo demonstrated superior efficacy vs chemo alone in pts with previously untreated, advanced, non-human epidermal growth factor receptor 2 positive GC/GEJC/EAC. Our study was the first to evaluate the RW adoption patterns and effectiveness of NIVO+chemo as a first-line (1L) treatment of advanced GC/GEJC/EAC in the immediate period after NIVO approval in this setting. We report the 18-mo follow-up results. Methods: Pts in the United States ≥ 18 years of age with previously untreated advanced or metastatic GC/GEJC/EAC receiving NIVO+chemo or chemo alone (FOLFOX or CAPEOX) between 04/01/2021 and 12/31/2022 were identified in the Flatiron Health database. Pts were followed from the start of 1L therapy to death, loss of data availability, or the end of data abstraction, whichever occurred first. Results: 528 pts were eligible for the analysis (231 [44%] NIVO+chemo, 297 [56%] chemo). The prevalence of PD-L1 combined positive score (CPS) ≥ 5 before the 1L therapy was 55% for NIVO+chemo and 27% for chemo. Baseline demographic and clinical characteristics were comparable between treatment groups in the overall cohort and the CPS subgroups. Median follow-up (interquartile range) was 6.0 (2.4−9.8) mo for NIVO+chemo and 6.1 (2.5−9.7) mo for chemo. There were 87 (37.7%) deaths in the NIVO+chemo cohort and 138 (46.5%) in the chemo cohort. NIVO+chemo demonstrated superior overall survival (OS) in the overall cohort, with a 12-mo OS rate of 53.3% vs 38.1% for chemo and a 2.6-mo improvement in median OS (12.6 [95% confidence interval (CI), 10.2−17.9] mo vs 10.0 [8.9−11.5] mo, P = 0.047). Univariate Cox regression analysis of OS yielded a hazard ratio (HR) of 0.76 (95% CI, 0.58−1.00; P = 0.048) and multivariate Cox regression yielded an HR of 0.74 (95% CI, 0.56−0.98; P = 0.033) for NIVO+chemo vs chemo. There was also a consistent trend toward OS benefit with NIVO+chemo vs chemo in all CPS subgroups (Table). Multivariate analysis in the CPS ≥ 1 subgroup yielded a HR of 0.51 (95% CI, 0.30−0.89) for NIVO+chemo vs chemo but was not feasible in other subgroups due to sample size. Conclusions: NIVO+chemo showed superior OS vs chemo alone in previously untreated pts with advanced GC/GEJC/EAC in the RW setting. A trend toward OS benefit was also observed in all CPS subgroups, which will be further examined in future analyses with larger samples and longer follow-up. Clinical trial information: NCT02872116 . [Table: see text]

Early Complete Responses with Mosunetuzumab Monotherapy in Treatment-Naïve Follicular and Marginal Zone Lymphomas with Only Low-Grade Cytokine Release Syndrome

Introduction Mosunetuzumab (mosun) is a CD20xCD3 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. Updated follow up of the pivotal study in relapsed/refractory patents (Sehn et al ICML 2023, median follow up 28.3 months) showed a CR rate of 60%. Among the patients in CR, 77% remained alive and progression free at 2 years. We hypothesized that mosun would be even more active in patients (pts) without prior lymphotoxic therapy. Therefore, we designed a response adapted study for pts with untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods This is a single center, open label, investigator-initiated response-adapted clinical trial in untreated pts with FL or MZL with indication for treatment. Pts received subcutaneous mosunetuzumab monotherapy for 8 cycles (21 day cycle, Part A) employing step up dosing in cycle 1 (5 mg, 45 mg, 45 mg). Dexamethasone prophylaxis was administered through C2D1, and could be omitted after that for patients without CRS in the previous cycle. A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. Pts with SD or PR could receive 6 cycles (21 day cycle, Part B) of polatuzumab vedotin and obinutuzumab, followed by an end of treatment (EOT) PET/CT. Total planned accrual is 42 pts. The primary endpoint is complete response (CR) rate. A pre-planned interim efficacy analysis is being reported after 20 enrolled pts. If 14 or fewer of the first 20 subjects do not achieve an objective response, the study will be suspended to enrollment. Additional planned safety analyses are in place with suspension rules to detect excessive G4 non-heme toxicity and G2+ CRS. Results 26 pts enrolled on study between March 24, 2022, and March 11, 2023, with 26 pts evaluable for safety, and 21 pts are evaluable for efficacy. Median age was 64 (42-83), including 16 (62%) age 60+. Histologies enrolled include G1-2 follicular lymphoma (19, 73%), G3A follicular lymphoma (4, 15%), and marginal zone lymphoma (3, 12%). The most common indication for treatment was symptomatic disease (19, 73%). All treatment was delivered as an outpatient. Three pts experienced a serious adverse event (one pt with G3 lung infection followed by G3 shingles, one pt observed overnight with G1 cytokine release syndrome, and one pt with a G2 URI). Other G3 non-lab AEs observed were diarrhea (1, 4%), syncope (1, 4%), and hypertension (1, 4%). Sixteen (62%) pts experienced G1 CRS, with no G2 or higher CRS observed or any grade ICANS observed. No pts required tocilizumab. All CRS events first occurred during cycle 1. Headache was common but low grade (G1 14, 54%, G2 1, 4%). Heme toxicity > G1 was uncommon, with G4 neutropenia (1, 4%), and G2+ thrombocytopenia (2, 8%). No G4 non-heme toxicity was observed. Nearly all pts (92%) experienced at least one injection site reaction, which were all G1 except a single pt with a G2 reaction. Seven (26%) pts experienced a treatment delay due to toxicity, primarily due to infection in 4 pts. Only one patient did not receive all doses of mosun - G3 ALT increase and prolonged G1 CRS led to discontinuation after cycle 1 (patient achieved CR). Twenty-one patients are efficacy evaluable, with an overall response rate (ORR) of 100%. Eighteen patients have completed mosun therapy, with an ORR and CR rate of 100% and 83%, respectively. Three patients proceeded to obinutuzumab and polatuzumab combination therapy, of whom two have completed all treatment (both converted to CR). All pts remain alive and progression-free. Updated data will be presented at the meeting. Conclusion Fixed duration mosun monotherapy achieves a high CR rate in untreated pts with follicular and marginal zone lymphoma with no G2+ CRS and no ICANS of any grade. Injection site reactions and headaches were common but reversible. Safety and efficacy has remained well within study suspension thresholds and accrual is ongoing to a goal of 42 total patients.

