Ailawadhi, Sikander

Abstract INTRODUCTION Sparse data exist regarding I+V in an off-trial setting, particularly in patients (pts) with progression of disease on either I or V as single agent treatment. The 1-year overall survival (OS) rates with V monotherapy following I range from 75%-91% (Eyre et al, BJH 2019; Jones et al, Lancet Oncol 2018); however, longer-term follow-up of these or other patient cohorts treated with V after I has not yet been reported. Effective options in double-refractory pts are lacking when a clinical trial is not feasible. Here, we report our experience with I+V in these patient groups. METHODS After IRB approval, we reviewed the records of pts seen at Mayo Clinic (between 4/2012-1/2021) who received I+V therapy off-trial for CLL progression. Pts treated with I+V for Richter's transformation were excluded. Time to next treatment (TTNT) was measured from I+V treatment start date to the date of next treatment start or last known treatment status with death as a competing risk. OS was measured from I+V start date until date of death or when the patient was last known alive; OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS Thirty-three pts with progressive CLL were treated with I+V (median duration 13.3 months [95% CI: 7.1 months-not estimable (NE)]). The median age was 70 years (range 47-86), 6 (18%) were women, and 20 (65%) had del(17p) or TP53 mutation. The median number of prior lines of therapy was 3 (range 1-15). Additional characteristics at the time of I+V start are shown in Table 1. Median follow-up from start of I+V was 23.8 months. Among 22 pts with prior progression on I only (V-naïve), the median duration of I+V was 14.8 months (95% CI 7.6 months-NE). The median duration on either I or V from the start of combination was 20.3 months (95% CI 8.3 months-NE). The median TTNT was 25.1 months (Figure 1A). Four pts proceeded to cellular therapy (alloSCT [n=3], CAR-T [n=1]) while on I+V. Next therapy (n=9) consisted of Richter transformation treatment (n=2), chemotherapy plus continued I+V (n=1), anti-CD20 plus continued I+V (n=1), duvelisib + I (n=1), TP-0903 + I (n=1), reintroduction of I at disease progression after previously stopping I during I+V therapy (n=1), and reintroduction of I (n=1) or V (n=1) at disease progression after previously stopping I+V. Of 9 pts who did not receive subsequent therapy, 4 pts remain on I+V (median duration 16.4 months), 4 pts continued V after discontinuing I (median duration on V from start of I+V was 21.5 months), and 1 pt discontinued I+V following a second cancer diagnosis and died without receiving additional CLL-directed treatment. Eleven pts received I+V in the double-refractory setting; 9 pts had prior disease progression on sequential I then V and 2 pts had prior disease progression on sequential V then I. The median duration of I+V was 7.5 months (95% CI 4.3 months-NE), and the median duration of either agent from I+V start was 10.8 months (95% CI 7.1 months-NE). The median TTNT was 14.0 months (Figure 1A). Eight pts required additional treatment, consisting of PI3K inhibitor (n=2), anti-CD20 added to I+V (n=1), CAR-T (n=1), anti-CD20 with (n=1) or without (n=1) bendamustine added to continued I, and Richter transformation treatment (n=2). One pt continues I+V (17.4 months ongoing) without further treatment. Two pts died from disease progression without receiving additional treatment. The median OS of all 33 pts was 27.4 months (95% CI 25.9 months-NE; Figure 1B). The median OS of the 22 pts with prior progression on I (V-naïve) was 47.1 months (95% CI 27.7 months-NE), and the median OS of the 11 pts with prior progression on I and V separately was 27.0 months (95% CI 15.5 months-NE). In univariate analyses, prior progression on V was a predictor of shorter OS (HR=3.9; 95% CI 1.4-11.2; p=0.01). CONCLUSIONS Combination I+V therapy in heavily pre-treated CLL pts who have disease progression after I provides durable benefit with a median OS approaching 4 years. In the double-refractory setting, repurposing both drugs as combination I+V therapy can be a useful strategy, despite the short-term disease control, for pts where clinical trial options are limited or not available. Further examination of these approaches in larger cohorts and understanding the operative resistance mechanisms in pts with double-refractory disease are key next studies. Figure 1 Figure 1. Disclosures Ding: Octapharma: Membership on an entity's Board of Directors or advisory committees; DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chanan-Khan: BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BieGene, Jansen, Ascentage: Consultancy. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees. Ailawadhi: Pharmacyclics: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Sanofi: Consultancy; BMS: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Ascentage: Research Funding; Medimmune: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Research Funding; Beigene: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy. Koehler: AbbVie: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Kay: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Combination ibrutinib and venetoclax in patients with relapsed CLL.

