Citations

11505 Background: Potentiation of chemotherapy, without increased toxicity, to improve outcome is an area of interest. Preclinical and clinical evidence shows simultaneous utilization of antiangiogenic agents and chemotherapy have a synergistic effect. We hypothesized that the dual targeting of VEGF and c-MET pathways with cabozantinib (CAB) would result in clinical benefit for patients with soft tissue sarcoma (STS) when combined with temozolomide (TMZ), an alkylating agent. Utilization of CAB/TMZ is anticipated to produce a synergistic antitumor effect worthwhile to explore in STS. Methods: A multicenter phase II study of CAB/TMZ in patients with unresectable/metastatic leiomyosarcoma (LMS) and other STS was conducted by the Midwest Sarcoma Trials Partnership. Age ≥ 18, adequate performance status, organ function, measurable disease (RECIST 1.1), and 0-5 prior chemotherapy regimens were required. CAB 40 mg PO daily plus TMZ 150-200 mg/m2 PO 1-5 days were given in 28-day cycles until disease progression or unacceptable toxicity. Patients enrolled in 2 cohorts: 1. Uterine and non-uterine LMS 2. Other STS. The first 14 subjects to be enrolled in the study in either cohort served as a safety lead in. The primary endpoint was progression-free rate (PFR) at 12 weeks for cohort 1. Secondary endpoints include overall response rate (ORR), clinical benefit rate, median progression-free survival (PFS), overall survival, and safety and tolerability. The exploratory endpoint was to estimate the correlation of PFR and OS to expression levels of VEGF, amongst others. A Simon 2-stage design was used. Results: A total of 42 patients were enrolled in Cohort 1, and 30 in Cohort 2, across 5 sites. For Cohort 1, median age was 59 years (range 35-86), 85.7% were non-Hispanic, 73.8% were female, 61.9% had ECOG of 0. The PFR at 12 weeks was 45.9% (for 37 evaluable patient) with a median PFS of 6.4 months (95% CI 4.6-6.7). Five PR were observed for an ORR of 13.5%. For Cohort 2, median age was 63 (20-86), 83.3% were non-Hispanic, 36.7% were female, 53.3% had ECOG of 0. The PFR at 12 weeks was 50% (for 28 evaluable patients) with a median PFS of 3.2 months (95% CI 1.4-4.6). One PR was observed. Reported grade 3-4 adverse events attributed to one or both intervention drugs affecting ≥10% of patients (n = 70) included hypertension (10%), decreased neutrophils (18.7%), decreased platelets (31%). Conclusions: The combination therapy of CAB/TMZ in patients with unresectable or metastatic LMS exceeded its primary endpoint with a PFR at 12 weeks > 39%. The PFS of 6.4 months in Cohort 1 exceeds rates achieved with second line tyrosine kinase inhibitors (TKIs) and alkylators in LMS patients. Treatment was feasible and did not reveal any previously unreported toxicities. The combination with CAB with TMZ demonstrated meaningful clinical benefit and is worth further exploration in LMS. Clinical trial information: NCT04200443 .

11503 Background: Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes. Methods: This open-label multi-arm study enrolled pts with locally advanced/metastatic AS. Arm 3, reported here, enrolled pts who had received a taxane for AS (including adjuvant) prior to study enrollment. Pts were not restricted on number of prior lines, but prior anti-VEGF and immunotherapies were not allowed. Eligible pts received C (40 mg po daily) with N (480 mg IV every 4 wks). Treatment was permitted beyond progressive disease (PD) in the 1st 12 wks (4 wk confirmatory scan), but PD response was censored at 12 wks. The Simon 2-stage design (null and alternative overall response rate (ORR) were 10% and 35%, respectively) required ≥1 confirmed response in 9 pts in the 1st stage, and >4 of 18 pts (91.4% power, alpha 0.095) for the primary endpoint. Secondary endpoints were adverse events (AEs), progression free, overall survival (PFS, OS), and pt-reported outcomes (PRO). Results: 21 eligible pts [median age 66 yrs (32-92), 10 female] received ≥1 dose of C+N. Primary disease sites: 12 cutaneous (scalp/face), 1 liver, 2 breast, 6 other. All pts received prior taxanes (11/21 = 52% as adjuvant therapy) and 5/21 (24%) had also received prior anthracycline (all relapsed AS). Primary endpoint: 13 of the first 18 evaluable patients (72%) experienced objective response (OR, 95%CI: 47%-90%). After a median follow-up of 11.2 mo, 13 of 21 pts achieved OR (11 partial response, 2 complete), for ORR 62% (95%CI: 38-82%). Responses were seen in pts with primary cutaneous disease 7/12 (58%) and noncutaneous disease 6/9 (67%). Median PFS was 9.6 mo (5.3-NR), and OS 20.5 mo (14.4-NR). Off treatment reasons include: progressive disease (14), comorbid condition unrelated to AS or study (1); 6 pts remain on study. Grade (G) 3 hypertension was the only possibly treatment related AE (TRAE) occurring in ³10%. No G 4/5 TRAE were reported. Conclusions: C + N demonstrated significant antitumor activity in taxane-pretreated AS and was well tolerated without new safety concerns. Activity of the combination was seen across AS subtypes. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; U10CA180820; https://acknowledgments.alliancefound.org . U10CA180868; U10CA180888. NCT04339738. Clinical trial information: NCT04339738 .