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Were Treated with Hypomethylating Agents (HMA)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction Recognition of the growing importance of genetic mutations in prognostication for pts with MDS prompted the development of IPSS-M to improve outcome prediction. Subsequent validation studies included a heterogenous groups of pts; treated & untreated pts with lower & higher risk (HR) disease, and thus the value of IPSS-M in predicting outcomes of pts with HR-MDS treated with HMA remains unclear. We aimed to evaluate the ability of IPSS-M to predict outcomes of pts with HR-MDS who were treated with HMA in a large multicenter cohort. Methods Using the multi-center VALIDATE database, we included pts with HR-MDS (Defined as IPSS score >1 or IPSS-R score > 3.5) who were treated with any HMA in the frontline setting and had available molecular data before HMA initiation. Time-to-event analysis used Kaplan-Meier estimator and the log-rank tests. Survival was measured from time of HMA initiation. We compared the different scoring systems by Harrell's c-index. Best response to HMA was assessed using the IWG 2023 response criteria in HR pts (n=480) who had a marrow evaluation within 180 days of HMA initiation. This study was supported by an independent research grant from AbbVie. Results A total of 925 pts were included in the analysis. Median age was 68 years (IQR: 62-75) and 66% of the pts were men. MDS excess blast 1/2 accounted for 65% of the diagnosis. Overall, 76% of pts were treated with HMA monotherapy (29% decitabine and 71% azacitidine), 24% received HMA combination therapy, and 39% of pts had HSCT. The most common mutations (MT) were TP53 (32%), ASXL1 (20%), TET2 (13%) and SRSF2 (12%); 36% of pts had MDS harboring >1 gene MT. As anticipated, the cohort was enriched with high risk (26%) and very high risk (46%) IPSS-R groups. According to pre-therapy IPSS-M, pts were classified into very low (2%), low (9%), moderate low (11%), moderate high (14%), high (29%) and very high (36%) risk groups. IPSS-M reclassified 54% of pts, of whom 184 (37%) were up-staged and 317 (63%) were down-staged. Specifically, 38%/21% of pts with intermediate risk IPSS-R MDS, and 30%/36% of pts with high risk IPSS-R MDS were up-staged/down-staged, respectively. In addition, 44% of pts with very high risk IPSS-R MDS were down-staged. The median follow-up time was 19 (IQR:10-35) months (mo). Median overall survival (OS) was 19 (95% CI: 17-22) mo. Overall, 35% of the pts progressed to AML during follow up. IPSS-M groups showed significant differences for both OS and LFS (p-value: <0.0001 for both). The median OS (mo, 95%CI) based on IPSS-M categories were: low (37, 25-62), moderate low (30, 23-47), moderate high (29, 22-35), high (17, 14-20), and very high (14, 12-15) (Panel A). The 3-year LFS (%) were: low (20%), moderate low (48%), moderate high (41), high (50%), and very high (59%). IPSS-M was significantly associated with OS in a multivariable model adjusted for age, sex, type of HMA, number of HMA cycles and receiving allogeneic HSCT (HR: 1.4, 95% CI:1.2-1.5). However, IPSS-M showed comparable performance when compared with the IPSS-R with c-index (95%CI): 0.599 (0.557-0.622) vs. 0.619 (0.560-0.641) for OS. In addition, IPSS-M showed similar performance for LFS: 0.583 (0.560-0.606) vs. 0.588 (0.565-0.610) (Panel B). When IPSS-M/IPSS-R were used as continuous scores, the c-indices (95%CI) for OS and LFS were: 0.617 (0.592-0.640) vs. 0.6400 (0.616-0.664) for OS and 0.598 (0.575-0.622) vs. 0.606 (0.581-0.632) for LFS. We then analyzed the performance of IPSS-R/IPSS-M in pts with HR MDS (IPSS ≥1.5). Both IPSS-R and IPSS-M had comparable performance for OS prediction (c-index:0.548 vs. 0.566) and LFS (0.551 vs. 0.538). Based on the proposed IWG 2023 response criteria, complete remission rate (CR)/ overall response rate (ORR) were 12/47%, 9/58%, 13/47%, and 17/57% of pts assigned to moderate low, moderate high, high, and very high IPSS-M risk groups. No significant association was observed between IPSS-M and ORR (OR: 1.1, p=0.475) or CR (1.1, p=0.286). Conclusions In our multi-center large cohort of pts with HR MDS treated with frontline HMA, IPSS-M significantly stratified pts for OS and LFS. However, when compared with IPSS-R, IPSS-M did not seem to substantially improve prediction of outcomes among HMA-treated pts. Our results emphasize the high predictive prognostic power of clinical features and cytogenetic alterations among HR-MDS pts treated with HMA.