Abstract Background: PD-(L)1 pathway inhibitors have demonstrated durable clinical benefit in both solid tumors and hematologic malignancies; however, as less than 1/3 of patients respond to anti-PD-(L)1 monotherapy, combination therapies may be needed for improved response rates and survival. T cell Immunoglobulin and ITIM domain (TIGIT) is expressed on activated T cell and natural killer (NK) cell subsets; TIGIT-CD155 binding suppresses T and NK cell function and inhibits the antitumor immune response. AB308, an Fc-enabled anti-TIGIT humanized IgG1 monoclonal antibody (mAb), has reversed TIGIT-CD155-mediated T cell inhibition in preclinical models. ARC-12 will assess whether TIGIT pathway blockade by AB308 can augment zimberelimab (zim; anti-PD-1 mAb) activity in patients with solid and hematologic malignancies. Study Design and Methods: ARC-12 is a phase 1/1b, first-in-human, open-label, dose-escalation study of AB308 + zim in patients with advanced solid tumors or hematologic malignancies. Dose expansion cohorts include relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). For the dose-escalation, eligible adults have solid tumors for which no standard-of-care therapy exists or have pathologically-confirmed R/R non-Hodgkin lymphoma (NHL) and have not received or are ineligible for allogeneic stem cell transplant or adoptive cell transfer; ≤5 lines of prior systemic therapy; ≥1 measurable lesion per RECIST (solid tumors) or Lugano Classification (NHL) criteria; and ECOG performance score of 0-1. As shown in the figure, patients will receive AB308 + zim intravenously (IV) once every 3 weeks (Q3W; Part A) or once every 4 weeks (Q4W; Part B). In Part A, the first 6 patients of Cohort 1 will follow 3+3+6 rules, allowing for AB308 dose adjustment if dose-limiting toxicities (DLTs) warrant; all other dose-escalation cohorts will use 3+3 rules. After the Cohort 2 DLT period has been cleared, Part B enrollment will begin in parallel with Part A to determine the recommended dose for expansion (RDE) for AB308 + zim for both the Q3W (Part A) and Q4W (Part B) schedules. Each part can independently proceed to dose-expansion once the RDE is determined for that dose schedule. In the dose-expansion, patients will be enrolled into disease-specific cohorts for non-small cell lung cancer (NSCLC), melanoma, gastrointestinal cancer, cervical cancer, and hematologic malignancies (DLBCL or MM). AB308 + zim may be dosed on either a Q3W or Q4W schedule; all patients in each expansion cohort will receive the same dose schedule. For both the dose-escalation and dose-expansion, the primary endpoints assess safety and tolerability of AB308 + zim; secondary endpoints include pharmacokinetics (PK), immunogenicity, and objective response rate for AB308 + zim. Additional secondary endpoints in the dose-expansion are disease control rate and duration of response. Safety and efficacy data will be analyzed using summary statistics and Kaplan Meier estimates as appropriate; PK parameters will be estimated using noncompartmental methods. ARC-12 is actively recruiting at sites in the United States (NCT04772989). Figure 1 Figure 1. Disclosures Ailawadhi: Pharmacyclics: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Ascentage: Research Funding; Genentech: Consultancy; AbbVie: Consultancy; BMS: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Medimmune: Research Funding; Cellectar: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; GSK: Consultancy, Research Funding. Foster: Arcus Biosciences, Inc.: Current Employment. Ryba: Arcus Biosciences, Inc.: Current Employment. Scharville: Arcus Biosciences, Inc.: Current Employment. El-Baghdady: Arcus Biosciences, Inc.: Current Employment. OffLabel Disclosure: AB308 and zimberelimab (AB122) are in clinical development and are not approved in the United States for the use under discussion.

