Progression-free Survival In Pts Research Articles

Abstract PO4-15-06: Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis

Abstract Background: Limited data are available to determine the best therapeutic strategy for hormone-receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (ABC) after progression on cyclin dependent kinase 4/6 inhibitors (CDK4/6i). The aim of this study was to characterize the genomic and prognostic profile of patients (pts) that experienced disease progression after first-line therapy with a CDK4/6i. Methods: The study retrospectively analyzed a multi-institutional cohort of 75 patients (pts) with HR+/HER2- ABC after experiencing progression on first-line endocrine therapy (ET) with CDK4/6i and characterized by circulating tumor DNA (ctDNA) next-generation sequencing (Guardant 360). Oncogenic pathways (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, p53, cell cycle, notch, and PI3K) were defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), and pathway classification were tested by uni- and multivariable logistic regression with respect to a CDK4/6i naïve group comprising 247 patients with HR+/HER2- ABC (control). Prognosis was analyzed through Cox regression for overall survival (OS). Result: Our study cohort included 75 ABC pts who experienced progression after first line CDK4/6i plus ET: 43 pts (57.3%) were treated with ET while 31 (41.3%) with a non-ET- second line therapy. The most common histology was invasive ductal carcinoma (70.6%), 37.3% of pts were negative for progesterone expression and 26.7% had de novo metastatic disease. The PI3K (33.3%), p53 (28%) and ER (25.3%) pathways were the most mutated in the CDK4/6i-treated cohort. Comparing our population with a CDK4/6i naïve cohort (N=247), the multivariate analysis showed a higher prevalence in the study cohort of SNVs mutations in: i) ESR1 gene [Odds ratio (OR) 2.93; p=0.005]; ii) cell-cycle pathway (OR 4.24; p=0.033); iii) ER pathway (OR 2.04; p= 0.034). Moreover, in the study cohort a numerical but not significant increase of RB1 SNVs was also observed. Multivariable analyses of the 43 pts that received ET second line therapy showed a negative prognostic impact with TP53 SNVs in both progression-free survival (PFS) [Hazard ratio (HR) = 3.34; 95% CI: 1.15-9.66, p=0.026] and OS (HR = 3.85; 95% CI: 1.52-9.77, p=0.005). The prognostic role of p53 pathway mutations was also confirmed for both PFS (HR = 4.71, 95% CI: 1.64-13.50; p=0.004) and OS (HR = 3.25; 95% CI: 1.27-8.3; p=0.014). The potential interaction between the prognostic oncogenic pathways and the outcome was investigated according to the treatment strategy (ET vs non-ET). A consistent impact was observed across the above prognostic pathways both for PFS and OS. A numerical difference was observed in terms of PFS in pts with p53 pathway mutations that underwent non-ET second line. Conclusions: The genomic landscape of progressive disease after CDK4/6i exposure is significantly different from the genomic alterations detectable in treatment-naïve pts, which could potential impact future treatment strategies for patients with disease progression after adjuvant CDK4/6i exposure. Our data suggest that the choice of second-line treatment could potentially be guided by the identification of actionable mutation by ctDNA, although further prospective studies are needed to validate the clinical utility of this approach. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew Davis, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Ami N. Shah, Jeannine Donahue, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Amir Behdad, William Gradishar, Emilio Bria, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli. Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-06.

Abstract PO4-04-12: A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer

Abstract Background: Endocrine therapy (ET) when administered with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has improved outcomes in patients (pts) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment. Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. Most pts will acquire resistance to ET, with mutations in ESR1 constituting the most common mechanism of resistance. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant in combination with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut xenograft models and showed efficacy in brain metastasis xenograft models. In a Phase 1/2 monotherapy study in pts with ER-positive, HER2-negative MBC, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose (RP2D) of 120 mg. The aim of this study is to evaluate the safety, PK, and antitumor activity of palazestrant + ribociclib or alpelisib in pts with ER-positive, HER2-negative advanced BC or MBC. Methods: Eligible pts have evaluable ER-positive, HER2-negative advanced BC or MBC; ≤2 prior ETs (prior CDK4/6 inhibitors allowed); and ≤1 prior line of chemotherapy. In the alpelisib arm, pts must have a PIK3CA mutation in the tumor or ctDNA. Patients are administered oral palazestrant at escalating doses of 30, 60, and 120 mg qd in combination with the approved dose of oral ribociclib (600 mg qd; days 1–21 of 28-day cycle) or approved dose of oral alpelisib (300 mg qd) in a 3+3 design to identify the RP2D. The dose-expansion part will assess additional safety and PK parameters and the antitumor activity of palazestrant in combination with ribociclib or alpelisib (NCT05508906). Results: As of June 15, 2023, 10 pts have received 30 mg and 60 mg doses of palazestrant in combination with ribociclib (n=6) or alpelisib (n=4). No dose-limiting toxicities have been observed. After administration in the first two combination dose levels of 30 and 60 mg, palazestrant exposure was consistent with monotherapy administration; exposure data show no drug–drug interactions (DDI) when compared to published exposure parameters. Most reported treatment-emergent adverse events (TEAEs) were grade 1 or 2 and consistent with the known safety profiles of all 3 drugs. In the ribociclib arm, the TEAEs occurring in ≥2 pts included grade 1 nausea (n=4), grade 1 constipation (n=2), and neutropenia (grade 2, n=1; grade 3, n=3). For the 3 pts in the 30 mg palazestrant + alpelisib cohort, the only TEAE occurring in ≥2 pts was grade 1 diarrhea. One pt had grade 1 hyperglycemia. Conclusions: In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels. Updated data will be presented. Citation Format: Virginia Borges, Carlos Alemany, Nancy Lin, Sara Nunnery, Cynthia Ma, Margaret Tonda, Morena Shaw, Arlene Chan. A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-12.

Abstract PO4-13-12: PIK3CA mutational status in tissue & plasma as a prognostic tool in HR+/HER2- breast cancer (BC)

Abstract Background: Activating mutations of PIK3CA gene are described in about 30-40% of BC. They confer overall worse prognosis and resistance to endocrine and chemotherapeutic therapy. Concordance between testing methods (tissue & plasma) are not widely studied. We aim to correlate tissue & plasma assays and to analyze the discordant cases and prognostic value of PIK3CA mutations (PIK3CAm) in HR+/HER2- BC. Methods: We performed a retrospective and unicentric analysis of PIK3CA mutational status in tissue & plasma samples in patients (pts) with HR+/HER2- BC from February/21 to April/23. PIK3CA test: Cobas®PIK3CA Mutation Kit. We correlated both diagnostic methods. Kaplan-Meier and Cox models were used to analyze progression-free survival (PFS) and comparison outcomes in PIK3CAm vs wild-type (wt). Results: We analyzed 225 samples from 161pts with HR+/HER2- BC (149 in tissue & 76 in plasma). PIK3CA mutations were detected in 62pts (38.5%), of which 39.6% (59pts) were detected in tissue and 11.8% (9pts) in plasma. Hotspot mutations: H1047X (45.7%), E545X (20%) and E542K (12.8%). In advanced disease, metastatic BC (mBC), tissue & plasma concordance was conducted in 64 cases, with overall correlation rate of 70.3%. We found PIK3CAm in 28pts: by both methods in 9pts (32.1%) and exclusively tissue detection in 19 cases (67.8%). Plasma detection was correlated with the presence of ≥3 metastatic sites (66.7% vs 31.6%; p=0.08) and with collection of samples during disease progression (66.7% vs 47.4%; p=0.43). 80pts received treatment with CDK4/6 inhibitors + endocrine therapy. PFS was slightly shorter in PIK3CAm vs wt (24m vs 30m; HR=1.39 [95%CI,0.7-2.4], p=0.26). A sub-analysis was performed based on exons 9 & 20, showing a significantly lower PFS in PIK3CAm exon 9 vs 20 population (9.7m vs 30.3m; HR=2.84 [95%CI,1.1-7.4], p=0.02). In addition, plasma detection of PIK3CAm was associated with worse PFS compared with PIK3CAm detected only in tissue (12.4m vs 29.3; HR=2.4 [95%CI,0.8-6.5], p=0.08). Although we observed a trend towards a poorer PFS in pts with visceral involvement in PIK3CAm (21.9m vs 30.1m; HR=2.82 [95%CI,0.6-12.3], p=0.14), in a multivariate analysis, mutations in exon 9 were an independent poor prognostic factor regardless visceral involvement and detection in plasma; p=0.05. Conclusions: Our results support the PIK3CA determination in tissue as the diagnostic method of choice, although further studies could better define the role of liquid biopsy in the detection of PIK3CAm. In our population, the presence of PIK3CAm confers poorer prognosis in luminal BC, being significantly worse in mutation carriers in exon 9 regardless visceral involvement and plasma mutation detection. Table. Tissue & plasma correlation in patients with PIK3CA mutational status tested in our population (mBC). Citation Format: Eduardo Terán Brage, Rebeca Lozano Mejorada, Aline Rodrigues Françoso, José Antonio Muñóz Leon, Álvaro López Gutiérrez, Luis Figuero-Pérez, Daniel Morchón Araujo, María Garijo Martínez, Jonnathan Roldán Ruiz, María Mar Abad Hernández, Magdalena Sancho de Salas, Emilio Fonseca Sánchez, César Augusto Rodríguez Sánchez. PIK3CA mutational status in tissue & plasma as a prognostic tool in HR+/HER2- breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-12.