Acalabrutinib with Rituximab As First-Line Therapy for Older Patients with Mantle Cell Lymphoma - a Phase II Clinical Trial

Introduction - Previously, our group reported results from ibrutinib with rituximab in older mantle cell lymphoma (MCL) patients (pts) with an atrial fibrillation rate of 22%. To develop a chemotherapy-free combination for elderly MCL pts, we designed this phase II clinical trial to investigate the efficacy and safety of acalabrutinib with rituximab (AR) as a first line approach in MCL pts (≥ 65 yrs). Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT05214183. Pts received acalabrutinib 100 mg orally twice a day and intravenous rituximab, weekly for first 4 weeks, followed by once a month for 12 months and subsequently once every 2 months totaling 24 months. Acalabrutinib was continued. The primary objective was to assess best overall response rate (ORR) rate after AR. Responses were assessed as per Lugano response criteria. Clonoseq based minimal residual disease (MRD) assessment was performed. Adverse events were coded as per CTCAE version 5. Genomic studies are ongoing. Results - Among 50 pts, the median age was 69 years (range: 65-81). Male/female were 36 and 14 respectively. Bone marrow was positive for MCL in 45/50 (90%) and GI tract in 35/47 (74%) pts. Forty-six pts had classic morphology while three were blastoid and one was pleomorphic. Ki-67% was available in 42 pts - 13/42 (31%) had high Ki-67% and 29/42 (69%) had a low Ki-67% (< 30%). Simplified MIPI risk stratification included: low (n=4), intermediate (n=35) and high risk (n=11). TP53 aberration status (mutations or deletion) was available in 43/50 pts and 12 pts had aberrant TP53 while 31/43 did not have aberrant TP53. Thirty-nine pts had baseline next generation sequencing (NGS) on tumor tissue biopsy and 25/39 (64%) had ≥ 3 mutations. Median number of AR cycles was 12 (range: 3-24). One pt was not evaluable for response at 12 weeks. Overall, the best response was 94% ORR and 90% CR, 4% PR; 6% were non-responders. Median number of cycles to get complete metabolic response was 3 (range 2-7). Fourteen pts were MRD negative at last follow-up of the 28 evaluable pts. With a median follow up of 17 months, the median PFS and OS were not reached (2 year 92% and 96% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. Nine pts (18%) came off study - 3 for adverse events (syncope, atrial fibrillation, intolerance), 3 for disease progression, one melanoma recurrence, one pt choice and one with an unusual monocytosis. Overall, 2 pts died (1 on trial with primary progression). The most common all-grade toxicities were fatigue (82%), myalgia (64%), headache (38%), bruising (28%) and <1% were grade 3 or higher. Among 50 pts, 1 pt had recurrence of grade 2 atrial fibrillation (2%) and one pt had recurrence of grade 3 unstable angina. Conclusions -Chemotherapy-free frontline therapy with AR is highly effective and safe and induced early CR in older pts with MCL.

Six Years Follow up of Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hyper CVAD/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial

Background - We reported the efficacy and safety of using a combination of ibrutinib plus rituximab (IR) induction followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years)patients (pts) with mantle cell lymphoma (MCL), Wang M et al Lancet Oncology 2022. Here we report the long term follow up of this study. Methods - We enrolled 131 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. High risk pts received ibrutinib for 1 year and rituximab once every 2 months for 24 months after completion of part B. Results - Among the 131 pts, the median age was 56 yrs (range - 35-65). High Ki-67 (≥30%) in 58/117 (49.5%) pts, 10 pts (8%) had high risk simplified MIPI score, 15 pts (11%) had aggressive MCL (blastoid/pleomorphic) and 114 pts (87%) had initial bone marrow involvement. Fifty percent of the patients had Ki-67 (≥30%). ORR in part-A was 98% (87% CR). After completion of part A and part B, ORR was 90% (89% CR). After a median follow up of 71 months, 43 patients progressed/died. The median progression free survival (PFS) and overall survival (OS) were not reached. Overall, 30 pts (23%) relapsed after treatment, including 5 who transformed to aggressive MCL. PFS among pts with high and low Ki-67% was 42 months vs not reached (P=0.01) while no difference was observed in OS. PFS was significantly shorter in pts with aggressive histology (p=0.001) but not the OS. PFS was similar in pts who received maintenance vs no maintenance therapy. Overall, 8 pts died (4 with progression, 2 due to disease transformation, one on study due to multiple complications including splenic hematoma, cardio-pulmonary arrest and progression and the last one expired outside and came off study due to encephalitis). 50 pts came off study for various reasons [30 disease progression (including 5 transformation), 10 pt choice, 8 intolerance, 1 second cancer and 1 lost to follow up]. Long term, grade 3-4 toxicities on part A were 6% myelosuppression and 10% each with fatigue, myalgia and rashes and 2% mucositis. Maintenance therapy did not show high toxicities. Conclusions -Long term follow up of chemo-free induction with IR induced durable and deep responses in young MCL pts in the frontline setting. Short course R-HCVAD chemotherapy minimized toxicities and consolidated responses. IR maintenance improved survival outcomes. This combined modality treatment approach may significantly improve young MCL pts outcomes across all risk groups.

