PURPOSE The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA-mutated human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α = .10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P < .001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non-small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration-approved.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. There are vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others having milder/more moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of patients with Castleman disease, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face a significant hospitalization burden, requiring more time in the hospital than iMCD-NOS patients during the year surrounding diagnosis (median [interquartile range]: 36 [18-61] days vs. 0 [0-4] days; P<0.001). In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO. iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004). Lastly, we observed severe iMCD-related morbidities, such as acute renal failure, sepsis and pneumonia, among others, arising after iMCD diagnosis, impairing the patients’ quality of life. These data demonstrate a substantial disease burden experienced by iMCD patients and emphasize the importance of ongoing research into iMCD to aid disease control.

Key Points • Fifty-two percent of patients with iMCD treated with siltuximab with/without corticosteroids achieved response.• Corticosteroids alone are not effective in iMCD symptom management.

Castleman disease (CD) is a rare and heterogeneous lymphoproliferative disorder with shared lymph node (LN) histology. 1 While multicentric CD (MCD) involves multiple enlarged LNs, systemic inflammation

3117 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in cohorts of pts with breast cancer (BC) and other solid tumors with PIK3CA mut treated with T are reported. Methods: Eligible pts had BC or other solid tumors, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. After antihistamine pre-tx, 25 mg of T was infused over 30-60 minutes once weekly until disease progression. Primary endpoint was disease control (DC), defined as complete or partial (PR) response, or stable disease of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. For the BC cohort, Simon’s optimal 2-stage design with null DC rate of 15% vs. 35% (power=0.85, α=0.10) was used with stage 1 (n=10) stopping for futility if < 2/10 pts had DC. Low accruing histology-specific cohorts with PIK3CA and T tx were collapsed into 1 histology-pooled (HP) cohort. For the HP cohort, the hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with α=0.10. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: 12 pts with PIK3CA mut with BC and 29 pts with PIK3CA mut in other solid tumors (across 9 tumor types) were enrolled. 2 pts (1 in each cohort) were found to be ineligible after enrolling and were not included in efficacy analyses. Demographics and outcomes for each cohort are shown. At the end of stage 1 in the BC cohort, 1 PR was observed for DC and OR rates of 9%; the cohort was closed for futility (p=0.83). For the HP cohort, 3 PR and 5 SD16+ were observed for DC rate of 29% (p=0.049) and OR rate of 11%; the null hypothesis was rejected. Cancer types in pts with OR or SD16+ included cervical, ovarian and head/neck; most common muts were H1047R/L (3), E545K (2) and E542K (2). 1 pt with ovarian and H1047R has ongoing PR at 86 wks. 11/41 pts had ≥1 tx-related grade 3-4 adverse or serious adverse event, including anemia, headache, hyperglycemia, hypertension, hypertriglyceridemia, mucositis oral, lymphocyte, neutrophil or platelet count decrease, pneumonitis, and sepsis. Conclusions: Although T does not appear to have antitumor activity in pts with BC with PIK3CA mut, it does show antitumor activity in pts with other solid tumors with PIK3CA mut and warrants further study. Clinical trial information: NCT02693535 . [Table: see text]

3115 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 28 pts with 16 solid tumors (6/28 pts had lung cancer) with BRCA1 (n=9) , BRCA2 (n=16) , or BRCA1/2 (n=3) mut were enrolled from Dec 2019 to Sept 2021. All pts were included in efficacy analyses. Demographics and outcomes are shown. 1 CR, 9 PR and 6 SD16+ were observed for a DC rate of 57% (1-sided 90% CI: 43% to 100%) and an OR rate of 36% (95% CI: 19% to 56%); the null hypothesis of a 15% DC rate was rejected (p<0.001). 11/16 pts with OR or SD16+ had a BRCA2 mut, 4 had BRCA1 mut, and 1 had both. The pt with a CR (duration of 93 wks) had non-melanoma skin cancer, with BRCA2 and ATM muts, and was microsatellite instability high with 41 muts per megabase. Pts with PR had various solid tumors; 6/9 pts had BRCA2 mut, 2 had BRCA1 mut , 1 had both. Of pts with DC, 11 had tumor types for which PARP inhibitors are not yet FDA approved. Median duration of PR was 20 wks (range, 11-80). 10/16 pts with DC had a co-alteration in the 24 homologous recombination-related genes examined, mainly ATM (3) or ARID1A (2). 13 pts had ≥1 grade 3 tx-related adverse or serious adverse events including: anemia, AST or bilirubin increase, hyponatremia, nausea, vomiting, neutrophil, platelet, or white blood cell decrease. Conclusions: Tala demonstrated antitumor activity in heavily pretreated pts with advanced solid tumors with BRCA1/2 mut. Additional study is warranted to confirm the efficacy of Tala in non-breast, non-ovarian cancer pts with BRCA1/2 mut. Clinical trial information: NCT02693535 . [Table: see text]