Abstract 7523: An integrated analysis of radiologic and pathological responses in patients with metastatic renal cell carcinoma who presented with primary renal tumor in situ and received first-line nivolumab plus ipilimumab followed by cytoreductive nephrectomy

Abstract Background: The decision to perform cytoreductive nephrectomy (CN) and timing of CN in patients (pts) with metastatic renal cell carcinoma (mRCC) and primary who respond to immune checkpoint therapy (ICT) is a matter of debate. In CheckMate-214, nivolumab plus ipilimumab (N+I) yielded a 35% objective response rate in the primary; however, there is a paucity of pathological data from nephrectomy specimens (Nx) after treatment with N+I. We sought to investigate the radiologic and pathological responses and correlate the findings with outcomes in pts receiving 1L N+I followed by CN. Methods: We reviewed the medical records and Nx of pts with mRCC who received N+I followed by CN at our institution (2016-2021). H&E slides were reviewed to determine the % of residual viable malignant cells. Pathological response was defined as tumor viability ≤20%, and pathological complete response (pCR) defined as absence of residual cancer. Radiologic response was defined as ≥30% reduction in primary size. Progression-free survival (PFS) and overall survival (OS) were determined from date of CN. Results: 22 pts (median age 59) are included: 18 (81.8%) males, 19 (86%) Caucasian, 20 (91%) had clear-cell histology, 20 (91%) had ECOG Performance Status 0-1, 10 (45%) had intermediate-risk disease and 12 (55%) had poor-risk disease by IMDC. Median ICT duration before CN was 6.5 months (mo) (range, 2-19 mo). 17 (77%) completed 4 cycles of N+I, and 16 (73%) received N maintenance before CN. 5 pts (23%) had grade 3/4 immune-related adverse effects; 1 pt did not complete 4 cycles of N+I due to hepatitis. There were no therapy-related deaths. 12 pts (54.5%) had progressive disease (PD); 3 pts (14%) died of RCC. Median PFS was 22 mo, median OS not reached (NR). Pts with pathological response had greater radiologic reduction in primary size compared to pts without pathological response (median reduction 38% vs. 15% p-value 0.01), smaller final primary pathological size (median 5.7 cm vs. 10.65 cm p-value 0.002), and lower pathological yT stage (pT0: 1, pT1: 6, pT2: 2 pT3: 3, pT4: 0 vs. pT0: 0, pT1: 1, pT2: 0, pT3: 8, pT4: 1 p-value 0.045); ICT duration was similar between groups (median 5.5 mo vs. 7 mo p-value 0.733). 6 pts achieved low viability within 5 mo of ICT. In 9 pts with optimal radiopathological response [viability ≤20% and ≥30% primary size reduction], PFS was longer compared to PFS in pts with suboptimal radiopathological response: median PFS NR vs. 17 months (HR 0.23, 95% CI 0.076 - 0.741; p-value 0.041). In 13 pts with suboptimal response, 10 (77%) had PD, the most common sites of PD were lymph nodes [6 pts (60%)] and brain [3 pts (30%)]. Conclusions: In this small cohort, N+I yielded a low pCR in Nx of pts with mRCC. Radiologic response but not ICT duration was associated with low tumor viability. Citation Format: Leticia Campos Clemente, Omar Alhalabi, Matthew T. Campbell, Guillermo Corredor Alonso, Kieko Hara, Pavlos Msaouel, Andrew C. Johns, Chad Tang, Jose A. Karam, Priya Rao, Nizar M. Tannir. An integrated analysis of radiologic and pathological responses in patients with metastatic renal cell carcinoma who presented with primary renal tumor in situ and received first-line nivolumab plus ipilimumab followed by cytoreductive nephrectomy [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 7523.

Outcomes of Patients with Primary Mediastinal B-Cell Lymphoma Refractory or Relapsed after Frontline R-EPOCH Chemotherapy

Outcomes of Patients with Primary Mediastinal B-Cell Lymphoma Refractory or Relapsed after Frontline R-EPOCH Chemotherapy

Comparison of Venetoclax Based Treatments for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Background: Venetoclax (Ven) is a BCL-2 inhibitor that produces deep responses with high rates of undetectable minimal residual disease (uMRD) for patients (pts) with chronic lymphocytic leukemia (CLL) (Al-Sawaf et al. 2020). Currently, ven is FDA approved as either monotherapy (mono) or in combination (combo) with rituximab (R) In patients with relapsed/refractory (R/R) CLL (Seymour et al. 2018). However, the optimal ven based treatment (tx) for pts with R/R CLL either as mono, or in combo with anti-CD20 monoclonal antibody (mab), or bruton tyrosine kinase inhibitor (BTKi) is uncertain. We performed a single institution retrospective analysis of pts with R/R CLL treated with ven based regimens evaluating efficacy of different ven based txs. Methods: 98 pts with R/R CLL treated between the years of 2012 and 2023 were evaluated. Ven based treatment consisted of ven mono or in combo with R, obinutuzumab (G), or ibrutinib (BTKi) with standard ven dose ramp up to a maximum dose of 400mg daily. R and G were administered per FDA standard dosing. Ibrutinib was administered as 420mg daily, as either fixed or continuous duration tx. Response assessment was performed using iwCLL criteria. Minimal residual disease (MRD) was assessed by multi-parametric peripheral blood flow cytometry with a sensitivity of 10 -4. Time-to-event analyses were performed with the Kaplan-Meier method, with log-rank test used to assess statistically significant differences between variables. Hazard ratios (HR) were calculated by use of Cox proportional modelling. Results: The pts had a median age of 68 years (range; 46-89). Rai stage at time of tx initiation with ven: I 14.2%; II 36.3%; III 8.8%; Stage IV 40.7%. The median number of previous txs was 4 (range; 1-14). Pts harbored the following cytogenetic abnormalities: del(13q) 50.5%; del(11q) 18.5%; trisomy 12 15.5%; normal 15.5%; del(17p)/TP53 mutation 24.7%; and complex in 33%. Seventy percent of pts harbored an unmutated immunoglobulin heavy chain. 25.5% of pts had genomic complexity, with ≥ 5 gene mutations. 43.9% of pts were treated with ven mono; 19.4% were treated with venR; 25.5% of pts were treated with venG; and 11.2% of pts were treated with ven + BTKi. The median number of months of ven based tx was 16.3 (range; 0.9-118.6). 14.3% of pts currently remain on ven. 60.8% of pts had progression after ven based tx; with 62.2% requiring additional tx. 15.3% of pts developed Richter's Transformation. The best overall response for the cohort was: CR 67%; PR 24.5%; SD 1.1%; and PD 7.4%. The best MRD response for the whole cohort was uMRD 76.8%; low MRD 19.5; and high MRD 3.6%. uMRD as best MRD response occurred in 66.7% of ven mono; 82.4% of venR; 86.4% of venG; and 70% of ven + BTKi treated pts. With a median follow-up of 52 months (mo), the median progression-free survival (PFS) for the whole cohort was 67.8 mo. Ven combo had superior PFS to ven mono; median PFS 76.6 vs 58.9 mo (p = 0.04; HR 0.5037; 95% CI 0.2583 - 0.9635). Among the combination treatment approaches, there was a trend for improved PFS for venG compared to ven mono; median PFS not reached (NR) vs 58.9 mo (p = 0.08; HR 0.4385; 95% CI 0.1608 - 1.0240). Similarly, there was also a trend to improved PFS for ven + BTKi compared to ven mono; median PFS NR vs 58.9 mo (p = 0.07; HR 0.2895; 95% CI 0.0462 - 0.9950). Both the presence of del17p/TP53 mutation; and the presence of MRD (+MRD) 12 months after stopping ven based tx were associated with inferior PFS. The median PFS for pts without del17p/TP53 mutation vs with del17p/TP53 mutation was 118 vs 39.7 mo (p < 0.0001; HR 0.2242; 95% CI 0.0533 - 0.8366). Median PFS for pts with uMRD vs +MRD 12 months after ven was NR vs 42.8 mo (p = 0.0001; HR 0.0689; 95% CI 0.0037 - 0.3810). Conclusions : In a high-risk population of pts with R/R CLL, we found that ven based tx leads to durable remissions, with high rates of uMRD. Combo approaches with the addition of either an anti-CD20mab or BTKi led to improved PFS. While venR is the current FDA approved combo regimen for pts with R/R CLL, we found that there was a trend for improved PFS with either venG or ven + BTKi compared to ven mono. Both the presence of a del17p/TP53 mutation and the presence of MRD 12 months after stopping ven based tx significantly adversely affected PFS. However, pts who maintained uMRD 12 months after completing ven, had exceptionally durable long-term remission. This has possible implications for employing MRD adapted txs for pts with CLL.

