Citations

4558 Background: In the past 7 years, 4 immuno-oncology (IO) based combinations have been approved for mRCC. However, QOL data on these combinations are limited to trials in which collection and reporting was not standardized, which further limits cross trial comparisons. Real-world QOL data with multiple treatment regimens are needed to understand how these regimens are tolerated in practice. Methods: ODYSSEY is a multi-site, prospective observational study of 500 US pts with mRCC. Pts must have mRCC (any histology), no prior ST, and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST. Of pts on ST, 114 were treated with IO-IO, 108 with IO-TKI, 33 with IO alone, 27 with Other, and 18 with TKI alone. Median follow up for all pts is 8.8 months (IQR 2.9, 16.2). IO-IO pts are median age 64 yrs, 81% male, 84% white, 56% prior nephrectomy, 84% clear cell; IO-TKI pts median age 66 yrs, 76% male, 92% white, 43% prior nephrectomy, 66% clear cell; IMDC risk profiles are similar. IO-IO pts are more likely to be KPS 100; whereas, IO-TKI pts have a higher median number of metastatic sites and are more likely to have bone or liver metastasis. With median follow-up of 6.0 (IQR 1.8, 14.9) and 8.8 months (4.5, 17.8) in the IO-IO and IO-TKI cohorts, 17 (15%) and 21 (19%) pts had died with a median time to death of 5.4 (2.5, 6.4) and 5.7 months (4.4, 12.8), respectively. 20 (18%) and 16 (15%) pts on IO-IO and IO-TKI had discontinued therapy at a median of 3.0 (IQR 2.0, 4.0) and 6.4 months (2.4, 13.0), respectively. Rates of discontinuation for disease progression and toxicity are similar. Baseline PROs for pts on ST are shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). Conclusions: In our prospective multi-center ODYSSEY study, we demonstrate that real world pts treated with contemporary ST have worse baseline QOL than those enrolled on pivotal RCTs. One-third of IO-IO and IO-TKI pts died or discontinued therapy within 6 months of initiation. Our data on real world vs RCT differences in baseline QOL may partially explain the limitations of current IO combination regimens in practice and support development of alternative treatment approaches. Instrument, Mean (SD) ODYSSEYIO-IO(N=114) CheckMate214(N=425) ODYSSEYIO-TKI(N=108) KEYNOTE426(N=402) CheckMate9ER(N=323) CLEAR(N=351) FKSI-19 total 56.0 (12.5) 60.1 (9.8) 53.8 (11.8) NA 58.7 (10.6) NA FKSI-DRS 27.5 (6.3) 30.7 (4.5) 27.0 (5.8) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 82.4 (16.7) 82.6 (15.0) 78.5 (16.0) NA NA NA

4553 Background: AS is a recognized strategy in select pts with mRCC to maximize QOL and delay potential toxicity of systemic therapy (ST); however, only 2 prospective studies of AS in mRCC have been published: only 1 with patient-reported outcomes (PRO) and none in the IO-TKI era. Methods: ODYSSEY is a prospective observational study of 500 US pts with mRCC. Eligible pts must have mRCC (any histology), no prior ST, age ≥19. Pts were excluded if treated for non-mRCC cancers or if not followed at a PCORnet study site. Pts completed QOL surveys at baseline, by phone every 3 months for 2 years and then every 6 months until end of follow up. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Here we report baseline pt characteristics in AS pts compared to ST pts, and baseline QOL differences between these cohorts. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST, and 93 pts deferred ST; of these, 53 pts (57%) were classified as AS. Pts on AS are median age 68 yrs, 66% male, 94% white, 81% clear cell, 50% favorable risk, 44% intermediate risk. Compared with ST pts, AS pts were more likely to have undergone nephrectomy (91% vs 53%), favorable risk profile (50% vs 15%), pancreatic metastasis (15% vs 5%), and longer time since RCC diagnosis (median 58 vs 3.3 months); and less likely to have bone, brain, or liver metastasis. After median 8.8 months follow-up (IQR 2.9, 16.2), 2 pts (4%) on AS had died compared with 45 pts (15%) on ST. One pt (2%) on AS started first-line therapy and 45 pts (15%) discontinued ST. Mean baseline QOL (FKSI-19 total, DRS and FACT-G) for AS and ST ODYSSEY pts is shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). ODYSSEY pts on AS had higher QOL for all measures compared with ODYSSEY pts on ST. FSKI-DRS was the same or lower for pts on AS compared to the pivotal trials, while ODYSSEY pts on ST had both lower FKSI-19 total and DRS. Conclusions: In our large prospective cohort from ODYSSEY, pts on AS had higher median QOL scores than pts on ST, but similar to those included in RCTs. These results suggest that some RCT pts could have benefitted from AS. Further follow up is needed to determine long term outcomes in pts on AS and how they respond to deferred ST. Clinical trial information: NCT04919122 . Instrument, Mean (SD) ODYSSEY AS (N=53) ODYSSEY ST (N=299) ODYSSEY Difference, AS vs ST (95% CI) CheckMate 214 (N=425) KEYNOTE 426 (N=402) CheckMate 9ER (N=323) CLEAR (N=351) FKSI-19 total 63.4 (9.2) 56.3 (12.5) 7.0(4.0, 10.1) 60.1 (9.8) NA 58.7 (10.6) NA FKSI-DRS 30.8 (4.2) 27.9 (6.0) 2.9(1.5, 4.7) 30.7 (4.5) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 87.9 (14.0) 82.4 (16.7) 5.6(1.1, 10.0) 82.6 (15.0) NA NA NA