TPS612 Background: The ongoing, multi-center FLEX trial (NCT03053193) began in the United States in 2017, with the ultimate goal of 30,000 patients enrolled. The primary objective is to create a large-scale collaborative registry of early-stage breast cancer patients that links comprehensive clinical and full genome expression data to reveal new prognostic and/or predictive gene signatures. A key secondary objective of the trial is to enable investigator-initiated studies to explore early-stage breast cancer at a relatively low cost to the investigator. Methods: The prospective FLEX trial enrolls patients aged ≥ 18 years with histologically proven stage I-III breast cancer, with negative or 1-3 positive lymph nodes. Eligible patients have received MammaPrint, with or without BluePrint testing as standard of care, and consent to clinically annotated full transcriptome data collection. The FLEX base study protocol permits investigators to submit their own concept proposal, and upon review and approval by the Research and Scientific Review Committees, investigators interrogate clinical and genomic data from the FLEX database. The 10-year enrollment goal is a minimum of 30,000 patients. Since April 2017, 9,170 patients have been enrolled at over 109 sites in the United States. To date, 38 investigator-initiated substudies have been approved and are in progress, and 28 abstracts have been published in the US scientific congresses. To ensure inclusion of diverse populations, patients from local communities and 11 National Cancer Institute-designated Comprehensive Cancer Centers were included. Our diverse data set is helping meet the needs of historically under-represented patients with breast cancer. Of the self-reported ethnicities within the FLEX database, 65% are White or Caucasian, 8% Black or African American, 4% Latin American, and 2% Asian. There are 5 ongoing FLEX sub studies investigating racial disparities. The molecular profiling and differential gene expression analysis in early-stage breast cancer patients of African American, Asian, Hispanic ancestries helps to provide critical insights that correlate tumor biology with treatment outcomes. FLEX is expanding globally with sites anticipated in multiple European countries. The FLEX trial continues to expedite the discovery and development of novel genomic profiles, bringing precision oncology into the clinic to improve breast cancer management. Clinical trial information: NCT03053193.

Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched‐control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD‐TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non‐fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.

Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder involving multi-organ dysfunction driven by inflammatory cytokines, often including interleukin-6 (IL-6). The five-year overall survival rate varies considerably between cohorts, ranging from 50 to 77%. It is not well understood why administration of therapies such as the anti-IL-6 monoclonal antibody siltuximab induces complete and durable remission in some patients, whereas others succumb to their disease despite therapy. The aim of this study was to identify laboratory parameters associated with mortality in iMCD. To this end, iMCD patients enrolled in the ACCELERATE registry with fatal and non-fatal outcomes were compared. To determine differences in the laboratory profiles at time of diagnosis between the non-fatal (control) (n = 66) and fatal (mortality) (n = 6) iMCD groups, we performed two-tailed t-tests with Welch correction. P < 0.05 was considered significant. Due to the exploratory nature of this study and limited sample size, we did not perform correction for multiple comparisons among the 25 parameters assessed. In the fatal iMCD group, all patients were white, aged 15-66, and 33.3% were male. Four patients had a hypervascular histopathological subtype; one subtype was not stated, and one was mixed. The non-fatal iMCD group was mixed race and included 57.6% male patients; 38 patients had a hypervascular subtype, 19 had a mixed subtype, five patients had a plasmacytic subtype, three were not stated and one had a hyaline vascular subtype. The mean time from final diagnosis to death was 586.2 days (range: 16-2952 days). Around the time of diagnosis, immunoglobulin M (IgM) (Figure 1A), international normalized ratio (INR) (Figure 1B), and platelet count (PC) (Figure 1C) were significantly decreased in the fatal group compared with the non-fatal group (Figure 1D), with three mortality patients below the lower limit of normal (LLN) for IgM, and four mortality patients below the LLN for PC. Unlike the other two parameters, the INR levels were closer to normal in the fatal group than the non-fatal group. While C-reactive protein (CRP) levels were higher and hemoglobin (Hb) levels were lower in the mortality group, they did not surpass the significance threshold. These data provide new insights into differences between patients who have fatal and non-fatal outcomes. These preliminary findings from a small cohort of deceased patients demonstrate that patients with iMCD who have fatal outcomes may differ from those who do not. For instance, patients in the fatal group may be in a state of greater immune dysregulation (indicated by a lower IgM) and at increased risk of bleeding events (lower PC), compared with patients who go on to survive. The lower PC in the fatal group is likely reflective of patients with the recently-defined thrombocytopenia, anasarca, fever/elevated CRP, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) clinical subtype of iMCD having lower platelets and a more aggressive course. Thus, early evaluation of platelet count may be an early and actionable indicator of someone's likelihood of death. Additional research is needed into the role of PC and markers of inflammation and anemia in predicting mortality as well as the timing of decline of these markers. If validated in a larger cohort, certain laboratory values may be of use to identify patients at increased risk of death. Figure 1 Figure 1. Kanhai: EUSA Pharma: Current Employment. Bagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: EUSA Pharma: Speakers Bureau; Takeda: Speakers Bureau; Foundation Medicine: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau. Uldrick: Celgene: Research Funding; Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.