End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA

Background : Lymphoma response criteria rely on PET/CT scans at end of therapy (EOT) to determine complete response (CR), which is necessary for cure. ~25% of patients achieve <CR by response criteria, but PET/CT scans have imperfect specificity and the positive predictive value of a single PET/CT scan at EOT is only ~50% (Kostakoglu 2021). To overcome this limitation, clinicians use additional tests including tissue biopsies or repeat PET/CT scans prior to salvage therapy to adjudicate positive results, but it remains unclear how often this occurs. Circulating tumor DNA (ctDNA) has improved tumor specificity that may reduce reliance on additional tests. We addressed these questions within a clinical trial delivering 1L therapy to pts with aggressive B-cell lymphoma. Methods : Pts were enrolled in a phase 2 study of DA-EPOCH-R or R-CHOP +/- acalabrutinib for treatment naïve DLBCL or high-grade B-cell lymphoma (HGBCL) [NCT04002947]. All pts were >18yrs old, stage II-IV, with adequate organ function. Pts completing induction therapy with available EOT PET/CT scans and EOT plasma samples were studied. PET/CT scans were interpreted by 2 nuclear medicine (NM) radiologists blinded to clinical outcomes using the 5-point Deauville Score (DS) with DS4/5 considered positive. Tissue biopsies and unplanned PET scans after the EOT PET/CT scan to determine remission status were recorded. Measurable residual disease (MRD) in plasma cfDNA was evaluated by Phased Variant Enrichment & Detection Sequencing (PhasED-Seq) at Foresight Diagnostics blinded to clinical outcomes. Tumor derived Phased Variants (PVs) were identified from baseline pretreatment plasma samples or baseline tumor tissue, with matched constitutional DNA from paired PBMCs used to censor germline variants and CHIP. PVs were used to assess EOT MRD. Results were reported as MRD positive when ctDNA levels exceeded an analytical detection threshold (~1:10 6 cfDNA molecules) corresponding to 98% specificity. The prognostic utility of MRD was compared to standardized PET/CT scan at EOT to freedom-from-progression (FFP) and progression-free survival (PFS). Results : 55 enrolled pts completing planned therapy had EOT PET/CT and MRD analyzed. 54 (98%) pts were successfully genotyped and comprised the study population. Median age was 61 (range 26-85), including 22 (41%) female, 44 (81%) with advanced stage, and 26 (48%) with IPI score ³3. Pathologic subtypes included 24 (44%) GCB, 21 (39%) non-GCB, 8 (15%) HGBL-DH, and 1 (2%) THRLBCL. 43 (80%) pts received DA-EPOCH-R and 11 (20%) pts received R-CHOP. Twenty-six (48%) pts received acalabrutinib with R-chemotherapy. After 26 months median follow-up, the 2-year FFP and PFS of the cohort was 89% and 84%. Fourteen (26%) pts had a positive EOT PET/CT scan and 40 (74%) were negative. The concordance rate between the 2 NM radiologists on positive scans was 100%. Only 2 of 14 patients with a positive EOT PET/CT had clinical progression requiring salvage therapy (14% PPV). Nine (64%) of these pts required additional tests to determine remission status including 5 repeat PET/CT scans and 4 tissue biopsies. The 2-year PFS for pts with a positive vs negative EOT PET/CT was 66% vs 90% (p=0.08, Fig.A). Twelve (22%) pts had detectable EOT MRD and 42 (78%) were undetectable. 7 pts with detectable EOT MRD had clinical progression requiring salvage therapy or have died. While no pt with undetectable EOT MRD progressed, 1 (2%) died in remission of sudden cardiac death. Of 14 pts with positive EOT PET/CT, 7 (50%) had undetectable ctDNA and none progressed, suggesting MRD testing could have potentially rendered additional tests unnecessary. Conversely, patients with positive PET/CTs who progressed invariably had detectable ctDNA at EOT, suggesting utility of MRD for adjudicating PET/CT results. The 2-yr PFS for pts with detectable vs undetectable EOT MRD was 33% vs 98% (p<0.0001, Fig.B). At EOT, the PFS hazard ratio for MRD was 35.7, as compared with 3.1 for PET/CT. Conclusions : Response evaluations relying on PET/CT scans often require additional tests and procedures to assess remission status in aggressive B-cell lymphomas. Initiation of salvage therapy without adjudication in patients not achieving CR by EOT PET/CT scans will result in overtreatment. Given the higher specificity and PPV of EOT MRD, we propose an integrated response evaluation strategy combining these methods to reduce unnecessary additional tests and overtreatment.

TP53 Mutations Detected By Clinical Laboratory Mutation Analysis Predict for Inferior Clinical Outcomes in Patients with Newly-Diagnosed Aggressive B Cell Lymphomas, Including Those with High-Risk Features

Introduction While comprehensive genomic analyses have identified genetic subgroups of diffuse large B cell lymphoma (DLBCL) when retrospectively performed on tumor biopsies (bx) from patients (pts) subsequently treated with R-CHOP (PMID 29713087, 29641966), it is unclear if these or similar assays can be applied in clinical practice. We aimed to determine if mutations (mut) detected in bx from newly-diagnosed DLBCL/high grade B cell lymphoma (HGBL) pts by clinical laboratory mutation analysis (CLMA) could predict for clinical outcomes following receipt of first-line therapy. Methods Pts with newly-diagnosed DLBCL/HGBL from January 2018-June 2022 whose bx underwent CLMA at the Penn Center for Personalized Diagnostics and received standard-dose R-CHOP or R-EPOCH as first-line therapy were included. Exclusion criteria were death due to non-lymphoma causes during first-line therapy and follow-up <1y after diagnosis if in remission. Pathologic workup of bx was performed as per institutional standard. Therapy was given at the discretion of the treating physician. Data were censored on July 1, 2023. Results One hundred thirty-seven pts met inclusion criteria, 15 were subsequently excluded and 117/122 pt bx underwent successful performance of CLMA (96%) with a median turnaround time of 17 days. Baseline characteristics, including mut occurring in ≥10% of cases tested, as well as genetic subgroup classification by LymphGen 2.0 based on available molecular data, are listed in the Table. R-CHOP was received by 72% of pts and R-EPOCH 38% of pts. The overall response rate (ORR) was 84% (complete response rate [CRR] 69%), and with a median follow-up of 31.3 months, estimated (est) 2 year (y) progression free survival (PFS), est 2y overall survival (OS) and est median OS post-relapse were 70%, 83% and 21.4 months (mo), respectively. Univariate analysis (UVA) identified HGBL classification, MYC rearrangement (R) and TP53 mut as significantly predictive of progression at 2y; however, only TP53 mut remained predictive on multivariate analysis (MVA) (HR 2.3, 95% CI 1.1-4.8, P=0.03). Additionally, UVA identified International Prognostic Index (IPI) score ≥3, HGBL classification, MYC-R, MYC-BCL2 double hit lymphoma, TP53 mut and TNFRSF14 mut as significantly predictive of death at 2y; however, only HGBL classification (HR 5.0, 95% CI 1.1-22.7, P=0.04) and MYC-R (HR 4.4, 95% CI 1.0-18.0, P=0.04) remained predictive on MVA. Given that TP53 mut predicted for both progression and death at 2y, we further analyzed bx with this mut. Forty-seven TP53 mut were detected in 42 pt bx, and were characterized as missense (mis) in 34, frameshift (fs) in 5, nonsense (non) in 5 splice site (ss) in 2 and other in 1. Thirty-eight (81%) TP53 mut were deemed loss of function (LOF), either as a mis/non mut designated as non-functional and/or LOF through The TP53 Database (https://tp53.isb-cgc.org/) or a fs/ss mut (PMID 22955915). Characteristics of pts with and without TP53 mut are listed in the Table. Significantly lower rates of ORR (71% vs 90%, P=0.009), CRR (55% vs 77%, P=0.01), est 2y PFS (57% vs 77%, P=0.006), est 2y OS (70% vs 91%, P=0.001) and est median OS post-relapse (6.1 mo vs not yet reached, P=0.001) were achieved by pts with vs without any TP53 mut. Est 2y PFS was 70% vs 33% ( P=0.01) and 2y OS was 85% vs 43% ( P=0.001) for pts with any TP53 mut treated with R-CHOP vs R-EPOCH. Additional analysis incorporating LOF status for TP53 mut revealed that for pts with at least one TP53 LOF mut vs only TP53 non-LOF mut vs no TP53 mut, 2y PFS was 51% vs 86% vs 77% ( P=0.002) as depicted in the Figure and 2y OS was 64% vs 100% vs 91% ( P=0.0004), respectively. Finally, stratified log-rank demonstrated either inferior or a trend towards inferior 2y PFS for pts with vs without TP53 LOF mut harboring high-risk features, including IPI score ≥3 (42% vs 80%, P=0.009), HGBL histology (25% vs 70%, P=0.046), non-GCB cell of origin by Hans algorithm (52% vs 81%, P=0.01), MYC rearrangement (33% vs 48%, P=0.17), MYC-BCL2 double hit lymphoma (40% vs 67%, P=0.34) and EZB genetic subgroup (30% vs 81%, P=0.04). Conclusions TP53 mut identified through CLMA, specifically those resulting in LOF, predict for inferior clinical outcomes in pts with newly-diagnosed DLBCL/HGBL. Results of CLMA can be practically used to inform prognosis and/or identify pts for clinical trials investigating therapies targeting derangements caused by specificmut.

