1L Therapy Research Articles

BNT321, a novel monoclonal antibody targeting sialyl Lewis A: Phase 1 monotherapy and combination with mFOLFIRINOX in patients with advanced CA19-9 expressing cancers.

654 Background: BNT321 is a high affinity human monoclonal antibody targeting the sialyl Lewis A epitope of CA19-9. This Phase 1/1b dose escalation/expansion study investigated BNT321 as monotherapy and in combination with mFOLFIRINOX (mFFX) in patients (pts) with advanced CA19-9 expressing cancers. Methods: Eligible pts: progressive CA19-9 expressing solid tumors, liver transaminases ≤ 2 x ULN, bilirubin WNL, ECOG PS 0-1. BNT321 given on Qwk, Q2wk, and Q4wk schedules. Lead in dose (1 mg/kg given 1 wk prior to assigned dose) evaluated on Q2wk + Q4wk schedules. BNT321 + mFFX given Q2wk as 1L or 2L metastatic therapy (1L+2L met). Dexamethasone given as premedication. Endpoints: safety, MTD, RP2D, efficacy, PK, changes in serum CA19-9. Results: 82 pts received BNT321 monotherapy and 15 received BNT321 + mFFX. BNT321 monotherapy MTD was 2 mg/kg Q2wk and MTD with mFFX was 1 mg/kg. Schedule and lead in dose did not significantly alter MTD. Dose limiting toxicities (DLTs) for BNT321 monotherapy and with mFFX were elevations in hepatic AST and ALT with or without bilirubin elevations. These events generally occurred early (cycle 1), resolved with drug hold, and did not preclude subsequent reduced dose BNT321. Frequent related AEs (total %/ > grade 3 %) for BNT321 include increased ALT (39%/19%), AST (35%/12%), T bilirubin (27%/9%), fatigue (21%/0%), infusion related reaction (IRR) (17%/1%) and for BNT321 + mFFX fatigue (67%/0%), increased AST (40%/27%), ALT (33%/20%), diarrhea (33%/0%), nausea (20%/0%). At combination MTD (n=7): fatigue (71%/0%), diarrhea (29%/0%), IRR (29%/0%), nausea (28%/0%), increased AST (14%/14%), ALT (14%/14%). BNT321 demonstrated a T1/2 of 11.75 days + dose proportional Cmax and AUC with intra-patient variability. Enhanced clearance observed among pts with higher baseline (BL) serum CA19-9. For BNT321 monotherapy stable disease (RECIST 1.1) was best response, with time on study > 90 days and > 180 days in > 20% and 10% of pts, respectively. Correlation between time on study and post BL normalization of CA19-9 was observed. For BNT321 + mFFX (1L+2L met), PRs were observed in 3/11 (27%) response evaluable pts who had time on study 10.0-15.8 months. Conclusions: BNT321 and BNT321 + mFFX MTDs were 2 mg/kg and 1 kg/kg, respectively. DLTs were hepatic AST, ALT and T bilirubin elevations which were generally cycle 1 and did not preclude subsequent BNT321 at reduced dose. BNT321 monotherapy resulted in disease stabilization and prolonged time on study (> 90 days for > 20%) in pts with advanced line, metastatic PDAC and other CA19-9+ cancers. BNT321 significantly decreased CA19-9 in the majority of pts and PK was similar to other human monoclonal antibodies. BNT321 + mFFX (1L+2L met) demonstrated multicycle tolerability and a 27% PR rate with 10+ months duration on study. BNT321 + mFFX is being evaluated in resected PDAC in the adjuvant setting. Clinical trial information: NCT02672917 .

Coformulated quavonlimab and pembrolizumab (pembro) in combination with lenvatinib (lenva) as first-line (1L) therapy for patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 2 KEYSTEP-004 study.

484 Background: Combinations of a PD-1/L1 inhibitor with a CTLA-4 or VEGF inhibitor have been approved as 1L treatment options for pts with advanced HCC. The multicenter, phase 2 KEYSTEP-004 study (NCT04740307) was conducted to evaluate the coformulation of quavonlimab (CTLA-4 inhibitor) and pembro (PD-1 inhibitor) in combination with lenva (multi–tyrosine kinase inhibitor) as 1L treatment for pts with advanced HCC. Methods: Pts were ≥18 y of age, had histologically or radiographically confirmed HCC with no prior systemic therapy, and were not amenable to curative therapy; had Child-Pugh class A; and ECOG PS 0 or 1. The study consisted of a safety lead-in phase (approximately 6-20 pts) to evaluate the tolerability of the recommended phase 2 dose of lenva with a possibility of dose modification based on dose-limiting toxicities (DLTs) and an efficacy expansion phase (approximately 110 pts). In the safety lead-in phase, pts received a fixed-dose coformulation of quavonlimab 25 mg and pembro 400 mg IV Q6W in combination with lenva 8 mg (body weight [BW] <60 kg) or 12 mg (BW ≥60 kg) PO QD. Allocation to the efficacy expansion phase was allowed if the doses of lenva were determined to be tolerable. Primary end points were ORR per RECIST v1.1 by BICR and safety. Secondary end points included DOR, DCR, and PFS per RECIST v1.1 by BICR and OS. Results: No DLTs were observed in the 6 pts enrolled in the safety lead-in phase. 115 pts in the safety lead-in phase or the efficacy expansion phase were treated with the fixed-dose coformulation of quavonlimab and pembro plus lenva 8 or 12 mg. 94 pts (81.7%) were male, median age was 64 y (range, 32-83), and 80 pts (69.6%) had AFP ≤400 ng/mL. As of the June 22, 2023, data cutoff date, median follow-up (time from first dose to database cutoff date or death) was 7.7 mo (range, 0.9-22.1), and 89 pts (77.4%) discontinued treatment, most commonly due to progressive disease (39.1%). Confirmed ORR was 37.4% (95% CI, 28.5-46.9), with 5 CRs (4.3%) and 38 PRs (33.0%). DCR was 79.1% (95% CI, 70.6-86.1). Median DOR was 10.6 mo (range, 1.2+ to 23.1+). Median PFS and OS were 8.2 mo (95% CI, 6.2-10.2) and 22.1 mo (95% CI, 15.5-not reached), respectively; 12-mo PFS and OS rates were 32.2% and 65.2%, respectively. Treatment-related adverse events (TRAEs) occurred in 109 pts (94.8%); most common (≥25%) were hypertension (35.7%) and diarrhea (27.8%). Grade 3-5 TRAEs occurred in 66 pts (57.4%); most common (≥5%) were hypertension (8.7%) and immune-mediated enterocolitis (7.0%). 8 pts (7.0%) died due to AEs; 2 were considered treatment related (acute respiratory failure and subarachnoid hemorrhage). Conclusions: The coformulation of quavonlimab and pembrolizumab in combination with lenvatinib demonstrated manageable safety; further investigation is warranted to understand the efficacy of this triplet as 1L treatment for advanced HCC. Clinical trial information: NCT04740307 .

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study.

LBA588 Background: Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor. Methods: Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS. Results: Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p < 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p < 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm). Conclusion: 177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488 .

Network meta-analysis of global trials of 1L therapies in locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.