Castleman disease (CD) describes a group of heterogeneous lymphoproliferative disorders with characteristic histopathology that are classified based on the number of enlarged lymph node (LN) stations, etiological drivers, and clinical phenotype. CD histopathology includes a broad spectrum from plasmacytic to hyaline/hyper vascular with a mixed pattern in between. Unicentric CD (UCD) involves a single enlarged LN station and mild symptoms, whereas multicentric CD (MCD) involves multiple stations of enlarged LNs and more severe symptoms. MCD is subclassifed into Human Herpesvirus-8 associated MCD, POEMS-associated MCD, and idiopathic MCD (iMCD). iMCD cases are further subdivided into thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), renal dysfunction, organomegaly (TAFRO) or iMCD-not otherwise specified (NOS), who often have thrombocytosis and hypergammaglobulinemia. Recently, it has been reported that some iMCD patients can have more oligocentric lymphadenopathy (above or below the diaphragm) whereas others have generalized lymphadenopathy (above and below the diaphragm). Given the heterogeneity across CD, we leveraged data from a longitudinal natural history study of CD to characterize the spectrum of CD. Specifically, we set out to determine if patients with multicentric lymphadenopathy localized to above or below the diaphragm (oligocentric CD, OCD) appeared to be more similar to UCD or iMCD with more generalized lymphadenopathy. In total, 130 patients enrolled in an international CD registry were confirmed to have CD by a panel of experts. Patients were assigned UCD, OCD, or iMCD per the following: UCD, 1 station of enlarged LNs (N=32); OCD, ≥2 stations of enlarged LNs, either above or below the diaphragm (N=29); iMCD, ≥2 stations of enlarged LNs, both above and below the diaphragm (N=69). Clinical data is provided closest to date of diagnosis +/-90 days. Sustained response is defined as ≥50% symptom improvement sustained without the addition of subsequent drug treatments. When appropriate, statistical testing was performed by Chi-square, Fisher's exact, or two-tailed T test. Among the 69 iMCD patients, 42 (61%) were classified as TAFRO and 27 (39%) were NOS. In contrast, only 1 of 29 OCD patients (3%) was TAFRO and 28 (97%) were NOS. No UCD patients were TAFRO. Breakdown of histopathological subtype can be found in Table 1. There was a mean (SD) of 8.4 (3.7) enlarged LNs in iMCD at diagnosis, compared with 2.8 (1.4) in OCD and 1 (0) in UCD. While enlarged LNs in the abdomen/pelvis region occurred in 56% of UCD, only 19% of OCD patients demonstrated lymphadenopathy in this region. Clinically, OCD patients demonstrated symptoms and laboratory abnormalities more comparable to UCD than iMCD (Table 2). In fact, there was no difference in symptoms between UCD and OCD groups, while there were significantly more symptoms in iMCD than OCD. iMCD had significantly worse anemia, albumin, creatinine, CRP, and other markers of inflammation than OCD, whereas OCD patients had significantly increased CRP (p=0.03) and alkaline phosphatase (p=0.03) compared to UCD. IgM was greater in OCD than both UCD (p=0.02) and iMCD (p=0.01) (Table 2). The number of patients receiving drug treatments differed by subtype: 7 UCD (22%), 18 OCD (62%), and 67 iMCD (97%). Fifty-five patients (UCD: 1, OCD: 7, iMCD: 47) received anti-IL-6 therapy (+/- steroids), including the only FDA-approved drug, siltuximab. Sustained response to anti-IL-6 (+/- steroids) was observed in 23/47 (49%) iMCD, 3/7 (43%) OCD, and 0/1 UCD. Within iMCD clinical subgroups, response was observed in 12/27 (44%) iMCD-TAFRO and 11/20 (55%) iMCD-NOS as well as across the histopathogical subtypes, suggesting that anti-IL-6 therapy can be effective across the spectrum. Overall, this study highlights the heterogeneity of CD. Importantly, it uncovers a group of CD patients that meet diagnostic criteria for iMCD but their lymphadenopathy is confined to above or below the diaphragm and they appear to behave more similarly to UCD. Given that 1/3 of OCD patients were managed without drug treatment, further work is needed to determine the relative benefits of UCD-like surgical treatment versus iMCD-like drug-based therapy for OCD. The clinical subtype of TAFRO, which was present in more than half of the iMCD patients, was observed in only one OCD case and no UCD cases. Further work is needed to determine optimal treatments across these subgroups. Figure 1 Figure 1. Bagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: Takeda: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau; EUSA Pharma: Speakers Bureau; Foundation Medicine: Speakers Bureau. Uldrick: Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment; Celgene: Research Funding. Fajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'; EUSA Pharma: Research Funding.