Abstract Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. The single-arm, open-label, Phase 2 HORIZON study (NCT02963493), conducted in Europe and the USA, demonstrated in patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM), including those with triple-class-refractory and extramedullary disease, that melflufen in combination with dexamethasone showed clinically meaningful efficacy and a manageable safety profile (Richardson PG, et al. J Clin Oncol. 2021;39:757-767). Comparative trials between all regimens/agents are not feasible, and hence, real-world datasets may be valuable to allow the comparison of patient outcomes in single-arm clinical trials with similar patient populations in the real world. The objective of the REAL-world Myeloma (REALM) study was to compare clinical outcomes between patients in the COTA database and those of patients in the HORIZON study in order to compare routine care with melflufen. Methods: REALM is a retrospective, observational study using real-world data from 605 patients with RRMM collected in the COTA database, a USA-based real-world evidence database comprising longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant data on the diagnosis, clinical management, and outcomes of patients with cancer. Patients in REALM met the main HORIZON eligibility criteria (aged ≥18 years; ≥2 lines of prior therapy [including an immunomodulatory drug and a proteasome inhibitor]; refractory to pomalidomide and/or daratumumab on or after January 1, 2015; and received a line of therapy after meeting the inclusion criteria). Propensity score (PS) matching is a commonly used approach for comparing the effectiveness of 2 treatment options across different studies where individual patient data are available for both treatments. This abstract presents adjusted clinical outcome results based on 1:1 PS matching of patients in the COTA and HORIZON datasets for 12 covariates (COTA PS and HORIZON PS, Table 1). These covariates were considered important because they reflect patient characteristics that impact clinical outcomes and were validated in a feasibility study, and by independent experts. The primary endpoint of the HORIZON study was overall response rate. The primary endpoints of the REALM study were time to treatment discontinuation (TTD) and time to next treatment (TTNT), to mitigate against missing treatment response data in the COTA database identified in the feasibility study. Results: Selected patient demographic and clinical characteristics were generally well matched (Table 1) between patients from COTA PS (n=110) and HORIZON PS (n=110), except for the Eastern Cooperative Oncology Group performance status, which was better in the COTA PS dataset than in the HORIZON PS dataset. Patients in both the COTA PS and the HORIZON PS datasets were predominantly male and White. Patients had a median age of 67 years in the COTA PS dataset and 64 years in the HORIZON PS dataset, with a median of 4 and 5 prior lines of therapy, respectively. The median time since first diagnosis to index data was 60.19 months in the COTA PS dataset and 72.56 months in the HORIZON PS dataset. The median TTNT (95% confidence interval [CI]) in the COTA PS dataset versus the HORIZON PS dataset was 4.6 (3.7-6.9) months and 5.9 (4.7-7.7) months, respectively (p=0.949). The median TTD (95% CI) in the COTA PS dataset versus the HORIZON PS dataset was 3.2 (2.6-3.9) months and 3.9 (3.0-4.6) months, respectively (p=0.642). Conclusions: Pharmacoepidemiologic methods using individual patient data play an important role in evaluating the effectiveness of treatments in the absence of randomized controlled trial data. Patients with RRMM receiving melflufen in combination with dexamethasone noted a trend toward improved TTNT and TTD compared with corresponding real-world treatment approaches. This benefit may be clinically meaningful especially in the triple-class-refractory patient population, which remains an unmet need in RRMM. Figure 1 Figure 1. Disclosures Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy. Wang: COTA, Inc.: Current Employment, Other: Equity ownership. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Jansson Blixt: Oncopeptides: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cripps: Oncopeptides: Other: Independent consultant. Zavisic: Oncopeptides: Current Employment, Current holder of stock options in a privately-held company. Ramasamy: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Celgene (BMS): Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Clinical availability of highly effective novel agents (including Bruton tyrosine kinase [BTK] and B-cell lymphoma 2 [BCL-2] inhibitors) is rapidly altering the therapeutic landscape of chronic lymphocytic leukemia (CLL) necessitating a review of treatment guidelines. However, there is limited real-world data to validate if the availability of these novel agents has translated to a true shift in treatment paradigm for patients treated in the community. As the majority of CLL patients are treated in non-academic community-based settings, we investigated the clinical adoption trends of commercially available FDA approved novel agents for treatment of CLL patients. In addition, given that the COVID-19 pandemic led to major alteration in clinical oncology practices, we further studied if this contributed to an alteration in the selection of therapeutic agents resulting in changes of CLL treatment patterns and the utilization of novel agents in the real-world setting. Thus, the objectives of this study were to examine the utilization pattern of various CLL therapies, as well as evaluate the