Efficacy of CD19-Directed CAR T Cell Therapy in Patients with Primary or Secondary CNS Lymphoma - an Analysis of the EBMT Lymphoma WP and the Gocart Coalition

Introduction: The prognosis of patients (pts) with relapsed or refractory (r/r) large B cell lymphoma (LBCL) and central nervous system (CNS) involvement is dismal. Standard treatment for pts with r/r LBCL are anti-CD19 chimeric antigen receptor T-cells (CART). Several reports with limited numbers of patients suggest that CART might also be an effective treatment for pts with CNS lymphoma. This EBMT registry study aimed at compiling data to investigate the potential of CART in pts with primary (PCNSL) or secondary CNS lymphoma (SCNCL). Methods: Centers contributing to the EBMT database were asked for cases of PCNSL and SCNSL, treated with CART between 01/ 2018 and 07/ 2022. Reported pts were identified in the database, patient characteristics and pre-treatment retrieved, and major clinical endpoints analyzed. To calculate overall survival (OS) and progression-free survival (PFS) from date of CART infusion Kaplan Meier estimates were used, whereas cumulative incidence was used for relapse incidence (RI) and non-relapse mortality (NRM). Results: 88 pts with PCNSL (n=10) or SCNSL (n=78) with complete information on major endpoints were analyzed. Median follow-up was 20.3 months [95% CI: 16-27]. Median age was 63 years (range 31-80), 52 pts (59%) were male. ECOG was ≥ 2 in 19 of 86 pts (22%). 41 of 65 pts (63%) had undergone ≥3 prior treatment lines, 56 of 82 pts (68%) were refractory to at least one previous line of chemotherapy. 29 of 86 pts (34%) had received autologous stem-cell transplantation (ASCT). Of 84 patients 68% were not in remission at time of CART, 8% were in complete remission (CR) and 24% in partial remission (PR). Information on disease status was missing for four patients. 49 pts were treated with axicabtagene ciloleucel, 39 pts received tisagenlecleucel. OS- and PFS-rates at 24 months were 47% [95% CI: 37-61] and 32% [CI: 23-45] for the whole cohort (figure 1). RI at 24 months was 58% [CI: 47-68], NRM 10% [CI: 4-19]. OS and PFS for pts in CR/PR were 58% [CI 40-85] and 51% [CI: 33-77]. For 57 pts not in remission at CART infusion OS and PFS were 42% [CI: 30-59] and 24% [CI: 14-39], respectively. Conclusion: With a 47% OS rate at 24 months CART seem to be a very effective therapeutic option in heavily pre-treated r/r LBCL with CNS manifestation. These results compare favorably with those reported for conventional treatment including pts treated with ASCT. Indeed, these results are similar to those reported by real-world analyses of CART in LBCL without CNS manifestation (Bethge et al., 2021, Le Gouill et al., 2021). Based on these promising early results, we consider treatment with CART for pts with CNS involvement and r/r LBCL as the preferred treatment option.

Impact of Maintenance Rituximab Following First-Line Systemic Therapy on Outcomes in Patients with Marginal Zone Lymphoma: Real-World Evidence from 10 US Centers

Introduction First-line treatment options for patients (pts) with marginal zone lymphoma (MZL) include rituximab monotherapy (R) and immunochemotherapy (IC), such as bendamustine with rituximab (BR) or RCHOP/RCVP. The efficacy of maintenance rituximab (M-R) has been studied in splenic (SMZL) and nodal (NMZL) MZL, showing a benefit in progression-free survival (PFS) when M-R is administered after BR (Rummel et al., ASCO 2018). However, the role of M-R in pts with extranodal MZL (EMZL) of the mucosa-associated lymphatic tissue (MALT), or those receiving R or RCHOP/RCVP, remains uncertain. In this study, we analyzed the outcomes of pts with MZL who received M-R after their first-line systemic therapy (R or IC) using data from a large multi-institutional retrospective cohort. Methods Adult pts with MZL (SMZL, NMZL, or EMZL) who were treated at 10 US medical centers from 2010 onwards were included. Pts who had received first-line treatment with either R or IC and achieved a partial (PR) or complete (CR) response to the initial therapy were divided into groups based on whether they subsequently received M-R or not. To avoid immortal-time bias, we required a minimum follow-up of 6 months from diagnosis. Outcomes included PFS, overall survival (OS) and cumulative incidence of histologic transformation (HT). Because of non-proportional hazards, Wilcoxon test was used to compare survival curves, and Cox models (augmented by multiple imputation to account for missing data) were bounded by 6 years of follow up. Multivariable models adjusted for prognostic factors including age, sex, performance status, stage, baseline hemoglobin, albumin, LDH, type of IC and CR/PR status at the end of therapy. Results The study included 427 pts with a median age of 63 years. Of these pts, 53% were women, and 49% had EMZL, 27% had NMZL, and 23% had SMZL. The first-line therapies received were R (54%), BR (36%), RCHOP (7%), or RCVP (3%). A CR was achieved by 70% (n=298) of pts after the initial therapy. Overall, 33% (n=140) received M-R with a median of 8 cycles. Among pts who initially had PR, 39% converted to a CR during M-R therapy. The median follow-up period was 5 years. Factors associated with a higher likelihood of receiving M-R included achieving a PR instead of a CR after the first-line therapy (41% vs 29% receiving M-R, respectively; p=0.02) and having the SMZL subtype (p=0.03, Fig 1A). Pts treated with RCHOP were less likely to receive M-R compared to those receiving other regimens (p=0.049). There was also evidence of hospital-level preference to either prescribe M-R or not. We analyzed survival outcomes separately for pts who received first-line IC or R monotherapy, stratified further by MZL subtype and the type of IC regimen. Among pts who received IC (n=197), M-R was associated with longer PFS (median of 9.0 vs. 6.8 years, p=0.008, Fig 1B). However, the statistical significance was lost in the multivariable model (adjusted HR=0.52, 95%CI=0.25-1.10). When evaluated by MZL subtype, pts with EMZL had a significantly longer PFS with M-R (p=0.01), while those with NMZL and SMZL did not (p=0.41 and 0.10, respectively). When examining the type of first-line IC, pts receiving RCHOP/RCVP had a prolonged PFS with M-R (p=0.03), whereas the difference was not statistically significant after BR (p=0.12). There was no difference in OS overall (p=0.09; adjusted HR=0.55, 95%CI=0.12-2.60) or in any subgroup. Among pts who received first-line R, there were no statistically significant differences in PFS (p=0.70; adjusted HR=0.99, 95%CI=0.59-1.66) or OS (p=0.17) based on the receipt of M-R, either in the entire cohort or any subset. A total of 14 transformation events occurred during the study, including 3 in the M-R group. The cumulative incidence of HT did not significantly differ between the two groups (sub-HR=0.76, 95%CI=0.21-2.82, p=0.68). Discussion In this large retrospective cohort study, the use of M-R in MZL was primarily influenced by local preferences, the quality of response after initial treatment, and the type of IC regimen. Receipt of M-R was associated with a longer PFS for pts receiving first-line IC, especially for those with EMZL and those receiving RCHOP/RCVP. These findings suggest a PFS advantage of M-R in EMZL, which is a novel observation. However, this advantage was not observed in terms of OS or the rate of HT. M-R after initial R did not show any significant differences in outcomes for MZL.

