Citations

7507 Background: CARTITUDE-1 evaluated cilta-cel in pts with heavily pretreated RRMM who historically have an expected median progression-free survival (PFS) of <6 months (mo) and median overall survival (OS) of ~1 year (y). At 33.4 mo median follow-up, median PFS was 34.9 mo, and median OS was not reached (36-mo OS rate, 62.9%; Lin et al, ASCO 2023). We report OS, ≥5 y progression-free outcomes, and safety with a median study follow-up of 60.3 mo. Methods: Pts in CARTITUDE-1 received a single cilta-cel infusion. Correlative analyses were performed utilizing drug product, baseline, and postinfusion samples. Pts are followed for progression, survival, and safety in a 15-y follow-up study, CARTinue (NCT05201781), with pt evaluations per local standard of care (reported annually at a minimum). Results: Of 97 pts treated, 32 (33.0%) remain alive and progression free for ≥5 y after cilta-cel, without further MM treatment. For these 32 pts, prior to enrollment in CARTITUDE-1, median time from start of last line of therapy (LOT) to progression was 4.0 mo (range, 0.7–48.6). Among the 32, median age was 60 y (range, 43–78), median number of prior LOT was 6.5 (range, 3–14), 23.3% had high risk cytogenetics, 12.5% had extramedullary disease (EMD), 90.6% were triple-class refractory, and 46.9% were penta-drug refractory. Baseline characteristics of pts who were progression free for ≥5 y, including those with high-risk cytogenetics and EMD, were comparable to pts with progressive disease (PD) within 5 y. Compared with pts who had PD within 5 y, biomarkers significantly associated with ≥5 y progression free status included a higher fraction of naïve T cells in the drug product, lower neutrophil to T cell ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio (Cmax to sBCMA at baseline). At Cmax, these pts also had significantly higher CD4 central memory CAR+ T cell subsets and CAR+ T cells that were positive for the activation markers CD38, CD25, and PD-1. Data were collected on a subset of pts from a single center where local serial MRD assessments were performed. All 12 pts at this center who were progression free for ≥5 y were MRD negative at 10 –6 and imaging negative by PET/CT yearly for 5 y. Overall, at 60.3 mo median follow-up in CARTITUDE-1 (N=97), median OS was 60.6 mo (95% CI, 41.9–NE). With continued follow-up, 3 additional pts reported a second primary malignancy (1 of which was acute myeloid leukemia; onset, 2.8 y after infusion). No new cases of movement and neurocognitive disorders were reported. Conclusions: The median OS for pts enrolled in CARTITUDE-1 was 5 y, and 33% of pts remain progression free for ≥5 y following a single cilta-cel infusion. These data provide the first evidence that cilta-cel is potentially curative in pts with RRMM. Clinical trial information: NCT03548207 , NCT05201781 .

5060 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) in men with BRCA-mutated chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) vs a control arm of physician’s choice of therapy (docetaxel or androgen-receptor pathway inhibitor [ARPI] therapy: abiraterone acetate or enzalutamide) in the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study. Herein, we conducted an analysis to determine the impact of germline vs somatic mutation status on the efficacy of rucaparib. Methods: Patients were randomized 2:1 to receive rucaparib 600 mg BID or physician’s choice of docetaxel or ARPI following progression while on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Color Health did genetic testing. Treatment-emergent adverse events (TEAEs) were reported for the BRCA subgroup. Results: In the rucaparib arm, 201/270 patients had BRCA mutations, and in the physician’s choice arm, 101/135 patients had BRCA mutations. Of patients with BRCA mutations: in the rucaparib arm, 80/201 (40%) were germline and 116/201 (58%) were somatic with 5/201 (2%) BRCA mutation status unknown, while in the physician’s choice arm, 39/101 (39%) were germline and 48/101 (48%) were somatic with 14/101 (14%) BRCA mutation status unknown. rPFS was significantly improved with rucaparib treatment vs physician’s choice in both the germline and somatic mutation groups (germline: HR, 0.52 [95% CI, 0.32–0.84]; somatic: HR, 0.38 [95% CI, 0.25–0.59]). Incidence rates of TEAEs were similar overall between patients with germline and somatic BRCA mutations in both arms. Conclusions: Rucaparib improves progression-free survival for patients with mCRPC with either germline or somatic BRCA mutations with a manageable safety profile. These data support the use of rucaparib as a beneficial treatment option for patients with BRCA-mutated mCRPC with germline or somatic mutations. Clinical trial information: NCT02975934 .