325 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies reported statistically significant improvement in PFS and OS with 1L zolbetuximab (anti-claudin-18 isoform 2 [CLDN18.2]) + mFOLFOX6 or CAPOX in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. This network meta-analysis (NMA) indirectly compared the relative efficacy of 1L therapies. Methods: A systematic literature review of phase 2, 3, or unknown phase randomized, global trials of 1L therapies (capecitabine + cisplatin [CX]; capecitabine + oxaliplatin [CAPOX]; fluorouracil + cisplatin [CF]; oxaliplatin + folinic acid + fluorouracil [FOLFOX]; S-1 + cisplatin [SC]; nivolumab + CAPOX/FOLFOX; pembrolizumab + CF/CAPOX or CX; and zolbetuximab + CAPOX/FOLFOX) in adults with LA unresectable or mG/GEJ adenocarcinoma. To form a connected main network, FOLFOX and CAPOX were assumed equally efficacious and combined. In the latest publicly available data, hazard ratios (HRs) of PFS and OS for intent-to-treat (ITT) populations were extracted or reconstructed from Kaplan-Meier curves when not reported as inputs for Bayesian fixed-effects NMAs. Comparative effectiveness was reported using median HR and 95% credible intervals (CrIs). Results: Trials reporting ITT populations were included, resulting in 9 trials (6663 pts) for PFS analysis and 10 trials (6735 pts) for OS analysis representing 8 regimens. Pts were randomly assigned to an experimental arm vs FOLFOX/CAPOX. Pts on 1L zolbetuximab, nivolumab, or pembrolizumab in combination with CF/CAPOX or FOLFOX/CAPOX had significantly reduced risk of disease progression or death vs FOLFOX/CAPOX (Table). Zolbetuximab + FOLFOX/CAPOX had the highest probability of being ranked first in treatment efficacy for both PFS (probability =0.54) and OS (0.36); followed by pembrolizumab + CX (0.27) and pembrolizumab + CF/CAPOX (0.13) for PFS; and by pembrolizumab + CF/CAPOX (0.3) and nivolumab + FOLFOX/CAPOX (0.24) for OS. Conclusions: This NMA examined the relative benefit of different targeted therapies when combined with chemotherapy. Zolbetuximab + FOLFOX/CAPOX for CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma confers a significant PFS and OS benefit, similar to that achieved with PD-1/PD-L1 inhibitors + CF/CAPOX or FOLFOX/CAPOX. [Table: see text]

Treatment patterns of gemcitabine-based chemotherapy in patients with de novo and recurrent advanced biliary tract cancer.

454 Background: Biliary tract cancers (BTC) are often diagnosed at advanced stages (aBTC) when prognosis is poor. In the Phase 3 TOPAZ-1 study (NCT03875235), durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival versus placebo plus GemCis. To better understand the context of the TOPAZ-1 trial results in the US, we looked at first-line (1L) treatment patterns in participants with aBTC treated with GemCis and other gemcitabine (Gem)-based chemotherapy (CT) regimens. Methods: This retrospective observational cohort study used linked electronic health records and medical and pharmacy claims data from the Optum Market Clarity Database. Adults diagnosed with de novo or recurrent aBTC, who initiated 1L Gem-based CT between January 2016 and March 2022, were identified and followed from the index date (defined as the first administration of Gem-based CT on or after initial BTC diagnosis date) until death, end of continuous enrollment, or end of study period, whichever occurred first. Variables including patient demographics, clinical characteristics, and treatment patterns were described. Results: A total of 580 patients were included in the analysis with either de novo aBTC (n=481, 82.9%) or recurrent aBTC (n=99, 17.1%) with median follow-up time of 10.4 (interquartile range: 6.4, 17.5) and 12.0 (interquartile range: 6.3, 21.9) months, respectively. Mean (SD) age was 64.6 (11.2) and 66.8 (10.4) years, with 45.7% and 54.5% male in the de novo and recurrent aBTC groups, respectively. Most patients were white (77.6%). The most frequent site of primary tumor diagnosis was single-site intrahepatic (overall 62.8%, de novo 66.7%, recurrent 43.4%). In the 12 months prior to index date, 38.5% of patients had biliary obstruction, 30.2% had biliary stents, 29.3% had jaundice, and 17.1% had nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Common comorbidities included cardiovascular disease (50.9%), obesity (46.8%), and diabetes (35.2%). The most common 1L CT was GemCis followed by Gem for both the de novo (n=355, 73.8% and n=36, 7.5%) and recurrent groups (n=58, 58.6% and n=26, 26.3%), respectively. Approximately half of participants (50.9%) switched to a new line of treatment, 33.3% discontinued 1L CT, and 15.9% remained on 1L CT at last follow-up. Most frequent 2L treatments included fluorouracil/oxaliplatin (36.9%) and capecitabine (14.2%). Further analysis will characterize outcomes and regimen duration. Conclusions: Findings from this retrospective study showed that the most common 1L therapies were GemCis and Gem among both de novo and recurrent patients with aBTC. These results provide insight into aBTC treatment practices and may help inform treatment decisions.

Clinical outcomes of ROS1-positive non-small cell lung cancer with limited access to ROS1-tyrosine kinase inhibitors (TKIs): experience from an Indian tertiary referral centre.

ROS1 as a driver mutation is observed in approximately 1%-2% of all non-small cell lung cancer (NSCLC). Given its rarity, we share our experience regarding ROS1-positive NSCLC including the access to ROS1 tyrosine kinase inhibitors (TKIs) in a low-middle income country like India. It is a retrospective analysis of ROS1-positive NSCLC patients registered between January 2015 to December 2021 for demographics, treatment patterns and outcomes i.e., overall survival (OS) and progression free survival (PFS). Baseline characteristics were available for 70 patients of 78 patients positive for ROS1 by fluorescent in situ hybridisation. Median age at presentation was 52 years, 39 (55.7%) were males, most (51, 72.86%) were non-smokers and ten patients (14.3%) had poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) i.e., PS >2 at presentation. A total of 67 patients receiving cancer directed therapy were analysed for survival. The first line (1L) therapies included - ROS1 TKIs in 38, chemotherapy in 20, epidermal growth factor receptor TKI in eight and chemotherapy-bevacizumab in one only. ROS1 TKI was provided to 20 patients as part of an assistance programme. The median OS for patients who received ROS1 TKI was not attained (95% CI 37.85-NA), while it was 8.11 (95% CI 6.31-NA) months for those who did not (HR-0.1673). The median PFS for the 1L ROS1 TKI compared to the no-TKI group was 27.07 (95% CI 24.28-NA) months versus 5.78 (95% CI 3.42-12) months (HR: 0.2047). Poor ECOG PS at presentation was the only independent prognosticator for survival. Using ROS1 TKI improves clinical outcomes in all-comers though statistically not significant. To further improve outcomes, future trials should pay special attention to patients with poor PS and find a way to increase the current limited access to TKI.

Real-world economic burden of metastatic castration-resistant prostate cancer before and after first-line therapy initiation

Aims To describe healthcare costs of patients with metastatic castration-resistant prostate cancer (mCRPC) initiating first-line (1 L) therapies from a US payer perspective. Methods Patients initiating a Flatiron oncologist-defined 1 L mCRPC therapy (index date) on or after mCRPC diagnosis were identified from linked electronic medical records/claims data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry and Komodo’s Healthcare Map. Patients were excluded if they initiated a clinical trial drug in 1 L, had <12 months of insurance eligibility prior to index, or no claims in Komodo’s Healthcare Map for the Flatiron oncologist-defined index therapy. All-cause and PC-related total costs per-patient-per-month (PPPM), including costs for services and procedures from medical claims (i.e. medical costs) and costs from pharmacy claims (i.e. pharmacy costs), were described in the 12-month baseline period before 1 L therapy initiation (including the baseline pre- and post- mCRPC progression periods) and during 1 L therapy (follow-up). Results Among 459 patients with mCRPC (mean age 70 years, 57% White, 16% Black, 45% commercially-insured, 43% Medicare Advantage-insured, and 12% Medicaid-insured), average baseline all-cause total costs (PPPM) were $4,576 ($4,166 pre-mCRPC progression, $8,278 post-mCRPC progression). Average baseline PC-related total costs were $2,935 ($2,537 pre-mCRPC progression, $6,661 post-mCRPC progression). During an average 1 L duration of 8.5 months, mean total costs were $13,746 (all-cause) and $12,061 (PC-related) PPPM. The cost increase following 1 L therapy initiation was driven by higher PC-related outpatient and pharmacy costs. PC-related medical costs PPPM increased from $1,504 during baseline to $5,585 following 1 L mCRPC therapy initiation. Limitations All analyses were descriptive; statistical testing was not performed. Conclusion Incremental costs of progression to mCRPC are significant, with the majority of costs driven by higher PC-related costs. Using contemporary data, this study highlights the importance of utilizing effective therapies that slow progression and reduce healthcare resource demands despite the initial investment in treatment costs.