Tagraxofusp in Combination with Azacitidine and Venetoclax in Newly Diagnosed CD123+ Acute Myeloid Leukemia, Expansion Cohort of a Phase 1b Multicenter Trial

Background: CD123 is a subunit of the interleukin 3 (IL3) receptor expressed on the surface of blasts in most acute myeloid leukemias (AMLs). Tagraxofusp (TAG), a CD123-directed therapy, is a recombinant protein drug consisting of IL3 fused to a truncated diphtheria toxin payload approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We found TAG resistance in AML cells was mediated by DNA methylation and silencing of diphthamide genes (e.g., DPH1), which causes resistance to diphtheria toxin (Togami, JCI 2019). The hypomethylating agent azacitidine (AZA) reversed TAG resistance, and TAG plus AZA prolonged survival vs. either alone in xenograft models. TAG-exposed AML cells were also sensitized to the BCL2 inhibitor venetoclax (VEN). We performed a phase 1b trial combining these agents in myeloid malignancies and reported acceptable safety in dose escalation of TAG with AZA-VEN (ASH 2021). Here, we report an expansion cohort in newly diagnosed AML treated with TAG-AZA-VEN. Methods: Patients (pts) were adults with AML ineligible or declining intensive induction chemotherapy. CD123+ blasts were required (tested locally by flow or IHC, any level). Eligibility included albumin >3.2 g/dL and normal cardiac ejection fraction. Pts were treated on 28-day cycles with AZA 75 mg/m2 d1-7, VEN 400 mg d1-21 with ramp up in cycle 1, and TAG 12 µg/kg d4-6 ( Fig A), with cycle 1 hospitalization to mitigate risks of capillary leak syndrome (CLS). Also included are 3 pts who received TAG 7 µg/kg (n=2) or 9 µg/kg (n=1) in escalation. TAG was given on d4 to avoid VEN ramp up overlap and because preclinical data showed AZA pretreatment can sensitize AML cells to TAG. Results: 26 pts with AML were treated; median age 71 (range 60-81). All were adverse risk per ELN 2022 criteria, including 13 (50%) with a mutation in TP53 and others with 1 or more of ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, or U2AF1. Eight (31%) had complex karyotype, 8 (31%) secondary AML, and 5 (19%) therapy-related AML. Adverse events (AEs) were like those seen with TAG or AZA/VEN, without evidence of exacerbation by combination. Grade 3+ AEs occurring in >15% of pts regardless of attribution included thrombocytopenia (54%), leukopenia (54%), febrile neutropenia (35%), and anemia (31%). CLS, a known TAG side effect, occurred in 19% (n=5; three grade 2, one gr 3, one gr 4; all in cycle 1) and was manageable by albumin supplementation and diuresis. Mortality at 30 days was 11.5%, with causes of death of sepsis (n=2), multiorgan system failure (n=1). 18 of 26 pts (69%) achieved a best response of CR (10; 39%), CRi (5; 19%), or MLFS (3; 12%). Of the 13 with TP53 mutation, 7 (54%) achieved CR/CRi/MLFS (CR=4, CRi=2, or MLFS=1). Bone marrow blasts decreased in all pts who had a biopsy after starting treatment ( Fig A). For the 18 achieving CR/CRi/MLFS, the median duration of response was 12.4 months (mo) (95% CI, 6.1-NA). 13 of 26 (50%) proceeded to allogeneic stem cell transplantation, which included 6/13 (46%) with TP53 mutation. The median number of cycles was 3 for both pts who did (range 1-15) and did not (range 2-4) proceed to transplant. The median follow-up was 10.7 mo, including post-transplant timepoints. Median overall survival (OS) was 14 mo (95% CI, 9.5-NA) and progression-free survival (PFS) was 8.5 mo (95% CI, 5.1-NA). In pts with TP53 mutation, median OS was 9.5 mo (95% CI, 1.8-NA); and not reached (NR) without ( Fig B). PFS for pts with TP53 mutation was 5.1 mo (95% CI, 1.8-NA), and 13.3 mo (95% CI, 8.6-NA) without. Measurable residual disease (MRD) was assessed by flow cytometry in 17 pts who achieved CR/CRi/MLFS; 12/17 (71%) were MRD negative (<0.1%). 4/7 (57%) with TP53 mutation achieving CR/CRi/MLFS were MRD negative. Median OS for pts who became MRD negative was NR. Median OS for the 13 pts who received allogeneic transplant was 18.2 mo (95% CI, 14.0-NA). Median PFS for the transplanted pts was 13.3 mo (95% CI, 8.2-NA). Conclusions: Treatment of AML with triplet TAG-AZA-VEN is feasible and shows encouraging activity as up-front therapy in adverse risk AML, including in pts with TP53 mutation. These data (OS 14 mo; TP53 mutant OS 9.5 mo) compare favorably to HMA/VEN in ELN adverse risk (OS 12 mo; Lachowiez, BloodAdv 2023) or TP53 mutant AML with poor risk cytogenetics (OS 5.2 mo; Pollyea, CCR 2022), albeit with some differences between populations. No new safety signals were observed. Further development of this combination is warranted, including directly compared to AZA-VEN.

Circulating Tumor DNA Analysis Associates with Progression-Free Survival (PFS) with Odronextamab Monotherapy in Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL): Identification of Minimal Residual Disease Status and High-Risk Subgroups from the Phase 2 ELM-2 Study

Background Molecular characterization of B-cell non-Hodgkin lymphoma (B-NHL), through circulating tumor DNA (ctDNA) assessment of minimal residual disease (MRD) has been proposed as a tool to predict clinical outcome. Odronextamab, a CD20×CD3 bispecific antibody, demonstrated deep and durable responses and a generally manageable safety profile in patients (pts) with R/R FL or DLBCL in the Phase 2 ELM-2 study (NCT03888105; Kim TM et al. and Kim WS et al. ASH. 2022). In the overall populations, 12-month PFS rates were 64% and 29%, respectively. Using ctDNA from ELM-2, we show that these assessments associate with clinical outcomes following odronextamab treatment. Methods In ELM-2, pts received IV odronextamab in 21-day cycles, with step-up dosing in Cycle (C) 1, 80 mg (FL)/160 mg (DLBCL) QW in C2-4, then 160 mg (FL)/320 mg (DLBCL) Q2W until disease progression or unacceptable toxicity. Baseline (BL) ctDNA and tumor biopsies were used for molecular profiling. BL and on-treatment ctDNA were used for MRD determination in the biomarker population (BP; pts required ≥1 available plasma biomarker sample to be included in the BP). The first post-BL ctDNA sample was collected on C5 Day (D) 1, at the time of positron emission tomography-computed tomography (PET-CT). A modified AVENIO ctDNA analysis workflow (Roche; research only) was used for next-generation sequencing, based on the cancer personalized profiling by deep sequencing technique (Kurtz et al. J Clin Oncol. 2018). Whole blood cell pellets were used to filter out germline allele variants. MRD negativity was reported when the P value for variant allele frequency was >0.005. Results The BP comprised 53 FL pts and 63 DLBCL pts; at BL, all FL pts and all but one DLBCL pt were MRD(+). Pts remaining on study until C5D1 had similar PFS regardless of whether they were in the BP or overall population (FL, n=111; DLBCL, n=83). Pts who were MRD(-) at C5D1 had significantly longer PFS vs. those who remained MRD(+) (FL: HR 0.27 [95% CI 0.09-0.84], P=0.024 [Fig. 1a]; DLBCL: HR 0.29 [95% CI 0.12-0.71], P=0.007). In pts with FL achieving complete response (CR) by PET-CT at C5D1, a trend for prolonged PFS was observed in those who were MRD(-) (n=26) at this timepoint vs. those who were MRD(+) (n=17; HR 0.29 [95% CI 0.07-1.1], P=0.072). Pts with DLBCL who were MRD(-) at C5D1 (n=20) had similar PFS benefit regardless of PET-CT CR status (HR 0.56 [95% CI 0.10-3.11], P=0.511). Four DLBCL pts who were MRD(-) and did not achieve CR by PET-CT at C5D1 (partial response, n=3; stable disease, n=1) went on to achieve PET-CT CR at a later timepoint. Mutational analyses of BL ctDNA identified TP53 as the most frequent mutation (FL, n=34/53 [64%] mutation-evaluable pts; DLBCL, n=44/58 [76%]). In FL pts, TP53 mutations were associated with MRD(+) status at C5D1 (Fisher's exact test, P=0.002) and predicted significantly shorter PFS (HR 3.57 [95% CI 1.01-12.69]; P=0.049); this association was not observed in DLBCL. LymphGen classification (Wright et al. Cancer Cell. 2020) of BL ctDNA in pts with DLBCL identified mostly MCD and EZB subtypes (MCD, n=15; EZB, n=14; ST2, n=1; BN2, n=1; other, n=26). EZB-subtype pts treated with odronextamab had significantly longer PFS compared with MCD-subtype pts (HR 0.23 [95% CI 0.07-0.83]; P=0.025 [Fig. 1b]). Using BL ctDNA, cell of origin was determined in 43/58 pts with DLBCL; odronextamab treatment led to similar PFS in higher-risk non-germinal-center B-cell-like (non-GCB, n=18 [42%]) pts vs. GCB pts (n=25 [58%]; HR 1.62 [95% CI 0.72-3.62]; P=0.244). Further molecular assessment focused on gene fusions in DLBCL pts in the BP (39 with local laboratory gene fusion and ctDNA analyses, 24 with only ctDNA analyses). Odronextamab led to similar PFS in pts with double-hit (n=15) or triple-hit (n=5) fusions compared to those without (n=43; P=0.343 and P=0.140, respectively). Conclusions This study is among the first to analyze ctDNA in pts with R/R FL and DLBCL in a pivotal trial. This non-invasive method allows molecular characterization of pts with no available tissue, enabling identification of high-risk subgroups. CtDNA MRD status at C5D1 of odronextamab treatment was highly associated with PFS in pts with FL and DLBCL and in the future could form the basis of response-directed treatment paradigms. Molecular characterization in tumor biopsies, including CD20, will be presented. Ongoing monitoring of ctDNA may serve as an important early progression marker in R/R FL and DLBCL.