pattern of adoption of novel agents for treatment and the impact of COVID. Methods: A retrospective observational study was conducted using the Flatiron Health database that comprised EHR-derived de-identified data. Adult patients (≥18 years) with newly diagnosed CLL from January 2014 to May 2021, with no prior treatment and who were continuously enrolled for at least 6 months before and 3 months after the index date, defined as the first date of CLL/SLL diagnosis were included. Treatment regimens were classified into seven mutually exclusive categories: bendamustine-based chemotherapy, other chemotherapy, anti-CD20-based therapy, ibrutinib, idelalisib, acalabrutinib and venetoclax. Further treatment categorization included chemotherapy vs. targeted therapy, and traditional IV vs. novel oral agents. The impact of the pandemic was examined by comparing the pre- and post-COVID cohorts (defined as 15 months pre- and post- of March 1, 2021). Descriptive analyses were conducted to examine the frequency of use of treatment regimens by quarter in each year, line of therapy and between different age, gender, US geographical region, insurance status, and race/ethnicity subgroups. Multivariable regression was conducted to examine factors associated with the likelihood of adoption of novel and oral agents. Statistical significance was determined at a p-value of less than 0.05. Results: A total of 3,037 newly diagnosed CLL patients (median age =73) were included in the study. Over half were male (62.3%), white (74.6%) and commercially-insured (54.1%). Patients were primarily treated in community practices (92%). Overall, a significant trend in adoption of novel agents was observed throughout the years following their approval (Figure 1A). Across the evaluation period, a significant decrease in chemotherapy use was observed from 61.3% (quarter 1, 2014) to 20% (quarter 2, 2021) in favor of targeted therapy as first-line therapy (Figure 1B). In contrast, the utilization of novel oral agents (vs. traditional IV agents) for first-line therapy increased from 9.5% to 70.9% for the same period (Figure 1C). Similar trends were observed for second-line and third-line therapies. Encouragingly, this change in treatment patterns was adopted comparably in all sociodemographic subgroups with no evidence of disparity. While there was no statistically significant difference between the pre- and post-COVID treatment landscape, the adoption of target and novel oral agents has been more pronounced with the COVID pandemic. Conclusions: Results from real-world data suggest that there is a clear shift towards the adoption of novel therapies with preference given to targeted agents and oral therapies in the US since 2014. Further research examining real-world outcomes associated with treatment regimens are needed to inform decision makers. Figure 1 Figure 1. Disclosures Chanan-Khan: Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Abstract Background: GLUT4 inhibition is an attractive therapeutic option in multiple myeloma (MM) given the dependence of MM cells on glucose transport. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor in MM cells to counter the possibility of therapeutic resistance to GLUT4 inhibition has demonstrated synergistic promise (Dalva-Aydemir et al, Clin Can Res 2015). Using a GLUT4 inhibitor such as the HIV protease inhibitor nelfinavir is an attractive choice since it not only inhibits the transport function of GLUT4, but it also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (Driessen et al, Blood 2018). Thus, in summary the FDA-approved oral HIV-PI nelfinavir, long used for the treatment of HIV disease, can bind to glucose transporters (GLUT4) on MM cells and reversibly inhibit glucose uptake, thus disrupting the Warburg effect. Nelfinavir can also enhance the activity of PIs such as bortezomib overcome its resistance in MM cells. Metformin, an oral FDA-approved drug for the treatment of Type II Diabetes has the ability to disrupt the electron transport chain of defective mitochondria within MM cells, thus blocking the ability of such mitochondria to generate energy and anabolic substrates as compensatory mechanisms required for proliferation in the setting of GLUT4 inhibition. Thus, this study will look at the safety and tolerability of repurposing the existing FDA-approved drugs for Type II diabetes and HIV in combination with bortezomib for the treatment of relapsed and/or refractory myeloma. Methods: This study is a phase 1 clinical trial of metformin and nelfinavir in combination with bortezomib for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design with 3 dose levels planned. Part B is a dose expansion cohort at the Maximal Tolerated Dose (MTD) determined in Part A. Up to a maximum of 36 patients will be enrolled and treated for a maximum of six 21-day cycles. Bortezomib is administered in its usual weekly subcutaneous dosing schedule of days 1, 8 and 15 of a 21-day cycle at a dose level of 1.3 mg/m2. Metformin will be administered for 14 days of a 21-day cycle and started at a dose level of 500 mg twice daily and will be investigated to a maximum dose of 1000 mg twice daily. Nelfinavir will also be administered for 14 days of a 21-day cycle and started at a dose level of 1250 mg twice daily and will be investigated to a maximum dose of 2500 mg twice daily. Key inclusion criteria include having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, adequate hematologic reserve, kidney function and liver function. This trial especially allows patients with non-secretory disease yet measurable by bone marrow assessments or cross-sectional imaging of plasmacytomas to be enrolled which constitutes an unmet need in the real-world MM population. Finally, this allows patients to be treated with a dexamethasone-free regimen. The primary objective of this trial is to determine the MTD of metformin and nelfinavir in combination with bortezomib. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated with this combination. Potential predictive biomarkers as well as resistance mechanisms using genomic RNA, immunohistochemistry and metabolomics-based assessment platforms will be evaluated in this study. Recruitment is ongoing with no safety concerns. This trial is registered on clinicaltrials.gov: NCT03829020. This investigator-initiated trial was funded by the generous gift of the Helen Diller Family Foundation. Disclosures Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Abstract Introduction: Prognostic testing, including immunoglobulin heavy-chain variable region gene (IgHV) mutation status, cytogenetic abnormalities by fluorescence in situ hybridization (FISH), and immunophenotyping has been recommended in all newly diagnosed patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) prior to treatment initiation, and even in previously treated patients in some settings. Recent data have shown that disease with high-risk genetic features is better managed with novel agents than traditional chemoimmunotherapy. As such, the need for testing has become more relevant for disease management. However, there is limited recent data on real-world patterns of testing for risk factor assessment and in-turn, patterns of evidence-based treatment selection. This study aimed to examine: (1) the frequency and results of testing, (2) timing of testing by line of therapy, and (3) factors associated with the receipt of testing. Methods: De-identified data from the Flatiron Health EHR-derived database was used to identify patients who were ≥18 years old with newly-diagnosed CLL/SLL, who had ≥6-month continuous enrollment, and no prior treatment from January 2014 to May 2021. Testing evaluated included IgHV mutation status, FISH cytogenetic (11q deletion [del(11q)], 13q deletion [del(13q)], 17p deletion [del(17p)], Trisomy 12 [+12]) and other biomarkers (including CD38 and ZAP-70) by immunophenotyping. Descriptive analyses were conducted to examine the frequency and results in the overall population, and compared by patient characteristics and across sociodemographic groups. Multivariable logistic regression was conducted to examine factors associated with the likelihood of receiving testing. Statistical significance was determined as a p-value of <0.05. Results: A total of 3,037 CLL patients were included (median age=73, 62.3% male, 74.6% white). The majority of patients (92%) received treatment in community practices, with 54.1% commercially-insured. We observed over half of CLL patients did not receive risk factor testing (Figure 1): IgHV mutation analyses (76.2%, n=2,315), FISH (61.5%, n=1,868) and immunophenotyping (72.1%, n=2,190). Of those who had testing, the majority (99%) had it done once prior to starting first-line therapy. Significant differences in the receipt of testing were observed between different age, gender, race/ethnicity, and regional subgroups (Table 1). Among patients who received testing, the presence of high-risk biomarkers was as follows: unmutated IgHV (56.1%), del(17p) present (14.4%), del(11q) present (16.9%), and CD38 present (30.8%). Compared to patients <65 years, testing results in elderly patients ≥65 years showed a lower presence of unmutated IgHV (53.8%) and del(11q) (15.7%) while higher del(17p) (14.7%) and +12 (28.1%). No significant disparity was observed in white vs. non-white patients except for a lower incidence of mutated IgHV and del(13q) presence. Compared to tested men, tested women had a lower presence of unmutated IgHV (53.9%), del(11q) (11.4%) and CD38+ (25.8%) while higher del(17p) (18.2%). We then investigated the impact of risk testing on therapy selection, and noted that patients with del(17p) had a higher likelihood than those who tested negative (73.6% vs. 48.4%) of being treated with novel agents (ibrutinib, acalabrutinib, or venetoclax). In contrast, 26.4% of those who tested del(17p) present and 39.8% among those who did not get tested received chemotherapy. Multivariable regression showed that patients who were older (≥65 years), female or those living in the west of U.S. were significantly less likely to receive testing. Conclusions: The NCCN guidelines recommend novel agents for patients with high-risk CLL/SLL. Thus, all patients are advised to complete risk-factor testing for both prognostication and selection of optimal, evidence-based therapy. Our real-world data highlights not only a significant gap in testing, but that this suboptimal testing is more common in vulnerable populations. We observed that despite identification of del(17), a quarter of CLL patients failed to receive novel agents in the frontline setting. Our analysis identified an unmet need for further education and refinement of clinical practice. This is necessary to achieve the best clinical outcome in CLL patients through robust risk-assessment testing and optimal therapeutic triaging. Figure 1 Figure 1. Disclosures Chanan-Khan: BieGene, Jansen, Ascentage: Consultancy; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BeiGene, Jansen, Ascentage: Honoraria. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Ascentage: Research Funding; Medimmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Xencor: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy; Beigene: Consultancy; Takeda: Consultancy.