4545 Background: The treatment landscape of front-line nccRCC has evolved with recent trials demonstrating the efficacy of combination systemic therapy. However, the efficacy of treatment after combination therapy is unknown. This study evaluates the efficacy of VEGF-based regimens in nccRCC patients (pts) previously treated with combination regimens. Methods: ORACLE is a real-world, multi-center, retrospective database that includes nccRCC patients that received combination systemic therapies (IO+IO, IO+VEGF and VEGF+ mTOR) in any line. Subsequent treatments were categorized as VEGF only regimens (cabozantinib vs other VEGF), IO+ VEGF and VEGF+ mTOR. The primary endpoint was objective response rate (ORR) assessed by investigator review using RECIST 1.1. Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving complete or partial responses or stable disease, time to treatment progression (TTP), calculated from the date of VEGF-based initiation to progression or last follow-up using the Kaplan-Meier method. Differences between groups were estimated with the log-rank test, and categorical outcomes were compared with the chi-square test. Results: 105 pts who received VEGF – based regimens after combination therapy were included in the analysis. Baseline characteristics: median age: 59years, 71 % male, 58% white, 25% black, 87% ECOG 0-2. IMDC-risk categories included:21% favorable, 59% intermediate and 20% poor risk. Histology included papillary (40%), unclassified (32%), chromophobe (16%) and other rare subtypes (12%). Prior combination therapies included IO+IO: 62%, IO+ VEGF: 34% and VEGF+ mTORi:4%. 70% pts received combination therapy in the first line setting while the remainder received combination therapy in a second or later line. Outcomes with subsequent treatments are described in Table1. IMDC risk score correlated with TTP. Conclusions: Modest antitumor activity was observed with VEGF- based approaches in combination therapy refractory nccRCC. Optimal management of nccRCC remains an unmet need. Outcomes of nccRCC patients by treatment and histologic type. Outcomes per Treatment n ORR (%) DCR (%) mTTP (mo.) Cabozantinib 56 18 47 3.6 VEGF/mTOR 19 16 42 9.3 IO+VEGF 17 29 47 5.6 Other VEGF 13 15 46 5.5 Outcomes per Histology Papillary 42 19 43 6.5 Unclassified 33 21 42 6.1 Chromophobe 17 29 59 8.9 Other * 13 0 46 NR

TPS2677 Background: Despite the success in hematologic malignancies, CAR T therapies face significant challenges in solid tumors due to the lack of tumor-specific targets that distinguish cancer from normal cells. EGFR plays a critical role in oncogenesis across several cancers and is often upregulated (TCGA 2022). While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin rash, which constrains dose escalation and efficacy (Macdonald, et al. J Am Acad Dermatol . 2015). A2B395 is an allogeneic, logic-gated, EGFR-targeted Tmod CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR, and a blocker targeting HLA-A*02. The activator recognizes EGFR on both tumor and normal cells, while the blocker inhibits CAR T activity against normal cells with preserved HLA expression and decreases the risk for graft-versus-host disease (Hamburger, et al. Mol Immunol . 2020). To address potential host-vs-graft response, an shRNA expression module targeting B2M is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response (DiAndreth, et al. Clin Immunol. 2022). Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy (Grierson, et al. SITC 2024. Abstract 588). A2B395 represents a novel approach for EGFR-expressing solid tumors with HLA-A*02 LOH. Methods: DENALI-1 (NCT06682793) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease via next-generation sequencing (Tempus AI, Inc.). Key inclusion criteria include histologically confirmed recurrent unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including colorectal, non-small cell lung, squamous cell head and neck, triple negative breast, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of phase 1 is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm RP2D and collect biomarker data. Phase 2 will assess overall response rate per RECIST v1.1. Clinical trial information: NCT06682793 .