Cytokines and other immune regulatory molecules are critical players in the immune response against cancer. There is growing interest in testing the potential utility of systemic immune biomarkers to track cancer progression and to use them as predictors of effective responses to cancer therapy. The central hypothesis guiding this project is that specific immune biomarkers will serve as predictors of effective vs. ineffective immunotherapy in patients with malignant diseases. The objective of this study was to establish baseline of immune markers in patients already started treatment with immunotherapy (n=10) (T), patients starting, but not yet treated (S) with immunotherapy (n=10) and subjects without diagnosed malignant disease (W) (n=10). Blood was collected and plasma was isolated and used in the biomarker (100 markers) analysis using a protein microarray method (RayBiotech). The biomarkers in the three groups were analyzed by Principal Component Analysis, heat map with clustering, and differential expression based on p value, and Significance Analysis of Microarrays (SAM). Although 15 biomarkers were significantly different between S vs. W groups, based on SAM, only seven were found differentially expressed. Similarly, although 10 biomarkers were significantly different between T vs. W groups, based on SAM, only one biomarker was found differentially expressed. Furthermore, SAM revealed that responders (n=4) vs. stable (n=5) subgroup of patients within the T group exhibited 22 differentially expressed biomarkers. Future larger studies will be needed to evaluate whether immune markers will be able to predict effective vs. ineffective responses to immunotherapy and whether they may have therapeutic potential.

OBJECTIVE To present the characteristics of the AKT1E117K gene variant and a description of the clinical application in a patient with metastatic breast cancer. RESULTS 63 y/o woman with Stage IV Invasive lobular carcinoma at diagnosis was treated with Palbociclib and aromatase inhibitors (AI). At progression, tissue was sent for comprehensive genomic profiling to Foundation Medicine (FM) which revealed AKT1E17K mutation. In lieu of available clinical data within the patient's tumor type (HR+ HER2- breast cancer), extrapolated data from the Flatiron Health-FM (FH-FMI) Clinico-genomic Database (CGDB) was discussed at our Molecular Tumor Board (MTB). After multidisciplinary discussion, the consensus recommendation was to start treatment with the combination of mTOR inhibitor everolimus, and AI, exemestane. Patient tolerated treatment without major side effects. By the second clinical visit the patient's breast showed signs of improvement. PET/CT showed diminished left axillary uptake, decreased right paratracheal lymph node PET avidity, and stable bone disease consistent with a partial response. The most recent office visit in January 2021, breast exam revealed a normal-appearing skin with only faint erythema. All other skin lesions have resolved. Although, the role of AKT1 variant described here is not well defined and therapeutic significance of M-Tor inhibitors not established in metastatic breast cancers, comprehensive approach to this case unraveled new and successful therapeutic option in this patient. CONCLUSION This demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.