1510 Background: The National Comprehensive Cancer Network (NCCN) Harmonized Guidelines for Sub-Saharan Africa (SSA) have emerged as leading cancer treatment guidelines in SSA. The NCCN-SSA guidelines, derived by adapting NCCN guidelines for the SSA context, offer standardized recommendations to guide cancer care and shape policy in SSA. This study examines the evidence cited in support of the NCCN-SSA guidelines, with a focus on population characteristics and generalizability to SSA. Methods: Two reviewers independently examined the NCCN-SSA guidelines for the eight most common cancers in SSA to identify all studies cited in support of treatment/management recommendations. Study selection discrepancies were resolved by discussion. Full-text articles were reviewed and data on age, sex, race, and recruitment geography were abstracted. Descriptive analyses were performed using R statistical software. Results: Overall, 4,589 citations were reviewed, and 2,938 (64.0%) studies with individual-level data were included, representing >10.4 million study participants. Of the 2,061 studies reporting geographic information (70%), 50 (2.4%) recruited in SSA; of these, 39 (83.0%) recruited from South Africa. Three studies (0.2%) recruited exclusively in SSA. Most studies (95.3%) recruited exclusively from high or upper-middle income countries. Only 29.2% of studies with race data included >10% Black study participants. Conclusions: Most studies cited in the NCCN-SSA guidelines were conducted in high-income countries outside SSA. A small minority of all study participants were Black. Our findings underscore potential limitations in the generalizability of the NCCN-SSA guidelines to SSA and highlight a pressing need to generate and incorporate context-specific data to guide care and inform policy. WHO region of recruitment, race, and country-level income of studies included in NCCN-SSA guidelines. Cancer type # (%) studies reporting geography # (%) studies by recruitment region*: Americas # (%) studies by recruitment region*: Europe # (%) studies by recruitment region*: Sub-Sah. Africa % participants, White % participants, Black % participants, Other race # (%) studies representing only HMIC (per World Bank) Overall 2061(70%) 1177 (57%) 921 (45%) 50 (2%) 79% 9% 11% 1964(95%) B-cell 325(57%) 173 (53%) 178 (55%) 5(2%) 82% 7% 10% 307(94%) Breast 206(44%) 123 (60%) 124 (60%) 12 (6%) 80% 9% 11% 179(87%) Cervical 163(90%) 100 (61 %) 44(27%) 3(2%) 64% 14% 22% 158(97%) Colorectal 584(82%) 278 (48%) 292 (50%) 11 (2%) 80% 10% 10% 571 (98%) Hepato-cellular 183(74%) 80(44%) 68(37%) 0(0%) 69% 9% 22% 169(92 %) Kaposi sarcoma 51(80%) 25 (49%) 19(37%) 5(10%) 38% 51% 10% 44(86%) Ovarian 115(56%) 76 (66%) 35 (30%) 0(0%) 83% 4% 13% 115(100%) Prostate 434(88 %) 322 (74 %) 161 (37%) 14 (3%) 79% 9% 12% 421(97%) HMIC = high and upper-middle income countries. *Percent of studies includes as the denominator only the number of studies with reported geographies.