Preliminary Results from a Phase 1b/2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine in Patients (Pts) with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase Polo-like kinase 4 (PLK4), a unique Polo-like kinase family member, that is a conserved upstream regulator of centriole duplication. Dysregulation of PLK4 expression causes loss of centrosome numeral integrity, promotes genomic instability and also potentially enables cancer cells to tolerate genomic instability (Mason et al, Cancer Cell 2014). Its inhibition likely causes mitotic catastrophe. An investigator-initiated study (IIS) demonstrated clinical activity in relapsed/refractory AML with adverse cytogenetics. Dose limiting toxicity was colitis, sepsis and the RP2D 96 mg, three CR's (9 evaluable pts) across 2 dose levels were observed [Data on File, Murphy et al]. We report updated data on a company sponsored study (TWT-202; NCT04730258). Study Design and Methods: TWT-202 is a study of CFI-400945 with 3+3 design in escalation and Simon 2 stage in expansion. For Part 1 (CFI-400945), pts with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Pts with MDS or CMML must have progressed or no response after 4 cycles of hypomethylating agents. For Part 2, (CFI-400945 with azacitidine), pts should have relapsed and/or refractory AML, untreated MDS or CMML. Untreated pts ineligible for intensive therapy may be included. The maximum tolerated dose (MTD) is defined as the dose where dose-limiting toxicities (DLTs) are <1 out of 6 at or below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: At 2May2023 cut, 26 pts were enrolled into Part 1. Eighteen (69%) pts had AML, 4 (15%) MDS, 4 (15%) CMML. The median number of prior therapies was 3 (range 1-8), 7 (27%) pts had received a previous stem cell transplant. Twenty (77%) were male, the median age 68 years (range 22, 85). Approximately 80% pts with AML were adverse risk by ELN 2022 criteria. Six pts with AML had TP53 mutations. At 21 days on/7 days off schedule, 5 pts received 32mg, 4 pts 48mg, 3 pts 64mg, 5 pts 80mg, 9 pts 96mg daily. The 28 days on/0 days off schedule was introduced at 96mg, 3 pts enrolled, with 0 DLTs to date. There was 1 DLT at 96mg on the 21/7 schedule (fungemia, gastroparesis, septic shock, enteritis). There have been 23 (89%) SAEs with the following occurring in >3 pts (febrile neutropenia (13 pts), sepsis (5 pts), diarrhea (4 pts), pneumonia (4 pts)). Common treatment emergent adverse events (TEAE) in > 5 pts, all grades, all doses; febrile neutropenia-15 pts (58%), nausea-11 pts (42%), diarrhea, vomiting-both 10pts (39%), hypokalemia- 9 pts (35%), dsypnea, hypophosphatemia-8pts each (31%), anemia-7pts (27%), and abdominal pain, fatigue, hypomagnesemia, pneumonia -6 pts each (23%). 31 % (33 events, 8 pts) ≥grade 3 TEAE's were considered related to CFI-400945 . Three pts (50%) with AML (all with prior venetoclax based therapies) at the 96mg dose level (21/7) from 6 evaluable achieved a response after 1 cycle. One pt (85M) with ELN2022 adverse genetics: complex karyotype, TP53 mutation, achieved CRi, and remains in remission after 3 cycles. One pt (70M) with AML (ELN2022 adverse genetics, complex cytogenetics, TP53 mutation), 2 prior regimens, achieved an MLFS and is pending count recovery. Third pt (51M) had AML normal cytogenetics, ELN 2022 adverse genetics (RUNX1, IDH2, SRSF2), and had relapsed/refractory disease after 5 regimens. The pt achieved an MLFS, however medical complications not related to study drug resulted in dose reduction, therapy hold and subsequent relapse. Pharmacokinetic (PK) evaluations indicated mean terminal-life ranged from 7 - 12 hours. Low accumulation was observed after 21d (AR <2-fold). Exposure in this study is overlapped with that observed in the IIS (Data on File, Murphy et al) study. PD studies evaluating the effect of CFI-400945 on markers of mitosis, ploidy and centriole function are ongoing. Conclusion: CFI-400945 has been generally well tolerated in this difficult to treat patient population, including patients whose disease progressed on or following venetoclax based therapies. Three of 6 evaluable patients with AML achieved a response (MLFS=2, CRi=1) at the 96mg dose. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose expansions are planned and a combination with azacitidine will open shortly. Murphy et al, Data on File, PMCC Mason et al Cancer Cell 26, 163-176