Tislelizumab versus chemotherapy as second-line treatment for European and North American patients with advanced or metastatic esophageal squamous cell carcinoma: a subgroup analysis of the randomized phase III RATIONALE-302 study

The phase III RATIONALE-302 study evaluated tislelizumab, an anti-programmed cell death protein 1 antibody, as second-line (2L) treatment for advanced/metastatic esophageal squamous cell carcinoma (ESCC). This prespecified exploratory analysis investigated outcomes in patients from Europe and North America (Europe/North America subgroup). Patients with tumor progression during/after first-line systemic treatment were randomized 1:1 to open-label tislelizumab or investigator's choice of chemotherapy (paclitaxel, docetaxel, or irinotecan). The Europe/North America subgroup comprised 108 patients (tislelizumab: n= 55; chemotherapy: n= 53). Overall survival (OS) was prolonged with tislelizumab versus chemotherapy (median: 11.2 versus 6.3 months), with a hazard ratio (HR) of 0.55 [95% confidence interval (CI) 0.35-0.87]; HR was similar irrespective of programmed death-ligand 1 score [≥10%: 0.47 (95% CI 0.18-1.21); <10%: 0.55 (95% CI 0.30-1.01)]. Median progression-free survival was 2.3 versus 2.7 months with tislelizumab versus chemotherapy [HR: 0.97 (95% CI 0.64-1.47)]. Overall response rate was greater with tislelizumab (20.0%) versus chemotherapy (11.3%), with more durable response (median duration of response: 5.1 versus 2.1 months). Tislelizumab had a favorable safety profile versus chemotherapy, with fewer patients experiencing ≥grade 3 treatment-related adverse events (13.0% versus 51.0%). Those on tislelizumab experienced less deterioration in health-related quality of life, physical functioning, and/or disease- and treatment-related symptoms (i.e. fatigue, pain, and eating problems) as compared to those on chemotherapy, per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and QLQ-OES18 scores. As a 2L therapy for advanced/metastatic ESCC, tislelizumab improved OS and had a favorable safety profile as compared to chemotherapy in European/North American ESCC patients in the randomized phase III RATIONALE-302 study.

Current and Upcoming Treatment Strategies After CDK4/6 Inhibitors for Patients With ER+/HER2- Advanced Breast Cancer

This industry symposium took place during the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, with a goal of presenting the latest recommendations and upcoming treatment strategies for patients with oestrogen-receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer, who experience disease progression after cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. An expert panel of clinicians explained that most patients will eventually develop resistance to endocrine therapy during the metastatic setting, and there remains a considerable margin for improvement in the second-line (2L) treatment of these patients. Data for current therapeutic options in this patient population were presented, showing that patients who have previously received CDK4/6 inhibitor therapy are often resistant to many of the available 2L therapies, including combination therapies, and that resistance appears during first-line (1L) treatment, becoming particularly significant in tumours harbouring ERS1 mutations. The recent approval of the oral selective oestrogen receptor degrader (SERD), elacestrant, was also discussed. The supporting data for this monotherapy at 2L was presented, along with changes made to the U.S. Food and Drug Administration (FDA) and European Union (EU) best practice recommendations to accommodate this therapeutic option. The panel stressed the importance of testing for ESR1 mutations at each progression during the metastatic treatment course, which is particularly relevant following the approval of elacestrant, for which ESR1 mutation is a predictive factor for efficacy.

Abstract C136: VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC)

Abstract Background VHL, PBRM1, and BAP1 are common mutations in clear-cell renal cell carcinoma (ccRCC). VHL and PBRM1 mutations result in downstream dysregulation of vascular endothelial growth factor receptor (VEGFR) that cause angiogenesis and uncontrolled cell growth. VEGFR tyrosine kinase inhibitors (TKI) are the mainstay of ccRCC treatment. The current first-line (1L) therapies for mRCC include combination anti-VEGFR TKI + anti-PD-1 immune checkpoint inhibitors (CPI), or combination CPI targeting PD-1 and CTLA-4. It is unknown whether VHL and PBRM1 mutations are predictive for response to 1L anti-VEGFR TKI, anti-VEGFR TKI + CPI, or combination CPI immunotherapy. In this retrospective observational study, we evaluated the real-world outcomes of 1L therapies in patients with mRCC with or without VHL, PBRM1, or BAP1 mutations. Methods This study used the nationwide de-identified Flatiron Health-Foundation Medicine RCC clinico-genomic database, originating from approximately 280 cancer clinics (~800 sites of care). Patients with metastatic ccRCC, diagnosed from 8/1996-8/2022, who received 1L therapy with anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or anti-PD-1 + anti-CTLA-4 therapy, and who had comprehensive genomic profiling were included. The primary endpoint was real-world overall survival (rwOS) in mRCC patients with VHL mutations. Secondary endpoints included rwOS and real-world progression-free survival (rwPFS) in patients with BAP1 and PBRM1 mutations, and rwPFS in patients with VHL mutations. The cox proportional hazard model was used to conduct the multivariable analysis adjusting for demographic/clinical factors for rwOS and rwPFS. The Kaplan-Meier method were used to estimate the median survival time. Results149 patients with complete data sets were included, of whom 99 had VHL mutations, 65 had PBRM1 mutations, and 31 had BAP1 mutations. Eight patients (5%) had favorable International Metastatic RCC Database Consortium (IMDC) risk, 110 (74%) had intermediate IMDC risk, and 31 (21%) had poor IMDC risk. The adjusted hazard ratio (HR) for rwOS in patients with VHL mutations compared to those without who received 1L anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy were 1.53 (95% CI: 0.78-3.00, p=0.221), 0.87 (95% CI: 0.29-2.61, p=0.798), and 1.64 (95% CI: 0.71-3.75,p=0.245), respectively. The median rwOS for patients with PBRM1 mutations who received anti-VEGFR TKI was 50.1 months (95% CI: 34.62-NR) and 30.6 months (95% CI: 19.4-63.2) in patients without PBRM1 mutations (adjusted HR 0.54, 95% CI: 0.29-1.00, p=0.049). The median rwPFS for BAP1 mutations with anti-VEGFR TKI therapy was 5.2 months (95% CI: 3.6-9.1) and 6.4 (95% CI: 4.7-10.8) in patients without BAP1 mutations (adjusted HR 2.45, 95% CI: 1.35-4.44, p=0.003). Conclusion No significant difference was observed in rwOS in mRCC patients with VHL mutations treated with first-line anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy, compared to patients without VHL mutations. Additional studies are needed to confirm this finding. Citation Format: Jessica Zhu, Junxiao Hu, Elaine T Lam. VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C136.