Abstract Bipolar Disorder (BD) is a highly complex and heterogeneous disorder. As such, accurate diagnosis is often delayed, and effective treatment options are limited. The Integrated Network, a program of Breakthrough Discoveries for thriving with Bipolar Disorder (BD 2 ), was designed as a platform for longitudinal deep phenotyping of a diverse group of people with bipolar disorder to define disease trajectories and to gain insight into the biological drivers of the illness. Biosamples, including whole blood, serum, plasma, and peripheral blood mononuclear cells (PBMCs) will be collected longitudinally and will also be made available. The Integrated Network is designed to be the largest and most comprehensive prospective longitudinal study conducted in bipolar disorder, allowing for the development of precision-based treatment strategies that optimize quality of life for people living with bipolar disorder.

Introduction: Machine learning (ML) has become increasingly pivotal in health care, particularly in colorectal cancer (CRC) detection and diagnosis with the use of predictive models and artificial intelligence-assisted colonoscopies. This study evaluates the efficacy of ML models in predicting the risk for CRC and advanced colorectal polyps (ACP) before colonoscopy. Methods: A systematic literature review was conducted following PRISMA guidelines, focusing on studies using ML for CRC and ACP prediction. Data extraction regarding study type, ML methodology, quality of data, and bias assessment was in line with the CHARMS checklist. Meta-analysis was also performed to assess the performance of models for the prediction of CRC, adenoma, or both. Results: This systematic review included 14 studies with 3618 median patients (333 to 263,879). Our study demonstrated considerable heterogeneity in methodologies and outcomes, with area under the receiver operating characteristic (AUROC) ranging from 0.6 to 1. The derivation+validation cohorts showed a pooled sensitivity of 0.832 (95% CI: 0.755-0.889) and specificity of 0.802 (95% CI: 0.722-0.863), with an overall AUROC of 0.883. Conclusion: The review underscores the significant role of ML in CRC and ACP diagnosis and its routine use could efficiently direct high-risk patients to timely colonoscopies and spare the low-risk ones from unnecessary procedures. Despite the promise shown, the variability in methodologies and outcomes highlights the need for standardized approaches and further investigation in this field.

501 Background: EA1181 (NCT04266249) is a single-arm trial of neoadjuvant THP for patients with clinical anatomic stage II/III HER2+ breast cancer; patients with cT4 or cN3 disease were excluded . Assessing the primary endpoint, 3-year recurrence-free survival in patients with a pCR (ypT0/Tis, ypN0), requires longer follow-up. Here, we present results for the secondary objective of pCR rate and its relation to clinicopathologic factors and the HER2DX pCR likelihood score (Reveal Genomics) derived from gene expression and clinical features. Methods: Patients received 4 cycles of trastuzumab and pertuzumab (HP) with weekly paclitaxel (12 weeks) or docetaxel (q3w x 4), followed by surgery. Clinicopathologic features were assessed for all patients and HER2DX pCR score (stratified by ER status) was determined using the diagnostic biopsy in a representative subset of study participants. Results: 2175 patients were enrolled. Median age was 55 years (range 22-88 years); 58% had clinical stage IIA, 33% stage IIB, and 9% stage III. 45% had nodal involvement (mostly cN1). 781 tumors were HER2+/ER- and 1394 HER2+/ER+ (locally tested ). 2141 patients started THP, for whom the pCR rate was 44% overall, 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Disease progressed during THP in 16 patients (0.7%). The pCR rate varied inversely to the proportion of cells staining for ER among patients with HER2+/ER+ breast cancer: 1-10%+, 62.5%; 11-69%, 51.6%; ≥70%, 22.5% (p <0.001). The pCR rate was significantly associated with higher grade, especially in HER2+/ER+ disease. T and N stage did not significantly affect pCR rate. Among 569 patients assessed for the HER2DX pCR score, the pCR rate was significantly greater for patients with a higher vs lower score, regardless of ER status (Table). Further correlations and interactions will be presented. Conclusions: Neoadjuvant THP resulted in pCR in nearly two-thirds of pts with clinical stage II/III HER2+/ER- and in one-third with HER2+/ER+ breast cancer. There was no association with clinical stage. Lower ER expression and higher grade were associated with higher pCR rates. The HER2DX pCR score was a significant predictor of pCR, regardless of ER status. Clinical trial information: NCT04266249 . All Participants HER2+/ER- HER2+/ER+ # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) Evaluable Cohort 2141 44%(42-46%) 774 64%(60-67%) 1367 32%(30-35%) HER2DX Cohort 569 48%(44- 52%) 230 69% (63-75%) 339 34%(29-39%) HER2DX pCR-high score 182 (32%) 68%(60-74%) 147 (64%) 70% (62-77%) 36 (11%) 58%(41-74%) HER2DX pCR-medium score 161 (28%) 67% (59- 74%) 70 (30%) 74%(62- 84%) 89 (26%) 61%(50-71%) HER2DX pCR-low score 226 (40%) 19%(14- 25%) 13 (6%) 31%(9-61%) 214 (63%) 18%(13-24%) P-value HER2DX score <0.001 0.010 <0.001