Efficacy of Brentuximab Vedotin Maintenance Therapy Following Autologous Stem Cell Transplantation in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma with and without Pre-Transplant Exposure to Novel Agents

Background: Maintenance therapy with brentuximab vedotin (BV) after autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) among high-risk patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the phase III AETHERA trial. However, cHL treatment has changed significantly since that trial with frequent incorporation of BV and PD-1 inhibitors into earlier lines of therapy. The efficacy of BV maintenance may be different among pts who receive novel agents before ASCT. Methods: Pts with a diagnosis of R/R cHL who underwent ASCT between 2010 and 2022 were identified at 5 US transplant centers. Pts receiving no systemic post-ASCT maintenance or BV maintenance were included, while pts receiving investigational maintenance treatments were excluded. Medical records were reviewed to identify clinical variables. Results: 921 pts were identified. Median age was 32 yrs (IQR 24-44). 641 pts (70%) had primary refractory disease or relapsed within 12 months of frontline therapy, 326 (35%) had extranodal disease at relapse, and 173 (19%) had B symptoms at relapse. Pts received a median of 2 (1-9) lines of therapy before ASCT, including 295 (32%) who received ≥3 lines. 425 (46%) pts received BV before ASCT (including 24 pts as part of frontline treatment). 70 pts (8%) were BV-refractory (defined as failure to achieve an objective response to any BV-based treatment). 169 (18%) received a PD-1 agent with salvage treatment. 638 pts (69%) had a complete response on pre-ASCT positron emission tomography (PET). BEAM (71%) or CBV (21%) conditioning were used for most pts and 236 pts (26%) received peri-ASCT radiation. 224 pts (24%) received post-ASCT BV maintenance (including 37% of pts undergoing ASCT from 2015-2022). Compared to pts receiving no maintenance, pts receiving BV maintenance were more likely to have primary refractory/early relapsed disease (79% vs 67%, p<0.001), have received only 1 salvage regimen (79% vs 65%, p=0.001), and received BEAM conditioning (83% vs 67%, p<0.001). BV maintenance pts were less likely to receive peri-ASCT radiation (20% vs 28%, p=0.022). The median number of BV maintenance cycles was 10 (1-18) and the most common reason for discontinuation was neuropathy. Median post-ASCT follow-up was 4.9 yrs. 5-yr PFS and OS after ASCT were 70% (95% CI 67-74%) and 85% (83-88%), respectively. Because BV-refractory pts were much less likely to receive BV maintenance (p=0.0044) and had inferior PFS (HR 2.2, p<0.001) (and therefore would serve as a confounder), we excluded BV-refractory pts from additional analyses. Use of BV maintenance was associated with improved PFS (5-yr 81% vs 67%, HR 0.47 [0.33-0.69], p<0.001) and OS (5-yr 92% vs 83%, HR 0.38 [0.20-0.73], p=0.004). The benefit of BV maintenance depended upon pre-ASCT therapy. BV maintenance was associated with a significant improvement in PFS for pts who received no novel agents before ASCT (HR 0.41 [0.25-0.65], p<0.001), but not for BV-treated (HR 0.69 [0.38-1.25], p=0.22) or PD-1-treated pts (HR 0.63 [0.13-3.03], p=0.56) ( Figure). Among pts with 0-1 modified AETHERA risk factors, BV maintenance was not associated with a significant PFS benefit in any treatment subgroup (no novel agents, HR 0.50, p=0.087; BV-treated, HR 1.28, p=0.67; PD-1-treated, HR 2.97, p=0.44). For pts with 2+ modified AETHERA risk factors, BV maintenance significantly improved PFS in the no novel agent group (HR 0.35, p<0.001) but not in the BV-treated (HR 0.55, p=0.099) or PD-1 treated groups (HR 0.24, p=0.19). In multivariable analyses that included key variables (age, year of ASCT, conditioning regimen, peri-ASCT radiation, early relapse/primary refractory disease, B symptoms, extranodal sites, pre-ASCT PET, lines of therapy), BV maintenance was associated with a significant PFS benefit among pts who received no novel agents before ASCT (HR 0.27 [0.12-0.65], p<0.001), but not for pts treated with BV (HR 0.56 [0.28-1.10], p=0.091) or PD-1 blockade (HR 1.10 [0.22-5.56], p=0.91) before ASCT. Conclusions: In this large cohort, BV maintenance was associated with the clearest benefit among pts who received only chemotherapy before ASCT. We were unable to identify a significant improvement in PFS for pts receiving novel agents before ASCT (which could be due to insufficient power to detect a small benefit in this population), suggesting that if these pts benefit from BV maintenance, its impact is likely more limited.

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 5-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 61.5 months. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10 -4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy. Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Median age was 64.5 years (range, 26-88 years). 86% had IGHV-unmutated CLL. 23% had del(17p)/ TP53 mutation. The median follow-up is 61.5 months. Six pts came off study during 1 st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. One pt had DLBCL transformation and 1 pt had CLL progression during the first 2 year of therapy (details below). The 5-year PFS is 90.1% and 5-year OS is 95.6% (Figure 1). The 5-year PFS for pts with del(17p)/ TP53 mutation (n=27) is 86.1%. Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median follow-up of 40 months post Cycle 24, 22 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 22 pts with MRD recurrence, 5 pt had CLL progression at a median of 18 months (range, 6-30 months) from MRD recurrence (details below); 16 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt died from mesothelioma. Among the 55 pts who remain in blood U-MRD remission, 53 remain in long-term follow-up in U-MRD remission; 1 pt had B-PLL transformation and 1 patient died (found unresponsive at home; was off therapy for 2 years). There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Only 2/23 pts are still receiving IBR (remaining pts have d/c IBR; all pts have d/c venetoclax); none of these 23 pts had clinical relapse. A total of 6 pts had CLL progression (1 during the first 2 yr of therapy; remaining 5 during off-therapy phase). 3/6 had evaluation of BTK, PLGG2 and BCL2 mutations at the time of relapse and none were detected. 5 pts have started subsequent therapy (acalabrutinib, n=4; ibrutinib, n=1; all are clinically responding); 1 pt has not yet started therapy. Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 5-year PFS of 90.1%. The 5-year PFS for pts with del(17p)/ TP53 mutation is 86.1%. Retreatment with BTK inhibitor appears effective for pts with disease relapse.

Final Analysis of a Phase 2 Trial of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma (NDMM) without Autologous Stem Cell Transplantation (ASCT)