Abstract A131: Clinical characteristics and outcomes of Black patients with multiple myeloma compared with other races

Abstract Introduction: Black patients with multiple myeloma (MM) in the US have a greater incidence rate, inferior survival, and younger onset of MM vs other races. This analysis evaluated differences in clinical characteristics between Black patients compared with other races with MM to determine the impact on survival outcomes. Methods: Data were retrospectively collected from the ConcertAI Patient360 database containing aggregated electronic health record data of patients treated in US-based oncology centers. Adult patients diagnosed with MM (2011–2022) who received ≥1 line of systemic therapy and had ≥3-month follow up were included. Patients were stratified by race (Black vs other [American Indian/Alaska Native, Asian, Native Hawaiian/other Pacific Islander, White, and other/unknown]). Baseline characteristics were compared between races using Chi-squared tests. Outcomes included first-line (1L), overall survival (OS), and progression-free survival (PFS), estimated by Kaplan-Meier. The impact of race and characteristics on outcomes was evaluated with Cox proportional hazards models. Results: Black patients (n=806) vs other races (n=3164), were younger (63.3 vs 67.4 years, p&amp;lt;0.001) with greater prevalence of concurrent cancer (13.3% vs 10.6%, p=0.027) at time of diagnosis, and higher baseline mean Charlson Comorbidity Index (CCI) score (0.48 vs 0.39, p=0.047). Black patients vs other races more frequently had diabetes without complications (14.8% vs 10.3%, p&amp;lt;0.001), renal disease (3.7% vs 1.7%, p&amp;lt;0.001), and AIDS/HIV (1.4% vs 0.1%, p&amp;lt;0.001), and 1L therapy regimen use (p=0.56) did not differ between races. The proportion progressing to 3L was 20.5% vs 19.2% among Black vs other races. Among overall patients, median (95% CI) 1L OS and PFS in months was similar between Black patients and other races (OS: 129 [109, 167] vs 133 [122, 157]; PFS: 39.5 [35.0, 45.3] vs 38.1 [36.2, 40.5]). Survival outcomes did not differ between races before (Hazard ratio [HR] [95% CI]; OS: 0.97 [0.84, 1.11]; PFS: 0.91 [0.82, 1.01]) or after adjusting for patient characteristics (OS: 1.13 [0.97, 1.31]; PFS: 1.0 [0.89, 1.12]). Characteristics impacting outcomes regardless of race included age (50–64 vs &amp;lt;50 years; OS: 1.48 [1.13, 1.95]); PFS: 1.32 (1.11, 1.57), CCI score (OS: 1.15 [1.10, 1.20]; PFS: 1.06 [1.02, 1.10]), and ECOG score 2–4 vs 0–1 (OS: 1.76 [1.08, 1.37]; PFS: 1.52 [1.35, 1.71]; p&amp;lt;0.01). Conclusions: Although 1L survival outcomes were similar between races, Black patients were younger at diagnosis with more comorbidities. Since improved survival outcomes were associated with younger age, fewer comorbidities and lower ECOG score, prompt diagnosis and care are needed. Funding: Financial support for the study was provided by AbbVie. AbbVie and Genentech participated in interpretation of data, review, and approval of the abstract. All authors contributed to development of the abstract and maintained control over final content. No honoraria or payments were made for authorship. Citation Format: Shelli Spence, Junhua Yu, Allicia Girvan, Sophia Ng, Sophia Li, Faiza Zafar, Archibong Yellow-Duke, R. Frank Cornell. Clinical characteristics and outcomes of Black patients with multiple myeloma compared with other races [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A131.

Physician Treatment Preferences in Relapsed/Refractory Follicular Lymphoma: A Discrete Choice Experiment

Introduction: Follicular lymphoma (FL) is an indolent form of non-Hodgkin lymphoma with limited treatment options at disease progression. Novel treatments, like bispecific antibodies and chimeric antigen receptor T-cell therapy, have recently emerged, each with novel safety and management profiles. Yet, contemporary research evaluating treatment preferences among physicians treating relapsed or refractory (r/r) FL is lacking. The objective of this study was to identify key treatment attributes that influence physicians' treatment decisions when treating patients with r/r FL. Methods: We fielded a multi-country survey of physicians from the United States (US), United Kingdom (UK), Brazil, Japan, Germany and France, with up to 50 participants in each country. Data collected as of June 13, 2023 are reported with the remaining data from all countries expected by July 31st. Physicians were recruited through a healthcare research panel for an online, cross-sectional survey that included two discrete choice experiment (DCE) exercises: one for 2 nd line (2L) and one for 3 rd line (3L) therapy. The DCEs prompted physicians to choose between 2 treatment profiles that varied on 7 attributes associated with treatment for r/r FL: progression-free survival (PFS), overall survival (OS), serious adverse events (AE), cytokine release syndrome (CRS) events, neurological events, fatigue and administration/impact on functioning. Attributes and levels of interest were informed by a targeted literature review, clinical data on r/r FL treatments and clinical input. Sociodemographic and practice characteristics were summarized using descriptive statistics. We generated attribute level preference weights using hierarchical Bayesian modeling. Relative attribute importance (RI) was computed based on differences in preference weights between the most and least favorable level of each attribute. Bivariate statistics were used to evaluate differences between physicians. Interim results from the UK and US are reported with plans to include additional countries at time of presentation. Results: This analysis included 98 physicians (49 US; 49 UK) who averaged 13.7 years treating patients with FL. Most physicians specialized in medical oncology or hematology oncology (US: 100.0%; UK: 83.7%). Overall, 55.1% of physicians practiced in academic settings whereas 44.9% practiced in community settings; the proportion of academic-based physicians was higher in the UK vs the US (79.6% vs 30.6%; p&amp;lt;0.001). Roughly 60% of patients managed by physicians were &amp;gt;50 years of age. The mean number of FL patients treated over the past six months among physicians from the UK was greater than physicians from the US [65.0 vs 43.0, respectively]. Yet, the mean proportion of patients receiving 2L and 3L therapy over the past six months was roughly equal between physicians from the US and UK [2L: 27.2% vs 26.1%; 3L: 15.9% vs 15.6%]. In the context of 2L (Figure 1) and 3L (Figure 2) therapy, improved PFS was selected as most important (2L RI=20.4%; 3L RI=27.5%) whereas reducing the risk of serious AEs was least important (2L=5.6%; 3L RI=6.7%). In 2L, reducing the risk of neurological events was the second most important attribute (RI=19.1%) followed by increasing OS (RI=16.2%). Conversely, in 3L therapy, increasing OS was the second most important attribute (RI=18.9%) followed by reducing the risk of neurological events (RI=14.3%). Reducing the risk of neurological events and the risk of CRS were relatively more important to physicians in the 2L vs 3L setting. In general, physicians from the US and UK assigned similar levels of importance to each attribute evaluated, regardless of treatment line. However, the RI of fatigue was higher among physicians from the UK compared to those from the US (13.5% vs. 10.0%; p=0.047). Conclusion: Assessing physician treatment preference facilitates alignment between what matters most to patients and physicians' treatment decisions in r/r FL, particularly amidst an evolving treatment landscape. PFS was the most important attribute influencing physicians' treatment decisions for patients in 2L and 3L settings, which suggests that preserving a longer treatment-free period is important to physicians at both lines of therapy. Future treatments for r/r FL may need to demonstrate PFS benefits to influence physicians' willingness to make trade-offs between efficacy and side effects in earlier treatment lines.