1015 Background: T-DXd is an antibody-drug conjugate approved for advanced HER2+/low/ultra-low breast cancer and multiple other solid tumors. T-DXd carries a rare but serious risk of ILD (incidence 12-15%), requiring frequent imaging and symptom evaluation. For > grade (G) 2 ILD, guidelines recommend permanent drug discontinuation. For asymptomatic G1 ILD, drug is held with the option for rechallenge (RC) if imaging findings resolve. Limited data exist on outcomes of RC after ILD in diverse real-world patients (pts). Methods: In this multi-center retrospective study, we analyzed pts with T-DXd related ILD treated from 2017-2024. Pts with ILD were identified via chart/ICD code review. Adjudication of T-DXd related ILD was based on treating providers’ assessment and graded via CTCAE v5. We collected pt demographics, T-DXd and steroid dosing, imaging results, and outcomes after RC. Statistical analysis was performed using Wilcoxon rank sum and Fisher’s exact tests. Results: Four centers treated 712 pts with T-DXd, with a 9.1% rate of any grade ILD (n=65). One other center reported only RC data in 18 pts with ILD. In total, 47 pts were RC; 38 after G1 ILD (81%), 9 after G2. Median (med) time to initial ILD was 145 days (d) after 1st dose (interquartile range [IQR] 78-205). Demographics for pts RC are shown in the table. Among 50 pts with G1 ILD, including pts not RC, 28/50 (56%) received steroids for a med of 36d (IQR 27-79). Radiographic improvement was seen at a med of 24d (IQR 19-63) for pts treated with steroids vs 82d (IQR 48-94) without (p<0.01); and a med of 35d (IQR 22-82) for pts RC vs 81d (IQR 68-105) for pts not RC (p=0.01). Among pts with G1 ILD, 38/50 (76%) were RC at a med of 42d (IQR 36-57) from last dose; 23/38 (61%) were dose reduced. After RC, pts remained on T-DXd for a med of 215d (IQR 60-334); 10/38 (26%) developed recurrent ILD (7-G1, 2-G2, 1-G3) at a med of 211d (IQR 47-273) from RC. No statistically significant differences were seen between ILD onset, time to RC, or demographics for pts with recurrent ILD vs not. Of the 9 pts RC after G2 ILD, T-DXd was continued for a med of 129d (IQR 49-171); 2/9 (22%) developed recurrent ILD (1-G2, 1-G3). No G5 toxicity was seen with RC. Conclusions: In this multi-center study, high RC rates were seen after G1 ILD with long duration of clinical benefit. Pts treated with steroids had faster radiographic ILD improvement, highlighting the importance of early steroid use. Among pts RC after G1 ILD, recurrent ILD rates were low, with the majority G1 and no G5 events. Notably, 9 pts with G2 ILD were RC, with a similar rate of recurrent ILD; this must be interpreted cautiously. Our large cohort data further supports the safety of T-DXd RC in diverse real-world settings. RC Pt Characteristics (n=47) n (%) or Median (IQR) Cancer typeBreastGIGyn 43 (91)3 (6)1 (2) Age (yrs) 57 (52-68) Prior # therapy lines in the advanced/metastatic setting 3 (1-5) Renal impairment (CrCl < 60 mL/min) 8 (17)

4516 Background: Ipilimumab/nivolumab (ipi/nivo) is a standard of care first-line treatment (tx) for patients (pts) with mccRCC; however, ideal timing of subsequent immunotherapy txs are not well defined. We performed an analysis of patients initially treated with ipi/nivo and subsequent cohort assignments on PDIGREE (A031704). Methods: The PDIGREE trial treated pts with IMDC intermediate/poor risk mccRCC with first-line ipi/nivo (Step 1) at NCTN sites (categorized as academic (A), academic regional (R), and community (C)). Subsequent management was based on iRECIST responses at 12 weeks: pts with complete response (CR) received 1-year nivo maintenance; pts with progressive disease (PD) received cabozantinib (cabo) monotherapy, pts with non-CR/non-PD were randomized to nivo with or without cabo (for primary endpoint of overall survival [OS], target sample size was 1175). Enrollment was held when the randomized sample target was reached. Pts with unresolved toxicity at week 22 were managed off protocol. Step 1 pt demographics, assignments into Step 2, and adverse event (AE) data are presented. Descriptive statistics were used, and cohorts were compared using a chi-square test. These data were released with DSMB approval and do not inform the primary OS endpoint (1EP). Results: From May 2019 to May 2024, 1111 pts were enrolled and treated with ipi/nivo. Pt characteristics included median age 64.0 years (range 29.0-86.0); 819 (73.7%) males; White (85.1%), Hispanic (10.4%), Black (4.2%), and American Indian/Native Hawaiian (1.3%); 849 (76.8%) intermediate risk/257 (23.2%) poor risk; 458 (41.2%) at Academic, 113 (10.2%) at Regional, and 540 (48.6%) at Community centers; and 603 (54.3%) with de novo metastases. 364 pts (33%) stopped tx in Step 1: 160 (44%) for AEs, 46 (13%) for PD/clinical PD/suspected PD, 42 (12%) withdrawals, 39 (11%) alternative txs, 37 (10%) deaths on the study, 12 (3%) other complicating disease, 8 (2%) MD decision and 19 (5%) other reasons. Of the 37 deaths, 15 (1.4%) grade 5 SAEs were reported, 6 of which were due to PD. Of 747 (67%) pts registered to Step 2 at 3 months, 9 (1.2%) achieved CR, and 141 (18.9%) pts were assigned to the PD cohort. 597 pts (80%) were randomized for the 1EP, notable with fewer pts with poor risk [(21 vs 27%, p = 0.01] and bone metastases [24.5% vs 34.2%, p = 0.0007] compared to Step 1 pts who discontinued tx. Gr 3/4 tx-related AEs in 314/1093 (29%) evaluable pts included diarrhea/colitis (8%), transaminase elevation (3%), rash (2%), adrenal insufficiency (2%), fatigue (2%), and hypophysitis (1%). Conclusions: The PDIGREE trial enrolled a representative US-based population with mccRCC. Step 1 pt characteristics and associated outcomes with induction ipi/nivo reveal new insights into the tolerability and tx response of 1L ipi/nivo. Clinical trial information: NCT03793166 .

