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PURPOSE Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)–dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development. PATIENTS AND METHODS This phase I (phI)/phase II (phII) open-label study (ClinicalTrials.gov identifier: NCT03604692 ) evaluated safety, tolerability, and efficacy of axatilimab in patients age ≥ 6 years with active cGVHD after ≥ 2 prior systemic therapy lines. Primary objectives in phI were to identify the optimal biologic and recommended phII dose and in phII to evaluate the overall (complete and partial) response rate (ORR) at the start of treatment cycle 7. RESULTS Forty enrolled patients (17 phI; 23 phII) received at least one axatilimab dose. In phI, a dose of 3 mg/kg given once every 4 weeks met the optimal biologic dose definition. Two dose-limiting toxicities occurred at the 3 mg/kg dose given once every 2 weeks. At least one treatment-related adverse event (TRAE) was observed in 30 patients with grade ≥ 3 TRAEs in eight patients, the majority known on-target effects of CSF-1R inhibition. No cytomegalovirus reactivations occurred. With the 50% ORR at cycle 7 day 1, the phII cohort met the primary efficacy end point. Furthermore, the ORR in the first six cycles, an end point supporting regulatory approvals, was 82%. Responses were seen in all affected organs regardless of prior therapy. Fifty-eight percent of patients reported significant improvement in cGVHD-related symptoms using the Lee Symptom Scale. On-target activity of axatilimab was suggested by the decrease in skin CSF-1R–expressing macrophages. CONCLUSION Targeting profibrotic macrophages with axatilimab is a therapeutically promising novel strategy with a favorable safety profile for refractory cGVHD.

PURPOSE Blood or marrow transplantation (BMT) is an integral part of consolidation and/or salvage therapy for patients with acute myeloid leukemia (AML). With the growing population of AML survivors, there is a need to understand the quality of their survival. MATERIALS AND METHODS This multisite study included 1,369 2-year survivors who underwent BMT for AML between 1974 and 2014 at age ≥ 21 years and 1,310 siblings. Using Common Terminology Criteria for Adverse Events, severe/life-threatening and fatal chronic health conditions were identified. Multivariable regression analysis was used to compare the risk of severe/life-threatening conditions and health status between survivors and siblings, and to identify risk factors for health conditions among BMT survivors. RESULTS The prevalence of severe/life-threatening conditions was 54.9% in BMT survivors compared with 28.5% in siblings ( P < .001), yielding 3.8-fold higher odds of severe/life-threatening conditions (95% CI, 3.1 to 4.7) among the BMT survivors. The most prevalent conditions included subsequent neoplasms, diabetes, cataracts, venous thromboembolism, and joint replacement. Survivors were more likely to report poor general health (odds ratio [OR], 3.8; 95% CI, 2.8 to 5.1), activity limitation (OR, 3.7; 95% CI, 3.0 to 4.5), and functional impairment (OR, 2.9; 95% CI, 2.3 to 3.6). Among BMT recipients, the 20-year cumulative incidence of severe/life-threatening/fatal conditions was 68%. History of chronic graft-versus-host disease was associated with a higher risk of pulmonary disease (hazard ratio [HR], 3.1; 95% CI, 1.0 to 9.3), cataract (HR, 2.6; 95% CI, 1.4 to 3.8), and venous thromboembolism (HR, 2.3; 95% CI, 1.3 to 4.7). Relapse-related mortality (RRM) plateaued at 30%, whereas non-RRM increased to 50% at 30 years. CONCLUSION The burden of severe/life-threatening conditions is substantially higher in BMT recipients when compared with an unaffected comparison group, contributing to an increasing incidence of non-RRM over time. Chronic graft-versus-host disease was an important risk factor for severe/life-threatening/fatal conditions among BMT recipients, informing the need for close monitoring to anticipate and manage morbidity.