Phased Variants Allow Robust Profiling of Circulating Tumor DNA in Untreated Follicular Lymphomas

Background: In the absence of tumor tissue, several studies have shown the utility of plasma cell-free DNA (cfDNA) for blood based noninvasive genotyping of diverse human tumors, including aggressive lymphomas. However, it remains unclear whether these same cfDNA advantages also apply to follicular lymphoma (FL), and if they could inform noninvasive minimal residual disease (MRD) monitoring in the context of modern regimens inducing deep FL remissions. Here, we address these questions in previously untreated patients with FL receiving standard first-line (1L) therapy, using Phased Variant Enrichment and Detection Sequencing (PhasED-Seq, Kurtz et al 2021, Nat Biotech) to monitor ctDNA and MRD. Methods: We profiled 298 samples from 61 patients with FL, including archival formalin fixed paraffin embedded (FFPE) tumor tissues, and serial blood samples before, during, and following 1L therapy. All patients were treatment-naive, with most (75%) presenting with advanced stage FL. Induction regimens primarily comprised Bendamustine/Rituximab (66%) and R-CHOP (26%). At a median follow-up of 23 months from start of 1L therapy, 80% of patients were alive and progression free, while 11% experienced progression within 24 months (POD24). MRD was analyzed by PhasED-Seq (Foresight Diagnostics). Phased variants (PVs) were genotyped either using baseline blood plasma, or alternatively from FFPE tumor tissue; matched leukocytes were used as a source of constitutional DNA to censor germline variants and clonal hematopoiesis of indeterminate potential (CHIP). Baseline PV genotypes from each baseline source were then used to longitudinally assess MRD serially during 1L therapy. Blood timepoints included baseline (pre-treatment), Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, at End of Induction (EOI), and serially thereafter. Levels of ctDNA were compared to known FL prognostic factors, including radiographic responses, POD24, and progression-free survival (PFS). Results: PVs were successfully identified from tumor FFPE samples in all patients (61/61), enabling ctDNA MRD assessment by PhasED-Seq. The median number of PVs identified was 530 (IQR 285-1152). Prior to therapy, ctDNA was detectable in 94% of cases (57/61). The median tumor fraction in baseline plasma was 0.28%, significantly lower than pretreatment ctDNA levels in diffuse large B-cell lymphoma (DLBCL) (DLBCL median = 6.1%, Roschewski, ASH 2022, P&amp;lt;0.0001 for FL vs DLBCL). Median pre-treatment ctDNA levels were significantly higher in advanced stage disease (stage I/II, 0.04%, stage III/IV, 0.53%, P=0.006), and correlated with FLIPI risk scores (P=0.04). We next tested whether adequate PVs can be directly identified from plasma without need for tumor tissue to allow MRD surveillance. Despite lower baseline ctDNA levels in FL, a sufficient number of PVs were identified directly in plasma to enable disease monitoring in 75% of cases (45/61). Moreover, ctDNA levels were highly correlated, regardless of the baseline sample used to identify PVs (i.e., tumor versus pretreatment plasma, Spearman rho=0.92, P&amp;lt;0.0001, Fig 1a). Despite high genotypic concordance of tumor vs plasma, we observed significant tumor heterogeneity across compartments with variable rates of concordance between specific mutated genes (Fig 1b). We next assessed the prognostic performance of ctDNA MRD to predict clinical outcomes. ctDNA levels prior to treatment were not significantly prognostic for time to progression. In contrast, in patients with ctDNA MRD assessed after two cycles of therapy (i.e., at C3D1), detection of residual ctDNA was significantly associated with inferior time to progression (log-rank P=0.03 HR = 8.9). Finally, we assessed the feasibility of serial ctDNA surveillance during radiographic remission. In patients with subsequent clinical relapse of disease, we detected reemergence of detectable MRD over two years prior to clinical disease progression. Conclusions: Circulating tumor DNA analysis with PhasED-Seq is feasible in FL, with baseline ctDNA levels significantly lower than those observed in DLBCL. In cases without tissue samples available, plasma DNA can frequently be used as a surrogate for tissue samples. ctDNA detection during treatment is strongly associated with eventual treatment responses, and serial disease surveillance with ctDNA can anticipate clinical relapse.

Real-World Treatment Patterns and Healthcare Resource Utilization in Patients with Waldenström Macroglobulinemia Initiating First-Line Treatment with Ibrutinib or Zanubrutinib

Background: A pivotal clinical trial comparing the efficacy and safety of ibrutinib with zanubrutinib in patients with Waldenström macroglobulinemia (WM) did not achieve its primary endpoint of complete response or very good partial response. In addition, median progression-free survival was not reached in either treatment arm. In the absence of treatment effectiveness differentiation based on clinical trial evidence, we conducted a real-world study to assess patient characteristics, treatment patterns, and all-cause healthcare resource utilization (HRU) in patients with WM who received ibrutinib or zanubrutinib as first-line (1L) therapy. Methods: In this retrospective cohort study, we used the ConcertAI Database to collect claims data of patients with WM aged ≥18 years who initiated single-agent ibrutinib (420 mg/day) or zanubrutinib (320 mg/day) as 1L therapy on or after 9/1/2021 (index date). A 6-month washout period of guideline-recommended WM antineoplastic agents was required to confirm 1L status. Patients were excluded if they were receiving ibrutinib and zanubrutinib concurrently, died within 30 days of the index date, had a record of hematopoietic stem cell transplant, had a record of other ibrutinib indications in the 6 months before index, or were participating in a clinical trial. Baseline demographics and clinical characteristics, therapy duration (number of days between the first and last day of the medication supply), and HRU (all-cause and WM-specific) per-patient-per-month (PPPM) were assessed. Results: The study included 51 patients (ibrutinib, n=30; zanubrutinib, n=21). In both cohorts, most participants were male (ibrutinib, n=20 [67%]; zanubrutinib, n=16 [76%]), and the mean age at baseline was 73 years and 75 years, respectively. At baseline, the median Charlson Comorbidity Index was 0, and the WM-related and ibrutinib/zanubrutinib-related clinical events were similar between the two cohorts. While the zanubrutinib cohort had a higher prevalence of infections (33% vs 3%) and musculoskeletal pain (24% vs 7%) at baseline, the ibrutinib cohort had a higher prevalence of hypertension (20% vs 14%). The baseline prevalence of anemia was similar in both cohorts (ibrutinib, 27%; zanubrutinib, 29%). Mean follow-up was 6.9 months (ibrutinib) and 6.3 months (zanubrutinib). The mean ± SD duration of therapy was 152 ± 112 days (ibrutinib) and 113 ± 99 days (zanubrutinib; p=0.195). The ibrutinib cohort had a significantly lower all-cause HRU PPPM (4.53 ± 3.96 vs 8.53 ± 6.66, p=0.020) and lower WM-specific HRU PPPM (0.11 ± 0.26 vs 0.54 ± 1.14, p=0.104). Conclusions: In this real-world analysis, patients with WM treated with 1L ibrutinib had a numerically longer duration of therapy and lower all-cause and WM-specific HRU PPPM, compared to those treated with 1L zanubrutinib. Due to a small sample size and short follow-up, these findings should be interpreted cautiously.

Patterns of Care and Resource Use Among Elderly Relapsed/Refractory Follicular Lymphoma Patients: US Medicare Claims Analysis