AbstractPatients with resectable Ewing sarcoma (ES) in select sites, such as the pelvis or chest wall, have a higher risk of positive microscopic margins following surgery. AEWS1031 was the first North American/Australasia ES cooperative group trial allowing standardized preoperative radiotherapy, intended to minimize the morbidity of combined modality local tumor control as well as improve the likelihood of clear surgical margins. In this study, we found that the use of low‐dose preoperative radiation to a smaller target volume resulted in a high rate of R0 resection. The robust pathologic response rate strengthens existing evidence illustrating the radiosensitivity of Ewing sarcoma.

BACKGROUND AND OBJECTIVES: Despite many publications about cavernous malformations (CMs), controversy remains regarding diagnostic and management strategies. To update evidence-based guidelines for the clinical management of brain and spinal cord CMs. METHODS: The Alliance to Cure CMs, the patient support group in the United States advocating on behalf of patients and research in CM, convened a multidisciplinary writing group comprising expert CM clinicians to help summarize the existing literature related to the clinical care of CM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and imaging standards, (4) neurosurgical considerations, and (5) neurological considerations. Building on prior evidence-based recommendations reflecting literature review through October 2014, the group conducted a systematic review of the more recent literature, identified references for mandatory citation, rated evidence, developed recommendations, and established consensus according to a prespecified protocol. Finally, the writing group outlined remaining knowledge gaps and controversies to guide future research. RESULTS: From 2672 publications published between October 1, 2014, and March 15, 2023, and meeting key word criteria, 234 were selected based on prearticulated criteria for mandatory consideration in evidence-based recommendations. Topic authors used these and other supporting references to summarize current knowledge and arrive at 53 management recommendations, with unanimous consensus based on a Delphi process. These were rated by class (strength of recommendation) and level (quality of evidence) per the American Heart Association/American Stroke Association criteria. Eighteen recommendations were class 1 (34%), class 2 in 31 (58%), and class 3 in 4 (8%). Three were level A (6%), 19 (36%) were level B, and 31 (58%) were level C. CONCLUSION: Current evidence supports prior and new recommendations for the management of CMs, but many reflect moderate classes and low levels, mandating further research to better inform clinical practice.