Introduction: A previous trial showed that Dara-KRd for 8 cycles without ASCT led to a minimal residual disease (MRD) negativity rate of 71% at 10 -5 in NDMM (Landgren et al. JAMA Oncology 2021). MRD-adapted Dara-KRd with ASCT led to an MRD(-) rate of 71% at 10 -6 with a 3-year progression-free survival (PFS) of 88%, 79%, and 50% in pts with 0, 1 or 2+ high-risk cytogenetic abnormalities (HRCA), respectively (Costa et al. EHA 2022). In this phase 2 study, we evaluated the safety and efficacy of 24 cycles of Dara-KRd without ASCT in pts with NDMM. Methods: Pts with NDMM with up to 1 cycle of prior therapy were enrolled regardless of ASCT eligibility. Pts received Dara-KRd for planned 24 cycles: daratumumab 16 mg/kg IV weekly for cycles (C) 1 & 2, q2weeks for C3-8, then q4weeks for C9-24; carfilzomib 20/36 mg/m 2 on days 1, 2, 8, 9, 15, 16 for C1-8, then 36 mg/m 2 on days 1, 2, 15, 16 for C9-24; lenalidomide 25 mg PO days 1-21 of a 28 day cycle for 24 cycles; dexamethasone 40 mg PO weekly (20 mg if age > 75) for C1-9, and 20 mg PO weekly for C9-24. Pts had the option to harvest stem cells (SC) to permit ASCT in the future. MRD testing was performed by NGS (clonoSEQ, Adaptive Biotechnologies) with sensitivity <10 -6 at the end of cycles 8 (C8), C12, and C24. Mass spectrometry (MS) of peripheral blood samples were also performed using MALDI and liquid-chromatography (LCMS) (The Binding Site Group). The primary endpoint was the rate of stringent CR and/or MRD(-) <10 -5 at the end of C8; the hypothesis was that >50% would meet the primary endpoint with Dara-KRd compared to historical 30% with KRd (85% power, one-sided alpha=0.10). Results: 42 pts enrolled from March 2019-January 2022. Median age was 58 years (range 39-79). 13 (31%) were Black and 5 (12%) were Hispanic. HRCA (t(4;14), t(14;16), t(14;20), +1q, del17p) were present in 24/42 (57%); 10 (24%) had 2+ HRCA. 34 pts (81%) underwent SC collection, all with plerixafor (median yield 8.91x10 6 CD34+/kg). 40 pts (95%) were evaluable for the primary endpoint at C8. Two pts withdrew before C8 for reasons unrelated to treatment. There were 32 (80%) MRD-evaluable pts at C8. The sCR and/or MRD(-) rate (<10 -5) was 30/40 (75%, 95% CI 61%-89%). The C8 10 -5 MRD(-) rate was 20/32 (63%) and at 10 -6 it was 12/32 (38%). Responses deepened over time; 1/12 (8%) and 6/20 (30%) pts converted from MRD(+) at C8 to MRD(-) at later timepoints at 10 -5 and 10 -6 thresholds, respectively, for a best MRD(-) rate of 21/32 (66%) at 10 -5 and 18/32 (56%) at 10 -6 . Sustained 10 -5 MRD(-) >12 months was achieved in 11 (26%) pts; 6 pts were <1 year from first MRD(-) result. Overall response rate at C8 was 38/40 (95%) with 27 (68%) sCR, 38 (95%) VGPR+, and 2 PD. Of the 39 pts with trackable mass spectra in the peripheral blood, the MALDI(-) rate was 22/39 (56%) after C8 and 24/39 (62%) as best response. The LCMS(-) rate was 7/39 (18%) after C8 and 12/39 (31%) as best response. Median follow-up was 27 months. 21 pts (50%) completed all 24 cycles, and 11 (26%) remain on protocol. 7 pts (17%) had disease progression (6 on protocol), including 4 pts who reached the primary endpoint at C8. 4 pts (10%) discontinued protocol therapy early (additional 2 pts due to nonadherence). 1 pt received ASCT after discontinuing while in response. 2 deaths occurred, both early in treatment and due to primary refractory disease. The 3-year PFS was 85%: 100% for standard-risk disease, 92% for 1 HRCA, and 60% for 2+ HRCA. Of the 7 pts with progression, 6 had at least one of: extramedullary disease (4), 2+ HRCA (4), or circulating plasma cells (1). Neither NGS nor mass spectrometry status at C8 were associated with PFS differences using the landmark method. The 3-year OS was 95%. All-grade/grade 3+ (G3) neutropenia occurred in 26%/21%, anemia in 59%/2%, and thrombocytopenia in 64%/26%. Notable nonhematologic adverse events were hyperglycemia (all 76%/ G3+ 7%), diarrhea (71%/5%), hypertension (57%/17%), and neuropathy (40%/0%). COVID infections occurred in 38% (2% G3) and upper respiratory infections in 45% (0% G3+). There was one case of thrombotic microangiopathy leading to discontinuation of carfilzomib. G3 atrial fibrillation and heart failure each occurred in 1 pt. Conclusions: Extended frontline Dara-KRd for NDMM without ASCT induced high rates of sCR and/or MRD(-) within 8 cycles, meeting the primary endpoint. The rate and depth of MRD(-) improved beyond C8. This ASCT-free approach led to lower PFS for pts with 2+ HRCA, as also seen with ASCT, but excellent PFS in those with standard-risk disease and 1 HRCA.

Impact of 1q21 Gain and Amplification on Daratumumab-Treated Multiple Myeloma Patients: Real-World Data from the Australia-New Zealand and Asia-Pacific Myeloma and Related Diseases Registries

Introduction: Gain/amplification of 1q21 (1q21+) is found in 40% of patients (pts) with newly diagnosed Multiple Myeloma (MM). There is increasing evidence that presence of gain of 1q21 [gain(1q21), 3 copies] or amplification of 1q21 [amp(1q21), ≥4 copies] are independent poor prognostic factors. A recent post-hoc analysis of the ICARIA-MM and IKEMA studies showed that the addition of monoclonal anti-CD38 antibody isatuximab in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone abrogated the negative impact of 1q21 on progression-free survival (PFS). However, the impact of 1q21+ has not been consistently assessed in daratumumab (Dara) exposed pts. Methods: We identified MM pts treated with Dara between Jan 2020 and Jan 2023 from the Australia-New Zealand and Asia-Pacific Myeloma and Related Diseases Registries. Pts who had interphase fluorescence in situ hybridization (FISH) testing were included. High-risk cytogenetics (HRCyto) was defined as the presence of t(4;14), t(14;16) or del(17p) by FISH, and standard risk cytogenetics (SRCyto) as pts without 1q21+ and HRCyto. Pt groups analysed were: (1) without 1q21+ vs with 1q21+ (2) SRCyto vs isolated 1q21+ vs HRCyto without 1q21+ vs HRCyto with 1q21+. Subgroup analyses performed include: (3) gain(1q21) vs amp(1q21). Overall survival (OS) and PFS from commencement of Dara were estimated using the Kaplan-Meier method. Comparisons of PFS and OS were performed using the log-rank test. Categorical data were compared using a chi-square test and continuous variables with a rank-sum test. Results: Of 654 pts who received Dara, 451 had interphase FISH testing performed and were included. There were 132 pts with 1q21+ [gain(1q): 23, amp(1q):14, gain/amp status unknown: 95] and 319 without. Median follow up was 15 months (95% CI 14-18). Median prior lines of therapy was 1 (IQR 1-2). Dara-based regimens used were: Dara monotherapy (17.7%), Dara-bortezomib-dex (54.6%), Dara-lenalidomide-dex (11.3%), Dara-pomalidomide-dex (DPd) (9.3%), Dara-carfilzomib-dex (DKd) (2.5%) and Dara-bortezomib-lenalidomide-dex (4.6%). There were no differences in age, gender, ECOG, line of therapy in which Dara was used, or rate of autologous stem cell transplantation between pts with 1q+ vs pts without (Table 1). Pts with 1q21+ had higher rates of other HRCyto (37.1% vs 20.4%; p=0.005) and ISS Stage 3 disease (44.1% vs 29.3%; p=0.005) vs those without 1q21+. There was no significant difference in overall response rate (65.9% vs 71.6%; p=0.32). Through univariate analyses, PFS for 1q21+ pts was significantly shorter than those without 1q21+ [median PFS 8.2 vs 18.4 months (HR 1.7, 95% CI 1.3-2.3; p<0.001)] (Figure 1). This difference was still significant when adjusted for ISS, the presence of other HRCyto and country of treatment (HR 1.61, 95% CI 1.17-2.22; p=0.004). Pts with 1q21+ with or without HRCyto, and those with HRCyto and no 1q21+ had inferior PFS vs SRCtyo (median PFS 7.7 vs 8.9 vs 8.5 vs 30.3 months; p<0.001) (Figure 2). Of the pts where 1q21+ copy number was available, OS was significantly poorer in pts with amp(1q) vs those with gain(1q) (median OS 22.6 vs 46.9 months; p=0.035). There was also a trend towards poorer PFS in pts with amp(1q) (median PFS 4.9 vs 10.5 months; p=0.096) Conclusions: 1q21+ often co-exists with other HRCyto abnormalities. However, it remains an independent negative prognostic marker. The use of Dara does not appear to abrogate the negative impact of 1q21+ on PFS. Amp(1q21) potentially confers an even poorer outcome. This finding differs from an earlier retrospective study (Parrondo et al, Blood 2022), although <10% of patients in our study received DKd and DPd combinations. As such, more data on Dara in combination with carfilzomib and pomalidomide is needed.

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

Phase 3 trial of subcutaneous epcoritamab + R-CHOP versus R-CHOP in patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL): EPCORE DLBCL-2.