Background: Follicular lymphoma (FL)is the second most common type of non-Hodgkin lymphoma (NHL) and most common indolent NHL. Rituximab-based chemotherapy is highly effective and considered the mainstay first-line (1L) treatment for FL, though many patients relapse and continue through successive lines of therapy. These relapsed/refractory (R/R) patients experience worse outcomes and represent an unmet need for more effective treatment approaches. This study examined treatment patterns, health care resource utilization (HCRU), and costs among R/R FL patients initiating third line (3L) therapy between 2011 and 2020. Methods: This retrospective, observational study used Center for Medicare and Medicaid fee-for-service Medicare data. The sample included treated patients with FL (identified via 1 inpatient or 2 outpatient claims) aged ≥66 years who initiated 1, 2, and 3L therapy between January 1, 2011, and December 31, 2020. Patients were required to have continuous coverage in the 12 months pre-FL diagnosis and 3 months post-diagnosis and were followed until discontinuation of enrollment or death. Line of therapy (LoT) was calculated until the end of treatment, death, or transformation to diffuse large B-cell lymphoma. Outcomes included patient characteristics, treatment patterns, health care costs and HCRU. R esults: This analysis identified 8737 1L, 1847 2L, and 410 3L treated FL patients. Median age at the start of each LoT was 75 years at 1L, 77 at 2L, and 79 at 3L. Of R/R FL patients initiating 3L, the most common baseline Charlson comorbidities included diabetes without chronic complications (23%), chronic pulmonary disease (22%) and renal disease (20%), 32% were defined as having progression of disease within 2 years of 1L (POD24), and 30% were defined as double refractory to both an anti-CD20 agent and an alkylating agent. Treatment utilization rates were similar across LoTs; the most used regimens were rituximab/obinutuzumab (R/O) (used 35% of the time in 1L, 33% in 2L, and 31% in 3L) and bendamustine + R/O (39% in 1L, 33% in 2L, and 21% in 3L). Mean duration of 1L treatment was longer for patients who only initiated 1L (10.1 months) vs. those with R/R FL who went on to initiate 2L and 3L (7.5 and 7.4 months, respectively). As R/R FL patients who initiated 3L moved through LoTs, increases were observed in the number of patients with at least 1 inpatient admission (17% in 1L and 31% in 3L) and with at least 1 emergency room visit (27% in 1L and 41% in 3L). Mean total all-cause costs per-member per-month (PMPM) also increased with each subsequent LoT ($15,917 in 1L, $17,767 in 2L, and $18,266 in 3L). In addition, mean total all-cause costs of R/R FL patients defined as POD24 and double refractory were higher in 3L; $20,172 PMPM and $21,724 PMPM, respectively). Conclusions: In this elderly R/R FL population, similar therapies were used across multiple LoTs. With each subsequent LoT, treatment duration shortened and notably, costs and HCRU increased. Additionally, patients defined as POD24 and double-refractory experienced higher costs. This research highlights a substantial unmet need in R/R FL for novel therapeutic options that can provide better outcomes and reduce HCRU.

Outcomes of Patients with Accelerated/Blast-Phase MPNs That Received Allogeneic Stem-Cell Transplant in the Current Era of Myeloid Therapies

Background Patients (pts) with Philadelphia chromosome-negative (Ph-neg) myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have a median overall survival (mOS) of less than 1 year (Odenike, Blood 2018; Tam et al, JCO 2009). Allogeneic hematopoietic stem cell transplant (allo-HCT) is the only curative approach for MPN-AP/BP, but mOS remains about a year for pts with MPN-BP that undergo allo-HCT (2005-2019) (Orti et al, AJH 2023). We previously reported on outcomes of pts with MPN-AP/BP treated in the current era of myeloid therapies (2017 onward) and found a mOS of 0.73 years in a multi-center cohort of 80 pts (Patel et al, ASH 2022). We aim to characterize treatment patterns and outcomes of pts with MPN-AP/BP that underwent allo-HCT via a multi-center retrospective analysis. Methods Retrospective chart review was performed at 8 institutions to identify pts with pathology-confirmed Ph-neg MPN-AP/BP diagnosed in 2017 or later. All patients that met inclusion criteria were included. Response was assessed using 2017 European Leukemia Net AML (2017 ELN) criteria (Dohner et al, Blood 2017). OS from diagnosis of MPN-AP/BP and from time of allo-HCT was calculated utilizing Kaplan-Meier analysis. Results The full MPN-AP/BP cohort consists of 180 pts. This analysis includes 58 pts that underwent allo-HCT for MPN-AP/BP across 8 institutions. Median age at MPN-AP/BP diagnosiswas 64 years. The most common therapies for chronic-phase MPN included hydroxyurea (55%), JAK inhibitor (JAKi) (26%), interferon (9%), and hypomethylating agent (HMA, 4%). No patient previously received allo-HCT for chronic-phase MPN. Driver mutations included JAK2 (60%), CALR (22%), MPL (10%), but some pts had triple-negative disease (7%). Sixty-two percent of pts had high-risk disease by 2017 ELN criteria. Forty-four pts had next-generation sequencing performed at time of MPN-AP/BP diagnosis. The most frequently co-occurring mutations detected at time of MPN-AP/BP diagnosis were ASXL1 (30%), SRSF2 (23%), RUNX1 (23%), TP53 (18%), TET2 (16%), IDH2 (11%), U2AF1 (7%), EZH2 (7%), and IDH1 (9%). Additional characteristics are in Table 1. One pt proceeded directly to allo-HCT at time of MPN-AP/BP diagnosis. Frontline therapies (1L) for MPN-AP included intensive chemotherapy (IC) (n=26), hypomethylating agent (HMA) + venetoclax (VEN) (n=16), HMA monotherapy (n=14), and low-dose cytarabine (LDAC) + VEN + JAKi (n=1). Responses are summarized in Table 2A. Thirty-seven pts proceeded to allo-HCT after 1L therapy (17 after IC, 10 after HMA+VEN, 9 after HMA, 1 after LDAC+VEN+JAKi). Twenty pts proceeded to allo-HCT after 2 nd-line and beyond (2L+) therapies. Therapies utilized and responses are summarized in Table 2B. Transplant-specific characteristics include 15 pts receiving myeloablative conditioning while 43 received reduced-intensity conditioning. Donor source was matched unrelated donor for 33 pts, haploidentical donor for 10 pts, matched related donor for 9 patients, mismatched unrelated donor for 5 patients, and cord blood for 1 patient. Twenty-two pts developed acute GVHD while 15 developed chronic GVHD. Amongst the 58 pts that underwent allo-HCT, 19 had relapse of disease and 8 patients received treatment after relapse. Amongst the full cohort of 180 patients, mOS was 0.72 years from time of MPN-AP/BP diagnosis. The mOS for the 58 pts that underwent allo-HCT was 1.82 years from time of MPN-AP/BP diagnosis and 1.30 years from time of allo-HCT. Survival analysis by initial MPN-AP/BP therapy demonstrated a mOS from time of MPN-AP/BP diagnosis of 1.9 years for HMA-based therapy, 1.9 years for HMA + VEN, and 1.5 years for IC ( p=0.006). We also analyzed mOS by disease status prior to transplant. Thirty-four pts had a complete response (CR) or CR with incomplete count recovery (CRi) with mOS of 1.7 years from time of allo-HCT, 12 pts with a partial response (PR) or morphologic leukemia-free state (MLFS) had mOS of 1.8 years, and 11 pts with treatment failure (TF) had mOS of 0.47 years (p=0.82). Conclusions Our cohort of 180 pts with MPN-AP/BP treated in the current era of myeloid therapies had limited survival with a mOS of 0.72 years from MPN-AP/BP diagnosis. Amongst the 58 pts that underwent allo-HCT the mOS was 1.82 years with longer mOS seen in pts that received HMA or HMA + VEN as their 1L therapy when compared to IC. This underscores the need for novel management strategies even in pts eligible for allo-HCT.