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

261 Background: Androgen deprivation therapy (ADT) plus either Abiraterone, Docetaxel or Enzalutamide (ADE) improves overall survival (OS) of men with metastatic M1 castrate-sensitive prostate cancer (mCSPC), compared to ADT alone and is currently standard of care. Men with mCSPC with a point mutation of the speckle-type pox virus and zinc finger mutation (mutSPOP) derive superior response to ADT compared to wild type SPOP. The additive benefit of ADE to ADT in this subclass of CSPC is unclear. We sought to evaluate the benefit of therapy in patients with mutSPOP in a real-world setting. Methods: Between November 2017 and July 2022, 1002, patients in the Kaiser Permanente Northern California (KPNC) health system with advanced prostate cancer had tumor specimens examined by next generation sequencing (NGS). Of these patients, we retrospectively identified 70 mCSPC patients with mutSPOP. Patient records were reviewed to determine baseline characteristics, therapy for CSPC, subsequent therapy for Castrate Resistant Prostate Cancer (CRPC), and clinical outcome. The primary outcome was progression-free survival (PFS) for patients who received ADT alone or ADT plus ADE. PFS was defined as time to either PSA progression by PCWG2 criteria, clinical progression, or time to next line of therapy. Results: Median age for the 70 patients with mutSPOP was 75 years (range 50-91). Thirty-six (51%) were non-Hispanic white; 11 (16%) were African American; and 13 (19%) were Asian. F133 was the most frequently mutated allele (64%), TP53 was the most common co-mutated gene (27%), and mutations in MSH2, MSH6 and BRCA1 were identified in one patient each. Two patients had concurrent ERG fusion. Thirty-six patients (51%) had a Gleason score 8-10 and 48 (69%) were diagnosed with de-novo metastatic disease. Twenty-seven patients (39%) received ADT alone, 41 (59%) received ADT + ADE, 2 patients elected observation only. PFS was 28.1 months (mos) for ADT alone vs 35 for ADT+ADE (p=0.08). Twenty-nine patients (41%) received 2nd line therapy at CRPC; among them 24 received ADT plus Abiraterone or Enzalutamide. Median PFS for all the CRPC patients who received 2nd line treatment was 15mos. Median PFS for CRPC patients who received 2nd line treatment with Abiraterone, or Enzalutamide was 15.3 mos. Median overall survival for the entire group was 173 mos (95% CI 135-NR). Conclusions: In this real-world study within KPNC, we confirmed the durable benefit of ADT based therapy in patients with mutSPOP. Patients with mutSPOP derived similar benefit regardless of 1st line therapy (ADT vs ADT + ADE). We also noted durable responses to abiraterone or enzalutamide for CRPC after initial treatment with ADE for CSPC. Confirmation of these findings from an another large NGS database is ongoing and will be reported later.

605 Background: BTC are genetically diverse and heterogeneous. Despite knowledge of molecular subtypes of BTC, the distribution of molecular aberrations in the Latinx population has been understudied. These may have prognostic and/or predictive implications. Therefore, we analyzed our cohort of Latinx-rich patients with advanced BTC. Methods: We analyzed patients with advanced BTC, who were seen at the Mays Cancer Center from Jan 2018-Dec 2021. Tumor samples profiled by Next Generation Sequencing (NGS) were identified retrospectively. Associations between demographics, clinical characteristics, and genetic alterations were identified. Results: 88 patients with locally advanced/metastatic BTC were identified. 50 (56.2%) were Latinx. 42 (47.7%) had intrahepatic CA (IHCA), 14 (15.9%) had extrahepatic CA (EHCA), 16 (18.2%) had Gall Bladder Carcinoma (GBC) and 16 (18.2%) had Ampullary/Periampullary Carcinoma (APC). 49 (56%) had NGS on their tumors out of which 30 (61.2%) were Latinx and 19 (38.8%) were non-Latinx. The most commonly altered genes were TP53 (34.7%), KRAS (24.5%), ARID1A (16.3%), BRCA-2 (12.2%), PDL-1 (12.2%), FGFR (12.2%), MET (10.2%), PTEN (10.2%) and HER-2 (8.2%). 14.3% patients had no identifiable mutations. There was no significant difference observed in the rates of different molecular mutations between Latinx and non-Latinx (p=1) and among different histologies of IHCA, EHCA, GBC and APC (p=1). The Median Overall Survival (OS) for Latinx population was 16.1 months (95% CI 12.3-28.2) which was similar to the median OS for non-Latinx population of 15.5 months (95% CI 11.6-28.6) (p=0.69). The median OS was not different due to the presence or absence of any one mutation (p values ranged from 0.04 to 0.9). Conclusions: BTCs are genetically diverse. Somatic alterations were identified in 85% patients who were tested. Only 56 % had molecular testing, when it should be 100% in advanced BTC, per NCCN guidelines. This may be due to inadequate tissue, lack of funding, use of alternate ctDNA, or the patient may have died before getting to testing/repeat biopsy. The likelihood of having a genetic alteration was similar between Latinx and non-Latinx patients and among different sites of disease. Latinx and Non Latinx with advanced BTC had similar survival rates. Survival rate was not different due to the presence or absence of any one mutation. Future studies should prospectively investigate implementation programs for NGS in tumor and blood in all patients with BTCs.