Background: Concern exists that the clinical trial populations differ from respective cancer populations in terms of their age distribution affecting the generalizability of the results, especially in underrepresented minorities. We hypothesized that the clinical trials that do not report race are likely to suffer from a higher degree of age disparity. Methods: Food and Drug Administration (FDA) drug approvals from July 2007 to June 2019 were reviewed to identify oncology approvals, and trials with age details were selected. The outcomes studied were the weighted mean difference in age between the clinical trial population and real-world population for various cancers, the prevalence of race reporting and association of age and race reporting with each other. Results: Of the 261 trials, race was reported in 223 (85.4%) of the trials, while 38 trials (14.6%) had no mention of race. Race reporting improved minimally over time: 29 (85.3%) in 2007–2010 vs. 49 (80.3%) in 2011–2014 vs. 145 (85.4%) during the period 2015–2019 (p-value = 0.41). Age discrepancy between the clinical trial population and the real-world population was higher for studies that did not report race (mean difference −8.8 years (95% CI −12.6 to −5.0 years)) vs. studies that did report it (mean difference −5.1 years, (95% CI −6.4 to −3.7 years), p-value = 0.04). Conclusion: The study demonstrates that a significant number of clinical trials leading to cancer drug approvals suffer from racial and age disparity when compared to real-world populations, and that the two factors may be interrelated. We recommend continued efforts to recruit diverse populations.

Background: It is standard of care and an accreditation requirement to screen for and address distress and psychosocial needs in patients with cancer. This study assessed the availability of mental health (MH) and chemical dependency (CD) services at US cancer centers. Methods: The 2017–2018 American Hospital Association (AHA) survey, Area Health Resource File, and Centers for Medicare & Medicaid Services Hospital Compare databases were used to assess availability of services and associations with hospital-level and health services area (HSA)–level characteristics. Results: Of 1,144 cancer centers surveyed, 85.4% offered MH services and 45.5% offered CD services; only 44.1% provided both. Factors associated with increased adjusted odds of offering MH services were teaching status (odds ratio [OR], 1.76; 95% CI, 1.18–2.62), being a member of a hospital system (OR, 2.00; 95% CI, 1.31–3.07), and having more beds (OR, 1.04 per 10-bed increase; 95% CI, 1.02–1.05). Higher population estimate (OR, 0.98; 95% CI, 0.97–0.99), higher percentage uninsured (OR, 0.90; 95% CI, 0.86–0.95), and higher Mental Health Professional Shortage Area level in the HSA (OR, 0.99; 95% CI, 0.98–1.00) were associated with decreased odds of offering MH services. Government-run (OR, 2.85; 95% CI, 1.30–6.22) and nonprofit centers (OR, 3.48; 95% CI, 1.78–6.79) showed increased odds of offering CD services compared with for-profit centers. Those that were members of hospital systems (OR, 1.61; 95% CI, 1.14–2.29) and had more beds (OR, 1.02; 95% CI, 1.01–1.03) also showed increased odds of offering these services. A higher percentage of uninsured patients in the HSA (OR, 0.92; 95% CI, 0.88–0.97) was associated with decreased odds of offering CD services. Conclusions: Patients’ ability to pay, membership in a hospital system, and organization size may be drivers of decisions to co-locate services within cancer centers. Larger organizations may be better able to financially support offering these services despite poor reimbursement rates. Innovations in specialty payment models highlight opportunities to drive transformation in delivering MH and CD services for high-need patients with cancer.

Waldenström Macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is often differentiated from myeloma based on the presence of lytic bone lesions (LBL). However, WM/LPL can present with LBL and management is poorly understood. We describe a case of an 81-year-old woman with LPL who presented with LBL and was successfully treated with chemoimmunotherapy.