A Real-World Evidence Study of the Temporal Evolution in Treatment Patterns and Outcomes for Chronic Lymphocytic Leukemia

CONCLUSIONS Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in North America. Treatment of CLL is currently indicated only for patients with disease-related symptoms or organ compromise, such as cytopenias, with no evidence of survival benefit for the treatment of asymptomatic patients. Patients with CLL are not cured with conventional therapy and typically require repeated treatments over their lifetime. Median overall survival (OS) is difficult to estimate given recent advances in therapy options but is dependent upon disease features, patient characteristics, and treatment choice. Since the recent introduction of targeted therapy for CLL, there has been limited Canadian data on the evolution of management approaches in a real-world setting. Data are needed to improve the current understanding of the treatment landscape of CLL. This retrospective observational cohort study used real-world, population-level data to describe the baseline characteristics, treatment patterns, clinical outcomes, and healthcare resource use of individuals diagnosed with CLL in Alberta, Canada. The study cohort included all individuals in Alberta over 18 diagnosed with CLL between 2010-2020 and who subsequently initiated systemic therapy. Data were collected through electronic health records and administrative databases. OS was defined as the date of diagnosis to death from any cause or last known contact with the health care system. A total of 890 individuals diagnosed with CLL between 2010-2020 who initiated first-line (1L) systemic therapy were included in the analyses. The mean age at initiation of 1L therapy was 69 years, and 68% were male. Among individuals who initiated 1L therapy in 2020+, the primary form of 1L systemic therapy was ibrutinib monotherapy (IBR) (29%), followed by bendamustine plus rituximab (BR) (21%). A considerable number of individuals did not initiate subsequent lines of therapy, with a drop of approximately 40-45% between each successive line. The treatment landscape changed over time, particularly with respect to decreased use of 1L fludarabine, cyclophosphamide, and rituximab (FCR; 40% in 2010-2013 vs. 9% in 2020+) and increased use of 1L IBR (6% in 2014-2017 vs. 29% in 2020+). Individuals treated at an academic centre were more likely to receive 1L IBR than those treated at a community centre. The median duration of 1L therapy was considerably longer for patients treated with targeted therapy (IBR: 9.8 months) compared to chemoimmunotherapy (BR: 5.6 months, FCR: 5.6 months). The majority of individuals did not initiate therapy immediately after diagnosis, with a median time from diagnosis to initiation of 1L therapy of 24 months (recognizing that the population described includes only those who initiated 1L therapy such that time to first therapy would be much longer for the entire CLL population). The time to next line of therapy (from the start of each line to the start of the subsequent line) was 17 months from 1L to second-line (2L), 14 months from 2L to third-line (3L), and 12 months from 3L to fourth-line. Median OS from initiation of 1L was 104 months, 2L was 70 months, and 3L was 64 months. On average, individuals had 39 healthcare encounters within the first year of initiating 1L systemic therapy, with an average of one hospitalization, six ambulatory care encounters, 25 non-cancer practitioner encounters, and seven cancer physician visits. The mean number of healthcare encounters within the first year of front-line therapy tended to decrease over time, which may be attributable to the changing treatment landscape. These findings highlight the rapid changes in CLL therapy that have occurred over the last decade. Our results demonstrate the significantly smaller cohorts of real-world patients receiving 2L or later therapies compared to 1L and highlight declining survival with subsequent lines of therapy, and a decreasing trend of healthcare resource use over time.

Optimizing Circulating Tumor DNA Limits of Detection for DLBCL during First Line Therapy

Background: Circulating tumor DNA (ctDNA) assessment is effective in diffuse large B-cell lymphoma (DLBCL) monitoring and risk stratification, with prognostic utility throughout first-line (1L) therapy. DLBCL ctDNA assays vary in analytical sensitivity, or limit of detection (LOD), which range from parts per thousand to below 1 part per million (1 in 10 6). With differing assays and time-points assessed in DLBCL studies, the relationship between analytical and clinical sensitivity for outcome prediction remains unclear. We assessed the prognostic ability of ctDNA at various LODs and used modeling strategies to project the efficacy of assays for minimal residual disease (MRD) detection. Methods: We previously reported a DLBCL dataset assessing plasma ctDNA before, during and after curative-intent 1L anthracycline-based treatment from multiple prospective studies, including RCHOP or EP[O]CH with acalabrutinib, lenalidomide, obinutuzumab, and polatuzumab (Roschewski et al. ASH 2022). In this study, ctDNA was evaluated by Phased Variant Enrichment Detection and Sequencing (PhasED-Seq, Foresight Diagnostics), a ctDNA MRD assay with LOD below 1 in 10 6. Samples from this study and a prospective DLBCL cohort treated with standard 1L therapy at Samsung Medical Center were considered in this analysis. We assessed the prognostic ability of ctDNA detection, considering LODs from 1 in 100 (10 2)to 1 in 10 6 to predict progression free survival (PFS) before, during and after 1L treatment. We assessed the desired sensitivity for ctDNA MRD during treatment by generating patient-specific log-linear models assuming exponential decay. We projected the distribution of variant allele frequencies (VAFs) during therapy from cycles 2 to 5 for patients who progressed to determine the minimal acceptable analytical sensitivity. Results: We included 230 patients consisting of 588 ctDNA samples, with 201 before therapy, 71 at C2D1, 101 at C3D1, 70 at C4D1 and 145 at end of therapy (EOT). Median follow-up was 17.5 months and 62 patients (27%) progressed. To evaluate the impact of LOD at treatment milestones, we applied a threshold for ctDNA positivity ranging from 1 in 10 2 to 1 in 10 6. Increased LOD had no effect on the performance of ctDNA before therapy (Figure A &amp; B). At C2D1, if the LOD was at least 1 in 10 4, there was no difference in MRD prognostic performance. Starting at C3D1, improving the LOD for ctDNA positivity down to 1 in 10 6 showed superior predictive power for PFS at 24 months. The power of ctDNA to predict PFS at 24 months improved later in therapy, with area under the receiver operator curves (AUROCs) for PFS24 of 0.68, 0.73, 0.77, 0.88, and 0.86, at pretreatment, C2D1, C3D1, C4D1, and EOT time-points respectively (Figure A). To further understand the desired LOD for ctDNA MRD, we developed personalized models of ctDNA VAFs. Exponential models fit the data well in 43/44 cases with ≥ 3 MRD-detectable samples through C4D1, with a median correlation of 0.91, confirming their utility for modeling ctDNA. We generated log-linear models for 106 patients with ≥ 2 MRD-detectable samples, and used log-fold change in VAF per cycle (i.e. the slope) to compare patients by progression. Median log-fold change in VAF per cycle was worse for patients who progressed at -1.1 (IQR -1.4, -0.7) compared to those who remained disease-free with median -1.5 (IQR -2.0, -1.1) (p&amp;lt;0.0001). Patients with primary refractory DLBCL on EOT imaging had less robust log-fold change per cycle with median of -0.9 (IQR -1.3, -0.5) compared to those who relapsed after CR with median -1.3 (IQR -1.7, -0.9) (p=0.0004). We used the distribution of slopes to project VAFs for cycles 2 to 5 for patients who progressed to determine the LODs that provide acceptable clinical sensitivity. We found the analytical sensitivity for detecting DLBCL extended lower for each cycle, demonstrating the need for a LOD at least 1 in 10 6 for robust MRD detection at late time-points during 1L treatment. Conclusion: When using an ultrasensitive assay, MRD assessment at later timepoints better predicts PFS than at early timepoints. While the technical LOD does not affect disease burden assessment before therapy, using more sensitive assays during and after therapy improves disease detection and outcome prediction. Utilizing the most sensitive ctDNA MRD assays in 1L DLBCL therapy will maximize the efficacy of MRD-driven therapeutic strategies and MRD as a surrogate endpoint in future trials.