21 Background: Studies have shown that Black patients receiving chemoradiation (CRT) for locally advanced rectal cancer (LARC) have achieved clinical outcomes less satisfactory than those achieved by other racial groups, but the source of this disparity is poorly understood. This study investigated the demographic, geographic, socioeconomic, and clinical factors that underlie this disparity. Methods: We interrogated the National Cancer Database from 2004-2017 to identify patients with T3-T4 or N > 0 LARC treated with CRT prior to surgery. Response to CRT was determined by the rates of pathologic complete response (pCR) and tumor downstaging after treatment. Univariate analysis (UVA) was performed with chi-square and Fisher’s exact tests. Multivariate analysis (MVA) was then used to identify independent factors associated with improved pCR. Results: A total of 37,783 patient records were reviewed for the study (7.8% Black, 86.0% White, 6.1% Other). Black patients were younger (p < 0.0001), more often female (p < 0.0001), and more likely to live in metropolitan areas (p < 0.0001). LARC in Black patients was diagnosed at a higher clinical stage (p = 0.0007) and was more often treated with abdominoperineal resection in preference to low anterior resection (p < 0.0001). Black patients were more often uninsured or covered by Medicaid (p < 0.0001) and less often covered by commercial insurance (p < .0001). UVA demonstrated that Black patients achieved pCR and tumor downstaging at lower rates than White patients (11.6% vs 14.5%; 46.9% vs 51.8%, both p < 0.0001). On MVA, Black race (OR 0.8015, 95%CI 0.7101-0.9047), a rural location (OR 0.8211, 95% CI 0.7082-0.952), absence of commercial medical insurance (Medicaid OR 0.8394 95% CI 0.7456-0.9449; Medicare OR 0.8989 95% CI 0.8226-0.9823; No Insurance OR 0.6107 95% CI 0.5103-0.7309), and higher tumor grade and stage remained independent risk factors for a lower pCR. Additional significant unfavorable prognostic factors for pCR included younger age, male sex, lower hospital treatment volume, and higher tumor grade or stage. Similarly, Black race, lower hospital treatment volume, absence of commercial medical insurance, and higher grade or stage were significant unfavorable prognostic factors for downstaging. Neither lower income nor fewer years of education was associated with pCR or tumor downstaging. Conclusions: The results confirm a lower rate of response to CRT in Black patients with LARC. The identification of race as an independent risk factor after adjustment for sociodemographic, geographic, and clinical factors suggests that other unknown variables–including genetic differences unaddressed in this study–must be pursued comprehensively in future studies. The more advanced stage of rectal cancers in Black patients suggests that critical evaluation of current cancer screening methods may play a role in this effort.