TPS7592 Background: In pts with newly diagnosed DLBCL, standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has a 5-year progression-free survival (PFS) rate of 67.0%, 58.4%, and 45.8% for International Prognostic Index (IPI) 2, 3, and 4–5, respectively (Ruppert et al, Blood 2020). Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell–mediated killing of malignant CD20+ B cells (Hutchings et al, Lancet 2021). Epcoritamab monotherapy demonstrated deep and durable responses (overall response rate [ORR], 63%; complete response rate, 39%) and was generally well tolerated in pts with relapsed/refractory (R/R) aggressive, large B-cell lymphoma (LBCL) (Thieblemont et al, J Clin Oncol 2022). Results from an ongoing phase 1/2 study in high-risk pts with newly diagnosed DLBCL (EPCORE NHL-2 arm 1; NCT04663347) show that epcoritamab + R-CHOP has promising efficacy and a manageable safety profile in high-risk pts with IPI 3–5. Among efficacy-evaluable pts (n = 31), ORR was 100% and complete metabolic response (CMR) was 77%; cytokine release syndrome (CRS) events (n = 17/33; 52%) were mostly low-grade, had predictable timing, and did not lead to treatment discontinuation (Falchi et al, ASCO 2022, abstract 7523). These encouraging data support further evaluation of epcoritamab + R-CHOP for the treatment of newly diagnosed DLBCL. Methods: This phase 3, global, multicenter, open-label study (NCT05578976) evaluates the efficacy and safety of epcoritamab + R-CHOP in adults newly diagnosed with one of the following CD20+ DLBCL (de novo or transformed from follicular lymphoma [FL]): 1) DLBCL, not otherwise specified (NOS); 2) high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; 3) T-cell/histiocyte–rich LBCL; 4) Epstein-Barr virus–positive DLBCL, NOS; or 5) FL grade 3b. Other key eligibility criteria include IPI ≥2 (pts with IPI 2 not to exceed ~30% of total pts), ECOG PS 0–2, and ≥1 measurable disease site. Approximately 900 pts will be randomized 2:1 to either epcoritamab + R-CHOP (6 cycles, followed by 2 cycles of epcoritamab) or R-CHOP (6 cycles, followed by 2 cycles of rituximab). The primary efficacy endpoint is PFS in pts with IPI 3–5 (based on IRC assessment per Lugano criteria). The secondary efficacy endpoints are PFS in pts with IPI 2–5, event-free survival, CMR, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (CRS, immune cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome. Enrollment began in January 2023 globally. Clinical trial information: NCT04663347 , NCT05578976 .

PHASE 3 TRIAL OF SUBCUTANEOUS EPCORITAMAB + R‐CHOP VERSUS R‐CHOP IN PATIENTS (PTS) WITH NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL): EPCORE DLBCL‐2

Introduction: In pts with newly diagnosed DLBCL, standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has a 5-year progression-free survival (PFS) rate of 67.0%, 58.4%, and 45.8% for International Prognostic Index (IPI) 2, 3, and 4–5, respectively (Ruppert et al., Blood 2020). Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell–mediated killing of malignant CD20+ B cells (Hutchings et al., Lancet 2021). Epcoritamab monotherapy demonstrated deep and durable responses (overall response rate [ORR], 63%; complete response rate, 39%; median duration of response, 12 months) and was generally well tolerated in pts with relapsed/refractory (R/R) aggressive, large B-cell lymphoma (LBCL) (Thieblemont et al., J Clin Oncol 2022). Results from an ongoing phase 1/2 study in high-risk pts with newly diagnosed DLBCL (EPCORE NHL-2 arm 1; NCT04663347) show that epcoritamab + R-CHOP has promising efficacy and a manageable safety profile in high-risk pts with IPI 3–5. Among efficacy-evaluable pts (n = 31), ORR was 100% and complete metabolic response (CMR) was 77%; cytokine release syndrome (CRS) events (n = 17/33; 52%) were mostly low-grade, had predictable timing, and did not lead to treatment discontinuation (Falchi et al., ASCO 2022, abstract 7523). These encouraging data support further evaluation of epcoritamab + R-CHOP for the treatment of newly diagnosed DLBCL. Methods: This phase 3, global, multicenter, open-label study (NCT05578976) evaluates the efficacy and safety of epcoritamab + R-CHOP in adults newly diagnosed with one of the following CD20+ DLBCL (de novo or transformed from follicular lymphoma [FL]): 1) DLBCL, not otherwise specified (NOS); 2) high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; 3) T-cell/histiocyte–rich LBCL; 4) Epstein-Barr virus–positive DLBCL, NOS; or 5) FL grade 3b. Other key eligibility criteria include IPI ≥2 (pts with IPI 2 not to exceed ∼30% of total pts), ECOG PS 0–2, and ≥1 measurable disease site. Approximately 900 pts will be randomized 2:1 to either epcoritamab + R-CHOP (6 cycles, followed by 2 cycles of epcoritamab) or R-CHOP (6 cycles, followed by 2 cycles of rituximab). The primary efficacy endpoint is PFS in pts with IPI 3–5 (based on IRC assessment per Lugano criteria). The secondary efficacy endpoints are PFS in pts with IPI 2–5, event-free survival, CMR, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (CRS, immune cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome). Enrollment began in January 2023 globally. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved. The research was funded by: This study was funded by AbbVie and Genmab. Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, immunotherapy Conflicts of interests pertinent to the abstract. L. H. Sehn Consultant or advisory role AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genentech/Roche, Incyte, Janssen, Kite/Gilead, Merck, Seattle Genetics Research funding: Teva, Roche/Genentech M. Chamuleau Consultant or advisory role AbbVie, Novartis, Incyte Research funding: BMS, Gilead, GenMab G. Lenz Consultant or advisory role Roche, Gilead, Janssen, Bayer, BMS, Novartis, AbbVie, Incyte, Genmab, Karyopharm, Constellation, ADC Therapeutics, Sobi, Miltenyi, PentixaPharm, Genase, Immagene, Hexal, Lilly Research funding: Janssen, Bayer, MorphoSys, AstraZeneca Other remuneration: Invited Speaker: Roche, BMS, Novartis, AbbVie, Incyte, Sobi, Hexal M. R. Clausen Consultant or advisory role AbbVie, Genmab, Janssen and Kite/Gilead C. Haioun Consultant or advisory role AbbVie, Genentech/Roche, Incyte, Kite/Gilead, Miltenyi A. Davies Honoraria: Roche, Kite, Incyte, BMS, AstraZeneca, AbbVie, Genmab Research funding: Roche, AstraZeneca, MSD, Cellcentric Educational grants: Roche T. Oki Employment or leadership position: AbbVie E. Szafer-Glusman Employment or leadership position: AbbVie R. Conlon Employment or leadership position: AbbVie Stock ownership: AbbVie H. Chiou Employment or leadership position: AbbVie D. Ipe Employment or leadership position: AbbVie B. Elliot Employment or leadership position: Genmab Stock ownership: Genmab J. Wu Employment or leadership position: AbbVie G. Salles Consultant or advisory role AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, Takeda

Eosinophil count and immune-related adverse events (irAEs) as predictive biomarkers of survival in patients with NSCLC treated with ICIs.

e21144 Background: Immune Checkpoint Inhibitors (ICIs) changed the algorithm of treatment for Non-Small Cell Lung Cancer (NSCLC). Consequently, an increased incidence of specific immune-related adverse events (irAEs) were reported, although a clear relationship between toxicity and response to ICIs was not identified. To date no strong predictive factor of response to ICIs are univocally recognized in NSCLC. Methods: This is an observational, retro-prospective, monocentric study aimed to evaluate, in patients (pts) with NSCLC treated with ICIs, the predictive impact of selected blood biomarkers and the occurrence of irAEs on survival. Differential cells count, and specifically the Absolute Eosinophil Count (AEC, N°/μL), were registered at baseline to evaluate their impact on response to ICIs. Patients were divided in two groups: those with high AEC ( > 190/µL, group A), and those with low basal AEC ( < 190/µL, group B). Results: We enrolled 48 pts, median age was 70 years. All pts were treated with an ICI as single-agent: 5 (10%) with Nivolumab (N), 37 (77%) with Pembrolizumab (P), and 5 pts received Atezolizumab (A). Thirty-seven pts were treated in first-line setting, 9 pts in second-line, and 2 pts in successive lines. Of total, 63% pts (30/48) developed at least one irAE: an endocrine event occurred in 11 pts (23%), gastrointestinal toxicity in 10 pts (21%), dermatological events in 19 pts (40%), while a pulmonary irAE in 6 pts (13%). Progression free survival (PFS) was higher in group A than in group B (16 vs 9.5, p = 0.041) with a trend for a superior median Overall Survival (mOS) (median not reached vs 23 months, p = 0.07, respectively). At a median follow-up of 18 months (mos), pts who developed at least one irAE had a significant benefit in PFS (15mos vs 8mos, p = 0.027), reporting a trend for better PFS for pts with endocrine toxicities (p = 0.057) and GI- toxicities (p = 0.051) vs no toxicities. Pulmonary irAEs are significantly related to a better PFS: median not reached vs 12 mos, p = 0.025. Conclusions: In this real-life experience we observed that baseline AEC values correlates with PFS in pts with NSCLC treated with ICIs. Additional analyses are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Moreover, our study underlines that the development of toxicities, in particular pulmonary ones, could be considered as a predictive indicator of response to ICIs in NSCLC. With all the limitations of being a small analysis, our real-life experience is innovative and explored prospectively the potential role of differential cell count and irAEs as predictive biomarkers of survival in NSCLC patients treated with ICIs.