Ibrutinib, Fludarabine, Cyclophosphamide and Obinutuzumab (iFCG) for Firstline Treatment of Patients with CLL with Mutated IGHV and without Del(17p)/ TP53 Mutation: Six-Year Follow-up Analyses

Background Patients (pts) with IGHV-mutated ( IGHV-M) CLL have favorable long-term outcomes after receiving first-line FCR (fludarabine, cyclophosphamide and rituximab). We designed an investigator-initiated, phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809), and we report here an updated analysis with a median follow-up of 72 months. Methods Inclusion criteria included diagnosis of previously untreated CLL/SLL needing treatment per iwCLL criteria, age ≥18, IGHV-M, absence of both del(17p) and TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (BM) (4-color flow-cytometry, sensitivity 10 -4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with U-MRD (CR/CRi or PR) at end of Cycle 12 stopped all therapy, including ibrutinib. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by clinical examination, blood counts and peripheral blood MRD every 6 months. Results Between March 2016 and August 2018, 45 pts initiated treatment. Data cutoff was July 15, 2023. Baseline characteristics are shown in Table 1. All pts per study inclusion criterion had IGHV-M; however, 1 enrolled pt was later reclassified as IGHV-unmutated. A total of 69% pts had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. Median follow-up duration is 72 months. 41/45 pts completed 12 cycles of treatment (4 pts came off study prior to Cycle 12). All 41 pts achieved marrow U-MRD and per protocol, discontinued ibrutinib. After a median follow-up of 61 mos post-discontinuing ibrutinib, 8 pts had MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 32 mos (range, 20-67 mos) after stopping all therapy. Of the 8 pts with MRD recurrence, 2 pts had clinical relapse (described below); remaining 6 pts are being monitored with no clinical progression or active therapy. The 6-year PFS and OS are 92.2% (95% CI= 77.7-97.4) and 97.7% (95% CI= 84.9-99.6), respectively. Two pts had clinical progression: one pt had IGHV 3-21; MRD recurred 28 mos after discontinuing ibrutinib, with clinical relapse 59 mos after discontinuing ibrutinib; this pt is now in remission with venetoclax-based therapy; the second pt with clinical relapse had IGHV-unmutated CLL, MRD recurred 24 mos after discontinuing ibrutinib, with clinical relapse 48 mos after discontinuing ibrutinib; this pt has not yet required therapy for relapse. No pt had progression to Richter transformation. One pt developed therapy-related myelodysplastic syndrome; this pt is being monitored for 58+ months without any active therapy for MDS with normal blood counts. One pt died from congestive heart failure during month 9 of the study. Conclusions iFCG regimen with only three cycles of combination chemotherapy achieves U-MRD rates of 98% in bone marrow on an intent-to-treat analysis and a 6-year PFS of 92% in IGHV-M CLL. These results are favorable compared to the 5-year PFS of approximately 65% with FCR (CLL10 trial) for the same genomic subgroup. Additionally, these results also appear favorable to the current targeted therapy regimens (such as BTKi, BCL2i+CD20 antibody) for IGHV-M CLL. With the caveat that the role of chemoimmunotherapy in CLL has significantly declined, the iFCG regimen provides for a very high rate of durable remissions among a chemo-sensitive subgroup of pts with CLL.

Nivolumab in Lymphomatoid Granulomatosis (LYG) and Other Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders (LPDs) and Non-Hodgkin Lymphomas (NHLs) with Systemic and/or CNS Involvement: Preliminary Analysis of Efficacy and Safety from an Ongoing Phase II Study