Abstract Case: A 42-year-old African-American woman sustained a type IIIA open pilon fracture requiring open reduction internal fixation complicated by wound dehiscence. Acute shortening for primary wound closure was performed followed by relengthening in a circular frame. Owing to the patient's intolerance to the circular frame, pre-existing osseous deformity, large body habitus, and soft tissue compromise, conversion to intramedullary stabilization with standard nailing was deemed exceedingly difficult. We describe the use of a photodynamic bone stabilization system allowing for percutaneous entry and implant flexibility for the purpose of early circular frame removal. Conclusion: This case demonstrates successful protection of immature regenerate using a photodynamic bone stabilization system, offering another tool to minimize time spent in a circular frame.

e18600 Background: Recent studies have suggested that basophilia in myeloproliferative neoplasms (MPN), in general, and in primary myelofibrosis (PMF), in particular, might be associated with poor prognosis. In the current study, we examined for clinical and genotype correlates as well as the prognostic impact of absolute eosinophil (AEC) and basophil (ABC) counts in essential thrombocythemia (ET) and polycythemia vera (PV). Methods: Diagnostic criteria were according to the International Consensus Classification. Study patients were selected based on the availability of information on AEC and ABC. Institutional reference range for AEC was 0.03 to 0.48 x 10 9 /L and for ABC 0.01 to 0.08 x 10 9 /L. "Eosinophilia" was defined as an AEC of ≥0.5 x 10 9 /L. "Basophilia" was evaluated both at an ABC of ≥0.1 x 10 9 /L and ABC of ≥0.3 x 10 9 /L, the latter representing 3 x the upper limit of the normal reference range. Results: Essential thrombocythemia 660 patients were considered. Median (range) values for AEC and ABC were 0.2 x 10 9 /L (0-2.8) and 0.07 x 10 9 /L (0-1.7), respectively. On univariate analysis, AEC and ABC, as continuous variables, were predictive of inferior overall (OS; p<0.01 for both) but not leukemia-free (LFS), myelofibrosis-free (MFFS), venous thrombosis-free (VTFS), or arterial thrombosis-free (ATFS) survival. In univariable analysis, AEC ≥0.5 x 10⁹/L and ABC ≥0.1 x 10⁹/L negatively impacted OS (p<0.01 for both); significance was sustained during multivariate analysis that included IPSET risk variables: AEC ≥0.5 x 10⁹/L (p<0.01; HR 1.9) and ABC ≥0.1 x 10 9 /L (p<0.01; HR 1.7). Polycythemia vera 478 patients were considered. Median (range) values for AEC and ABC were 0.27 x 10 9 /L (0-6.5) and 0.12 x 10 9 /L (0-3.2), respectively. In univariable analysis, neither AEC nor ABC, as continuous variables were predictive of OS, LFS, MFFS, VTFS, or ATFS. AEC ≥0.5 x 10⁹/L also did not have any impact on disease progression or thromboses. However, ABC ≥0.1 x 10 9 /L was associated with a lower risk of post-diagnosis arterial thrombosis (p=0.03; HR 0.6), and ABC ≥0.3 x 10 9 /L was predictive of inferior LFS (p<0.01; HR 6.5) and MFFS (p<0.01; HR 2.5). ABC ≥0.3 x 10 9 /L sustained prognostic relevance in LFS (p<0.01; HR 7.6) during multivariable analysis that included leukocytosis, platelet count, basophil percentage, age, and palpable splenomegaly. Similar findings were noted with regards to MFFS for ABC ≥0.3 x 10 9 /L (p=0.01; HR 2.3) when compared against palpable splenomegaly and age. Conclusions: The current study suggests that AEC ≥0.5 x 10 9 /L and ABC ≥0.1 x 10 9 /L in ET are independently associated with shortened overall survival, while basophilia (ABC ≥0.3 x 10 9 /L) in PV is an independent predictor of leukemic and myelofibrotic disease progression.

Abstract Regenerative medicine is a rapidly advancing field, particularly within the field of physical medicine and rehabilitation. While orthobiologics are currently being used in clinical practice, there remains a need for high-quality clinical trials and translational research to standardize treatments and improve patient outcomes. Education is vital for streamlining development of evidence-based, practical, and effective treatments. In this article, we highlight the need for a 1-yr advanced fellowship in translational orthobiologics aiming to create a standardized core curriculum targeting physicians involved in treating musculoskeletal diseases. The fellowship’s objectives include advancing translational orthobiologics research, ethical considerations, and promoting effective communication regarding orthobiologic therapies. Such a program would serve as a foundation for physicians interested in conducting clinically oriented orthobiologics research for musculoskeletal disorders while improving the development of safe and effective therapeutics related to musculoskeletal disorders.