Second-Line Chimeric Antigen Receptor T Cell Therapy (CAR-T) As Standard of Care for Relapsed-Refractory Large B-Cell Lymphoma (LBCL)

Introduction: The randomized registrational ZUMA-7 (Locke, NEJM 2022) and TRANSFORM (Kamdar, Lancet 2022) trials in second line (2L) LBCL showed superiority of CAR T when compared to standard of care (SOC) chemotherapy-based regimens with a goal of consolidative autologous stem cell transplant. These results led to the FDA approval of axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) in 2L for LBCL with refractory disease or relapse within 1 year of completing induction chemotherapy. Significant differences exist between the registrational trial patient population and the real-world commercial CAR-T recipients in 3L+ setting (Nastoupil, JCO 2020, Jacobson, JCO 2020). Herein, we describe the outcomes of patients with LBCL treated with 2L commercial CAR T therapy. Methods: Five US academic institutions contributed data to this retrospective study. CAR T associated toxicities were graded by ASTCT consensus grading criteria (Lee, TCT 2019) and investigator assessed responses were reported per Lugano 2014 criteria. Patients who received CAR T therapy in 2L after the histologic diagnosis of LBCL were included, with leukapheresis between SOC approval on 4/1/2022, and 4/25/23. Patients were included if they received intermediary therapies before CAR T-cell infusion. These intermediary therapies included disease-holding therapy, defined as therapy given between relapse and the time of leukapheresis, given with the intent to “hold” patients' disease under control until CAR T-cell therapy was arranged (Bucklein, Hemasphere 2023). Patients who received therapy after relapse with the intent of restaging to decide on subsequent CAR T-cell therapy were excluded. Patients who received bridging therapy, defined as therapy given between leukapheresis and the start of lymphodepleting (LD) chemotherapy were also included. Kaplan-Meier analysis was used to calculate median progression-free survival (PFS) and overall-survival (OS). Results: 112 patients were leukapheresed with intention to receive commercial CAR T as 2L (103 axi-cel, 9 liso-cel). All but two patients received CAR T infusion (one manufacturing failure and one delayed due to infection). The median follow-up of the cohort was 6.2 months (95%CI 4.32 - 7.61). Median age of the cohort was 66.5 yrs (range 23-83) with male predominance (66%). The median international prognostic index (IPI) score was 3 (range 0-5) and 72% of the patients had stage III/IV disease. Fifty-nine percent of the patients had primary refractory disease. The median time between documentation of progression after 1L therapy and patient evaluation for 2L CAR T was 22 days (IQR 15-32). The median time from patient evaluation to CAR T infusion was 47.5 days (IQR 36.25 - 67). Forty-two patients (37.5%) received disease-holding therapy and 77 (69%) received bridging therapy. Twenty-nine patients (26%), received both disease-holding therapy and bridging therapy. Receipt of these therapies was associated with longer CAR T evaluation-to-infusion times, with a median time of 61 days for patients who received both disease-holding therapy and bridging therapy, as opposed to 38 days for patients who didn't receive either therapy. This is presumably related to washout requirements and the time needed to allow for count recovery prior to either leukapheresis or LD therapy. Among 110 CAR T infused patients, cytokine release syndrome(CRS) occurred in 88% (n=97) of the patients with grade 3 or 4 in 6.3% (n=7). Immune effector cell associated neurologic syndrome (ICANS) occurred in 59% (n= 65) with grade 3 or 4 in 30% (n= 33). No deaths from CRS or ICANS were observed. Overall response rate (ORR) was 82.7% and complete remission rate was 61.8%. Median PFS and OS were not reached. Point estimates of PFS and OS at six months were 64.1% (95% CI: 52.8 - 73.4), and 84.4% (95% CI: 73.8 - 90.9), respectively ( Figure 1). Conclusions: This multicenter retrospective study provides insights into practice and outcomes of SOC CAR T therapy for 2L relapsed-refractory LBCL. In clinical practice, patients commonly receive “disease-holding therapy” to control disease while organizing CAR T-cell consultation and leukapheresis. Despite the relatively short follow-up duration, the best response and toxicity profiles were comparable to those observed in the pivotal clinical trials. Updated follow-up and subgroup analysis will be presented at the meeting. SD and JYS contributed equally.

Cytokine Release Syndrome and Neurological Event Management Resource Use and Costs Among Patients with Relapsed or Refractory Large B-Cell Lymphoma Who Received Second-Line Lisocabtagene Maraleucel Treatment in TRANSFORM and PILOT

Background:CAR T cell therapies are associated with cytokine release syndrome (CRS) and neurological events (NEs). Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. There is limited published research on AE management-related health care resource utilization (HCRU) and costs in the second-line (2L) setting. The objective of this study was toestimate HCRU and costs for managing CRS and/or NEs after liso-cel administration among patients with R/R large B-cell lymphoma (LBCL) treated with liso-cel as 2L therapy in the TRANSFORM (NCT03575351) and PILOT (NCT03483103) studies. Methods: A microcosting methodology was used to assess CRS and/or NE management-related HCRU identified from pooled TRANSFORM and PILOT case report forms and to estimate associated costs among patients who experienced CRS or NEs after liso-cel administration. CRS or NEs were only included if the AE initiated within 90 days after the patient received liso-cel. HCRU categories captured the following: facility (eg, standard inpatient hospitalizations and ICU admissions and length of stay [LOS]), procedures (eg, dialysis and mechanical ventilation), diagnostics (eg, laboratory, imaging, and biopsy), and medications (eg, oncology supportive care, prophylactics, and other AE management). In the nonconcurrent and concurrent CRS/NE categories, events were classified per the highest grade event. HCRU by grade, per the study's management guidelines, were identified from onset of the AE through resolution. Lee criteria were used to determine CRS event grades (Lee DW, et al. Blood 2014), while the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used to determine NE grades. Unit costs from publicly available data sources (United States [US] Centers for Medicare &amp; Medicaid Services, Healthcare Cost and Utilization Project, and IBM ® Micromedex ® RED BOOK ®) or published literature were applied to each HCRU after being adjusted to 2021 US dollars using the Consumer Price Index as needed. Analyses were stratified by grade and concurrency. Results: Among 150 patients treated with liso-cel, 92 (61%) experienced CRS and/or NEs, which were mostly grade ≤ 2 events (n = 76 [83%]). Most patients experienced CRS only (n = 34 [37%]) or NE only (n = 24 [26%]) that ranged in total median cost of $675 for grade 2 NE only to $35,181 for grade 2 CRS only (Figure). In the remaining patients, most experienced AEs concurrently (22/34 [65%]) vs nonconcurrent (12/34 [35%]) with total median costs ranging from $5018 for nonconcurrent grade ≤ 2 CRS/NE to $33,918 for concurrent grade ≥ 3 CRS/NE. Median total cost for grade ≥ 3 CRS/NE was equal to $24,219 versus $5312 for grade ≤ 2, reflecting an additional $18,907 or 356% increase in cost of grade ≥ 3 compared with grade ≤ 2. Facility and medications were the major contributors to CRS/NE management costs. Only 20% (18/92) of patients were hospitalized and 2% (2/92) of patients admitted to the ICU, with proportions higher among grade ≥ 3 CRS/NE than grade ≤ 2 (standard inpatient hospitalization: 6/16 [38%] vs 12/76 [16%]; ICU: 2/16 [13%] vs 0/76 [0%]; Table). Patients with grade ≥ 3 CRS/NE had a median total 4.5 days longer LOS than grade ≤ 2 (median [range], 9.5 [2-19] vs 5 [2-15], respectively). Some medication usage was also higher among patients with grade ≥ 3 CRS/NE compared with grade ≤ 2 (tocilizumab: 10/16 [63%] vs 26/76 [34%]; corticosteroids: 15/16 [94%] vs 39/76 [51%]; vasopressors: 1/16 [6%] vs 2/76 [3%]). No dialysis or mechanical ventilation was recorded for patients experiencing CRS/NE. Conclusions: Over half of patients with R/R LBCL experienced any-grade CRS and/or NEs after liso-cel administration in TRANSFORM and PILOT, and the majority of these (83%) were low grade. Resource use and costs for management of AEs among patients with less severe CRS/NEs were relatively minimal compared with patients who had more severe CRS/NEs (with the exception of a few outliers). In general, HCRU and costs increased with greater severity. These results are largely consistent to those for third-line-treated patients (Abramson JS, et al. Blood Adv 2021). Additionally, results presented here further support that CAR T cell therapies with low rates of CRS/NEs (and few events are of higher severity) have the potential to minimize AE management-related HCRU and costs among patients with LBCL.