Background: Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. We previously demonstrated increased PD-1 expression on CD8+ T-cells compared to healthy controls in pts with LYG, which could be reversed with immunotherapy using interferon alpha-2b (Melani et al. Lancet Haematol. 2023). Additionally, elevated expression of programmed death-ligand 1 (PD-L1) has been observed in other EBV-LPDs and NHLs as well as in chronic viral infections, such as EBV. Given this likely shared disease pathobiology, we hypothesized that treatment with the anti-PD-1 antibody, nivolumab, may reverse T-cell exhaustion and result in anti-tumor responses in pts with LYG and other EBV-LPDs and NHLs, including those with systemic and/or CNS involvement. Methods: Relapsed/refractory (R/R) EBV-LPD and NHL pts age ≥ 12y with adequate organ function were eligible. Untreated pts were eligible if EBV-LPD. Exclusions included prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, solid organ transplant, and HIV infection. Pts with a known immunodeficiency or autoimmune illness were eligible if not requiring steroids or immunosuppression within 14d of study. CNS involvement was permitted if no seizure activity within 4w of study. Nivolumab 480 mg IV was given q4w for up to 2y. Pts who achieved CR discontinued nivolumab after 1y of treatment. Responding patients with relapse or progression within 1y of discontinuing treatment were eligible for retreatment. Baseline evaluation included CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy, and optional tumor biopsy. Restaging CT scans were performed after cycles 3, 6, 13, and 19, and end of treatment (EoT). PET was performed after cycles 1, 3, and EoT. Surveillance CT was performed q3m for 1y, q6m for yrs 2-5, and annually thereafter. Results: 11 pts were enrolled and treated; 6 (55%) with EBV-LPD and 5 (45%) with EBV-NHL (all DLBCL). EBV-LPD subtypes included 4 pts with G1-2 LYG and 1 pt each with EBV B-LPD of the CNS and CAEBV. Median age was 48y (range 20-67), and all pts had stage III/IV disease with extranodal involvement of the lung most common in 64% (7/11) and CNS disease in 18% (2/11). Median baseline absolute CD8 count (cells/mcL) was 86 (range 9-1237; normal: 178-853), CD4 count (cells/mcL) was 255 (range 99-1304; normal: 359-1565), and EBV VL in plasma (Log10 IU/mL) was undetected (range undetected-6.78; normal: <2.3). Median prior therapies were 1 (range 0-6) with 3 previously untreated LPD pts and 50% of previously tx pts were refractory to last tx. In 10 pts evaluable for response(1 came off tx prior to restaging), ORR and CR rate were both 60% (6/10). CR rate was 67% (4/6) in EBV-LPD, including 75% (3/4) with LYG, and 50% (2/4) in EBV-NHL (Fig 1A). One (50%) of 2 EBV-LPD pts with CNS involvement achieved CR after 3C of therapy and remains in ongoing response. Median TTR was 3.0m with 50% (3/6) responses ongoing from 3-56m after first response (Fig 1B). With a median follow up of 32m, 2y PFS and OS was 33% and 72% overall. By cohort, median PFS was 36m in EBV-LPD and 1m in EBV-NHL (p=0.003), with a 2y OS of 100% in EBV-LPD and 40% in EBV-NHL (p=0.04). Three EBV-NHL pts died, all of disease progression. One EBV-NHL pt stopped therapy after 2C due to radiographic disease progression in the kidney, but later developed CR without further therapy and remains in remission 56m after stopping therapy consistent with initial pseudoprogression. Adverse events (AEs) were as expected for nivolumab therapy with the most common AEs (% pts) including maculopapular rash (27%), diarrhea (18%), hypothyroidism (18%), and fatigue (18%). One pt developed an immune-mediated G2 myositis and G3 hepatitis following 3C of therapy which resolved after drug discontinuation and corticosteroids. Conclusion: Nivolumab is well tolerated in pts with LYG and other EBV-LPDs and NHLs without unexpected toxicities. Preliminary activity, including durable CRs, is noted across all pt cohorts, including 1 EBV-LPD pt with CNS involvement. With small numbers, statistically longer PFS and OS was observed with nivolumab in LYG and EBV-LPD compared to EBV-NHL, indicating that monotherapy may be sufficient for LYG and other EBV-LPDs, but combination therapy is likely needed for pts with EBV-NHL. Study enrollment continues to better assess the activity and durability of nivolumab in LYG and other EBV-LPDs and NHLs.

#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.

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

Introduction: Mosunetuzumab (mosun) is a CD3:CD20 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. We hypothesized that mosun would be even more active in patients (pts) without prior lymphotoxic therapy. Therefore, we designed a response adapted study for pts with untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: This is a single center, open label, investigator initiated clinical trial in untreated pts with FL or MZL with indication for treatment. Pts received subcutaneous mosunetuzumab monotherapy for 8 cycles (21 day cycle, Part A) employing step up dosing in cycle 1 (5 mg, 45 mg, 45 mg). A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. Pts with SD or PR could receive 6 cycles (21 day cycle, Part B) of polatuzumab vedotin and obinutuzumab, followed by an end of treatment (EOT) PET/CT. Total planned accrual is 42 pts. The primary endpoint is complete response (CR) rate. A pre-planned interim efficacy analysis is being performed after 20 enrolled pts. If 14 or fewer of the first 20 subjects do not achieve an objective response, the study will be suspended to enrollment. Results: 20 pts enrolled on study between March 24, 2022, and March 11, 2023, and as of the submission date 17 pts are evaluable for safety, and 15 pts are evaluable for efficacy. Patient characteristics are listed in the table. All treatment was delivered as an outpatient. Two pts experienced SAEs (one pt with G3 lung infection followed by G3 shingles, and one pt observed overnight with G1 cytokine release syndrome (CRS). The only other G3 AE observed was diarrhea (1, 6%). Seven (41%) pts experience G1 CRS, with no G2 or higher CRS observed or any grade ICANS observed. No pts required tocilizumab. All CRS events occurred during cycle 1. No heme toxicity greater than Grade 1 was observed (neutropenia 12%, anemia 6%, thrombocytopenia 59%). Three (18%) pts experienced a treatment delay due to G2 hyperglycemia, G2 upper respiratory infection, and G3 pneumonia. No dose modifications were required and all pts have received expected doses of mosun. Nearly all pts (94%) experienced at least one injection site reaction, which were all G1. Since 14/15 (93%) pts so far have achieved an objective response at any time point meeting the interim efficacy threshold, the study is proceeding with total enrollment of up to 42 pts. Among patients who have received all 8 cycles of mosun, 9/11 (82%) have achieved a CR. All pts remain alive and progression-free. Updated data will be presented at the meeting. Conclusion: Mosun is safe and highly active in untreated pts with follicular lymphoma with no G2+ CRS and no ICANS of any grade. The trial met its initial efficacy target allowing full study accrual to proceed. To our knowledge this represents the first presented safety and efficacy data for mosunetuzumab in untreated pts with FL or MZL. The research was funded by a research grant from Genentech Keywords: Combination Therapies, Immunotherapy, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. R. C. Lynch Consultant or advisory role: Cancer Study Group, SeaGen, Foresight Diagnostics Research funding: TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt M. Shadman Consultant or advisory role: Genentech Research funding: Genentech B. G. Till Consultant or advisory role: Mustang Bio, Proteios Technology Research funding: Mustang Bio, BMS Other remuneration: Patent- Mustang Bio S. D. Smith Consultant or advisory role: Genentech, Abbvie Research funding: Genentech C. Ujjani Consultant or advisory role: Genentech A. K. Gopal Consultant or advisory role: Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi Research funding: Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab Other remuneration: Stock Options: Compliment Corporation