224 Background: Driver mutations in the exonuclease domain (ExoD) of DNA polymerase epsilon ( POLE) have been associated with high tumor mutation burden (TMB). High TMB is an important marker for immunotherapy, and thus understanding the mechanisms that lead to high TMB is an area of active investigation. Many tumors with POLE ExoD driver mutations have additional POLE variants of uncertain significance (VUS). Some of these VUS lie within the ExoD, while most lie outside the ExoD. This study investigates the role of such POLE VUS on TMB and POLE functionality of ExoD-mutated tumors. Methods: Retrospective colorectal cancer (CRC) genomic profiles from Caris Life Sciences (n=1,870) were separated into groups based on the presence of POLE ExoD mutations and the TMB status. Groups were defined as: ‘TMB-high (TMB-H) POLE ExoD driver without additional POLE VUS’, ‘TMB-H POLE ExoD driver plus POLE VUS’, and ‘TMB-low (TMB-L) POLE variant(s) without ExoD driver’. An additional group with ‘TMB-H POLE variant(s) without ExoD driver’ was identified as potentially novel drivers for future study. The microsatellite instability status (MSI or MSS) was also considered. The level of TMB, the presence of polymerase proofreading-associated mutational signatures and POLE stability/functionality analyzed using AlphaFold2 models and Rosetta Molecular Modeling Suite, were evaluated. Results: POLE variants were identified in 4.9% of the CRCs studied (92/1870). In all, 52.2% (48/92) of those tumors were TMB-H, and 38.0% (35/92) of them contained POLE ExoD drivers. The highest median TMB (mTMB) was found in the ‘TMB-H POLE ExoD driver plus POLE VUS’ group, and this was significantly different from the ‘TMB-H POLE ExoD driver without additional POLE VUS’ and the ‘TMB-L POLE variant without ExoD driver’ group, even when MSI tumors were excluded (p

14 Background: Oral anticancer drug annual out-of-pocket costs (OOPCs) for Medicare beneficiaries are frequently > $10,000. Many of these medications are available as multiple formulations (e.g., tablet/capsule) and multiple strengths (e.g., 25mg/50mg). Oral medications are typically priced per unit (pill), allowing for more cost-effective prescribing when patients use fewer pills to obtain a recommended dose. It is unclear whether cancer drugs follow this traditional paradigm. We sought to assess the relationship between drug formulation features and OOPCs. Methods: We included 20 oral anticancer drugs with the highest spending in Medicare Part D in 2020. For each drug, we identified formulations, strengths, and schedules using NCCN guidelines and UptoDate. For each product, we calculated a lowest expected annual drug OOPC for all relevant strengths/schedules using the 2022 Part D Plan Finder. For example, the drug osimertinib is available in 40 and 80 mg tablets, with total daily doses of 80 and 160mg, reflecting 4 pricing scenarios. We assessed costs for 1 year of monthly fills. We compared cost ratios across formulations for each drug. Results: Of the 20 drugs, 17 (85%) were available as brand-name only; 3 (15%) were also available as generic. Fifteen (75%) were available as a single formulation only (e.g., tablet only); 5 (25%) were available as multiple formulations (e.g., tablet and capsule). Eighteen (90%) were available in multiple strengths. Median annual drug OOPCs was $12,979. For brand vs generic comparisons (n = 4, keeping other variables constant, 1 drug could have > 1 comparison due to different strengths), brand coverage for imatinib and 250 mg abiraterone tablets was limited, leading to high cost ratios (brand/generic > 50). For 2 other comparisons, the brand was less costly (abiraterone 500 mg tablets, ratio 0.85) and more costly (everolimus 10 mg tablets, ratio 1.18) for 1 each. For tablet vs capsules/others (n = 4), tablets were cheaper for 2 (ratio, 0.63- 0.96), a little more costly for 1 (ratio 1.04), and a lot more costly for 1 (ratio 2.13, ibrutinib 140 mg). For comparisons across strengths of the same formulation to achieve the same total dose (n = 14), using lower strength/higher fill quantity was more costly for 10 drugs (median ratio 1.79), the same for 1, and less costly for 3 (ratios 0.35- 0.89). Conclusions: Even when considering the least costly Part D plan, 2022 oral anticancer drug OOPCs remain high. Counter to expectations, in some cases generics were more costly than brands, and more pills at a lower dose were less costly than fewer pills. There was no consistent pattern. Oncologists and pharmacists cannot be expected to know the unpredictable OOPC ramifications of biologically equivalent prescription decisions. As cancer primarily affects older adults, often living on fixed incomes, policy-level change to lower OOPCs are necessary to avoid financial ruin and enhance access for Medicare beneficiaries.