Background: Major League Baseball (MLB) recently instituted a combine for their prospective players. Purpose/Hypothesis: The purpose of this study was to report initial epidemiological findings for both physical examination and imaging findings for the MLB Combine. It was hypothesized that most players would have no significant abnormal physical examination findings, but most would have abnormal findings on their shoulder and elbow magnetic resonance imaging (MRI) scans. Study Design: Descriptive epidemiology study. Methods: All players who attended the 2023 MLB Combine were included. History was taken and physical examination was performed by an MLB team physician, and MRI of the shoulder, elbow, cervical spine, and lumbar spine was performed on all players and read by 1 of 2 musculoskeletal radiologists. Physical examination notes and imaging reports were reviewed by the authors and recorded. Data were analyzed separately for pitchers and position players. Results: Overall, 219 players (112 pitchers [51%], 107 position players [49%]) were included. The mean age was 20.4 ± 1.5 years. The majority of players (95%) had no current pain or limitations; 54 players (25%) had a history of previous surgery. For pitchers, 18% underwent previous elbow surgery. With regard to MRI, >80% of pitchers had some abnormality within their ulnar collateral ligament (UCL), the majority of which was UCL scarring/remodeling. 70% of pitchers and 60% of position players had evidence of an olecranon osteophyte. Increased signal within the ulnar nerve was common in pitchers (40%) but rare in position players (4%). For the shoulder, 95% of pitchers and 93% of position players had some rotator cuff abnormality (often tendinosis within the supraspinatus and infraspinatus muscles). Also, 75% of pitchers had MRI evidence of a superior labrum anterior to posterior (SLAP) tear, while 24% of position players demonstrated this. Lumbar spine MRI showed that 47% of position players had a disk protrusion and 46% had a previous pars fracture. Conclusion: Most baseball players who participated in the 2023 MLB Combine had MRI evidence of rotator cuff abnormalities, and many showed evidence of an olecranon osteophyte. Eighteen percent of pitchers had a previous history of elbow surgery. The majority of pitchers had some abnormality within their UCL and evidence of a SLAP tear on MRI scans.

Abstract The past decade has witnessed remarkable advances in deciphering the pathophysiology of acute lymphoblastic leukemia (ALL) and in developing novel targeted therapies. Basic research and genomic mapping have identified new prognostic biomarkers, targets, and ALL subtypes (e.g., Philadelphia‐like ALL). The ongoing therapeutic revolution in ALL is driven by the addition to the treatment arsenal of therapies that target the ABL fusions, like the BCR::ABL1 tyrosine kinase inhibitors, as well as novel agents that target CD19 and CD22: the CD22 antibody–drug conjugate inotuzumab ozogamicin, the bispecific CD3/CD19 T‐cell engager antibody blinatumomab, and CD19 chimeric antigen receptor T‐cell therapies. These combinations have improved the long‐term survival rates in B‐cell ALL to 70%, and in Philadelphia chromosome‐positive ALL to 80%–90%. The desired goals are to achieve cure rates comparable to those in pediatric ALL and to reduce or eliminate the need for prolonged intensive/maintenance chemotherapy and associated toxicities.

Abstract An individual participant data (IPD) meta-analysis can assess the predictive value of data on outcomes at the individual level, offering a potential tool for developing personalized pain management. Pretreatment quantitative sensory testing (QST) may stratify patient groups, which are then linked to treatment outcomes. Our objective was to determine if measures of QST at baseline are related to treatment outcomes (at any time point) for pain and disability in lower-limb osteoarthritis. We performed a systematic review with an IPD meta-analysis. Searches were conducted in 9 databases until May 5, 2023 for intervention studies that measured baseline QST and longitudinal measures of participant-reported pain and disability. We performed a 2-stage approach to analyse longitudinal data. Individual models were fitted to each study and combined using random effects multivariate meta-analytic models. Study quality was assessed using the Joanna Briggs Institute checklist, and certainty of the evidence was assessed using GRADE. We identified 3082 records and included 1 hip and 28 knee datasets consisting of 2522 participants from 40 studies. Local warm detection thresholds (P = 0.024) predicted knee osteoarthritis pain outcomes (very-low certainty). Local warm detection thresholds (P = 0.030), remote cold detection thresholds (P = 0.05), and remote pressure tolerance thresholds (P = 0.007) predicted knee osteoarthritis disability outcomes (very-low certainty). Other QST variables were associated with hip and knee osteoarthritis pain and disability levels (eg, pressure pain thresholds), but this relationship did not change over time. This review finds that mechanism-based, QST methodologies do not consistently predict pain or disability on an individual level in hip or knee osteoarthritis.