Treatments and clinical outcomes in stage II colon cancer (CC) patients (pts) with 12-gene Oncotype DX Colon Recurrence Score assay-guided therapy: Real-world data.

3620 Background: The role of adjuvant chemotherapy (CT) in stage II CC is debated. The validated 12-gene Oncotype DX Colon Recurrence Score test provides a Recurrence Score (RS) result (range, 0-100) which estimates recurrence risk (RR) in stage II/III pts. We studied treatment and clinical outcomes in CC pts in whom treatment decisions incorporated the RS result. Methods: This prospectively designed cohort study included all stage II, MMR-P, CC pts who underwent the 12-gene Oncotype DX testing through Clalit between 1/2011 and 12/2016 and had available data with minimum 3-yr follow-up. Kaplan-Meier (KM) estimates and log-rank tests were used to compare RR and CC specific mortality (CCSM) between RS categories. Multivariable analysis (MVA) identified variables associated with RR/CCSM. Results: The analysis included 938 pts. Median age, 68 (IQR, 60-76) yrs; 96% had T3 tumors, and 89% had ≥12 nodes examined. Median RS was 26 (IQR, 19-33). The 3 RS categories (0-29, 30-40, and 41-100) included 65%, 24%, and 11% of pts, respectively. The overall CT use rate was 24%, with a significant difference between the 3 categories (14%, 36%, and 60%, respectively, P< .0001). Pts with very low RS (0-15) comprised 14% of the cohort (CT use rate, 11%). Younger pts, and those with invasion/perforation/obstruction were more likely to receive CT. Clinical outcomes with a median follow up of 6.9 (IQR, 5.5-8.6) yrs are presented (Table). Among untreated pts, KM estimates for RR and CCSM differed significantly between the 3 RS categories ( P< .0001). Outcome of untreated RS 0-15 pts was excellent. In an MVA model, male sex, presence of invasion/perforation/obstruction and higher RS category (RS 41-100 vs 0-29 and vs 30-40, but not RS 30-40 vs 0-29) were associated with increased RR. For CCSM, the results were similar, but this time age ≥70 yrs replaced sex as a significant prognostic variable. Clinical outcomes within each RS group did not differ significantly between treated and untreated pts, but were numerically better with CT in the RS 41-100 group. Conclusions: This real-world analysis showed that the RS results provide independent prognostic information in stage II CC. Further studies are needed to investigate the potential role of the RS result as a predictor of CT benefit, but the data suggest that this benefit may be limited to pts with high RS results. [Table: see text]

Phase II, single-arm, open-label study of dostarlimab monotherapy in previously untreated patients with stage II/III dMMR/MSI-H locally advanced rectal cancer.

TPS3639 Background: For patients (pts) with locally advanced rectal cancer (RC), organ-sparing non-operative management (NOM) following a clinical complete response (cCR) to treatment avoids the potential complications and quality of life impact associated with surgery/chemoradiotherapy. Although neoadjuvant chemotherapy is standard treatment, pts with mismatch repair deficient (dMMR) tumors respond poorly. Efficacy of the programmed death (PD)-1 inhibitor dostarlimab in previously untreated pts with locally advanced dMMR RC was evaluated in a Phase II study. All 12 pts who completed 6 months of treatment had clinical complete response (cCR) and received NOM, with no Grade ≥3 adverse events reported. Further research with a larger multicenter population/longer follow-up is needed to confirm these findings. AZUR-1 will evaluate the efficacy and safety of dostarlimab in pts with previously untreated locally advanced dMMR/microsatellite instability-high (MSI-H) RC. Methods: AZUR-1 (NCT05723562) is a global, multicenter, single-arm, open-label, Phase II study. ~100 pts will be enrolled across 10 countries. Key eligibility criteria include age ≥18 years, no prior radiation/systemic therapy or surgery for RC, Eastern Cooperative Oncology Group performance status 0–1 and no tumor-caused symptomatic bowel obstruction. Pts must have a tumor with dMMR status or MSI-H phenotype, determined locally or by the central reference laboratory. Prescreening is available at sites without local dMMR/MSI-H testing; prescreening is not required if dMMR/MSI-H status has been previously determined. Dostarlimab (500 mg) will be administered intravenously every 3 weeks for ≤9 cycles. The primary endpoint is cCR by independent central review (ICR) at 12 months, defined as achieving and maintaining cCR for 12 months (the 12-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR). Secondary endpoints include cCR by ICR at 36 months, 3-year event-free survival (EFS3) by investigator assessment, 5-year disease-specific survival, and 5-year overall survival. Pts with cCR by end of treatment will be assessed (CT/MRI, rectal MRI, endoscopy, rectal primary biopsy) every 4–6 months for recurrent disease for 5 years (NOM). Efficacy and safety will be assessed in all pts who received ≥1 dose of dostarlimab. For a range of plausible observed cCR12 rates (60–95%) in the primary analyses, the planned sample size of 100 pts will provide a Clopper–Pearson exact binomial two-sided 95% confidence interval with lower confidence limit within ~10% of the observed cCR12 rate. No interim analyses are planned.

Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 4-y follow-up from the FD cohort of the phase 2 CAPTIVATE study.

7535 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line ibrutinib (I) + venetoclax (V) in CLL/SLL. Follow-up results from the fixed duration (FD) cohort showed 3-y PFS rate of 88% overall and rates ≥80% in patients (pts) with high-risk features (Wierda, ASCO 2022). Here we present updated results from the FD cohort with 4-y follow-up. Methods: Pts aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; <10‒4) was assessed by 8-color flow cytometry. Results: 159 pts were enrolled, including pts with high-risk features of unmutated IGHV (uIGHV) (56%) or del(17p) and/or TP53 mutation (17%). Median time on study was 50 mo (range 1‒53). At 4 y of follow-up, the best CR rate was 58% and ORR was unchanged at 96%. At 4 y, PFS rate was 79% (95% CI 71‒84) and OS rate was 98% (95% CI 94–99). 4 y PFS rates were numerically lower in pts with uIGHV (73%) or del(17p) and/or TP53 mutation (63%), while OS rates remained consistently high (Table). 4 y PFS rates by MRD status 3 mo after stopping treatment (EOT+3) were significantly higher overall in pts with uMRD vs detectable MRD (dMRD) in PB (90% vs. 66%, Table); this difference was minimal at 24 mo (100% vs 91%). Median TTNT was not reached overall (range 1–53 mo); the 4 y rate of freedom from next treatment was 84% (95% CI 77–89). Second malignancies continue to be collected off treatment; 1 AE of prostate cancer occurred during this y of follow-up. To date, 19 pts with PD after completing fixed duration I+V in either the FD cohort or MRD cohort placebo arm initiated retreatment with I. Responses in 17 pts with available data were 1 CR, 13 PR, and 1 each PR with lymphocytosis, SD, and PD. Median time on retreatment was 11 mo (range 0–39). The most common AEs (≥10%) with retreatment were diarrhea (n=3), COVID-19 (n=3), and anemia (n=2). In addition, 4 pts have started I+V retreatment to date. Conclusions: Results of the CAPTIVATE study support I+V as an all-oral, once-daily fixed-duration regimen for previously untreated pts with CLL/SLL. With 4 y follow-up, fixed-duration I+V continues to provide deep, durable remissions with clinically meaningful PFS and time off treatment, including in pts with high-risk disease features. New safety findings off-treatment were expectedly negligible, highlighting the benefits of a fixed duration regimen. Promising responses were observed upon retreatment with I in progressing pts. Clinical trial information: NCT02910583 . [Table: see text]

Efficacy of immunotherapy in MSI metastatic colorectal cancer patients: A Real-World Italian multicentric retrospective study (Colon-MSI Study).

e15595 Background: The treatment with Immune checkpoint inhibitors (ICIs) is the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The aim of the study was to describe a cohort of MSI mCRC pts treated with ICIs, before pembrolizumab approval, to evaluate efficacy and toxicity in a real-world setting and to identify possible predictive factors of response. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs (anti-PD1 or anti-CTLA-4 antibodies, or in combination) before June 30, 2021, in 14 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. Survival analyses were stratified between treatment naïve and pre-treated pts. We explored the correlation between clinicopathological factors and refractory pts who underwent progression disease (PD) within 3 months from the start of ICI. Results: In this preliminary analysis, we reported 60 consecutive pts with data available. Among all, 30 (50%) were male, 37 (62%) with ECOG PS 0-1; 21 (35%) were at stage IV, and 37 (62%) had right colon tumor site. The most common metastatic sites were lymph nodes, liver, and peritoneum, and 34 (57%) pts had a single metastatic site. 23 (38%) pts had a mucinous adenocarcinoma, and 20 (33%) were BRAF mutated. Nivolumab, Pembrolizumab, and Ipilimumab plus Nivolumab were administered in 24 (40%), 34 (57%), and 2 (3%) pts, respectively, and as first-line therapy in 13 (22%) pts. The median duration of treatment was 22 months (0-43), with 21 pts still ongoing. 13 (22%) pts were refractory to ICIs, and only 4 (7%) pts discontinued treatment for G3-G4 adverse events. The OS, PFS and DCR were different between treatment naïve and pre-treated pts with a positive trend (not statistically significant) toward untreated pts (Table 1). Male gender (p = 0.03), stage IV (p = 0.04), and ≥ 2 metastatic sites (p = 0.01) were significantly associated with refractory ICIs pts, but none of these factors was correlated with poor outcomes in multivariate analysis. Conclusions: Our preliminary data confirm that immunotherapy is an effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest better outcomes when ICIs are administered in the first-line setting. Further analysis will be provided after the completion of the accrual. [Table: see text]