11005 Background: Despite progress in the enrollment of underrepresented in medicine (UIM) individuals in medical schools, hematology/oncology (HO) remains one of the least diverse medical subspecialties. We evaluated current recruitment efforts and barriers to the inclusion of UIM individuals in HO fellowship programs. Methods: We conducted a national online survey of program directors (PDs) and associate PDs (reported in aggregate as PDs) of adult and pediatric HO fellowships. Each PD received a unique survey link via email and 4 email reminders over the 8-week study period. Interim results at 4-weeks are presented and summarized with descriptive statistics. Results: At a pre-defined interim time point of 4 weeks, 78 HO PDs participated (18% response rate) and 69 completed the survey (88% completion rate). Most self-identified as women (57%, n = 38) and White (55%, n = 37), were affiliated with an academic program (79%, n = 53), and led an adult HO fellowship (73%, n = 49). Most PDs reported under or no representation of UIM faculty in their divisions; 9% (n = 6) self-identified as UIM. PDs reported their HO fellowships matched a median of 3 UIM fellows over the last 5 years (IQR 2-5 over 5 years); 46% (n = 32) reported UIM recruitment was unchanged and 4% (n = 3) decreased during this period. About half of PDs (51%, n = 35), matched a UIM candidate in the 2023 match. Of the 21% (n = 14) of PDs whose programs had no UIM fellows, 0% matched a UIM applicant in the 2023 match. 52% (n = 36) of PDs endorsed an inability to match UIM applicants despite consistently ranking them highly. PDs perceive the top 3 barriers to UIM recruitment as: low number of UIM applicants (53%, n = 41), geographic program location (50%, n = 39), and lack of diverse faculty/fellows in their program (42%, n = 31). 10% (n = 7) also reported meeting resistance about DEI initiatives. While 53% (n = 41) of PDs believe fellow demographics should reflect the local population, 23% (n = 16) don’t know how to increase diversity and 11% (n = 8) do not believe their program’s diversity needs to increase. In answers to open ended questions, some PDs expressed disagreement with the definition of UIM and reported a perceived limited number of qualified UIM applicants. Almost all institutions provide DEI training (96%, n = 72) for faculty and most PDs believe it has improved recruitment and inclusion of diverse individuals (52% and 65%, respectively). Yet, 34% (n = 23) agree that UIM fellows in their program are treated differently because of their race/ethnicity and 22% (n = 15) agree that UIM fellows repress their identity or background to be respected by faculty, peers, and staff. Conclusions: Historically and currently excluded populations remain underrepresented in the HO workforce. PDs face multiple barriers to the recruitment of diverse fellows, including differing views on the definition of UIM and perception of the value of diversity in the physician workforce.

e22537 Background: Germline and tumor next-generation sequencing (NGS) are complementary tests whose benefit in capturing patients (pts) potentially eligible for precision therapies is maximized when the tests are paired, as qualifying pathogenic variants (PVs) are missed if either test was done in isolation (Lincoln et al. 2020). Germline NGS has the additional benefit of informing prevention through surveillance and cascade testing. We highlight the benefits of a universal approach to concurrent testing in a subset of the previously reported cohort of pan-cancer pts who underwent universal germline NGS (Samadder et al. 2020). Methods: Unselected pts with solid tumors underwent an 80+ gene germline panel and 315+ gene tumor panel. Variants in genes unique to the germline or tumor panels, including microsatellite instability (MSI) and tumor mutation burden (TMB), were also evaluated. Results: 104 pts [81.7% White, non-Hispanic, 71.2% male] with 23 cancer types [28% colorectal, 13% lung, 11% prostate, 49% other] were included. Five (5%) pts had no actionable tumor alterations or germline variants identified (Table). 18 pts (17%) had 19 pathogenic germline variants (PGVs) identified, 11 (58%) of which were detected on tumor NGS (Table). 92 pts had >1 tumor alteration identified, of which 12% were confirmed as PGVs (Table). Notably, tumor NGS revealed 81 pts (78%) pts with biomarkers that would could not have been identified with germline testing alone, such as variants in genes not on germline panel (80) or MSI-high (4), or TMB-high (21) status of the tumor. Conclusions: Germline and tumor NGS are complementary tests that often detect different actionable alterations. There is value in confirming both the presence and absence of somatic variants in the germline in order to make appropriate clinical recommendations for the patient and their family members. [Table: see text]

e22514 Background: Several colorectal cancer (CRC) screening tests, shown to reduce CRC incidence and mortality, are recommended for average-risk adults aged 45-75 years. CRC screening is underutilized in the US with access to facility-based options, such as colonoscopy, representing a barrier to screening. Stool-based tests are guideline-endorsed and offer patients a convenient and more accessible CRC screening option that can be completed at home. Provider recommendation is consistently identified as the primary factor driving patient adherence. Understanding how aspects of patient-provider communication influence CRC screening can inform interventions to improve adherence. We developed a survey, informed by behavioral theory, to identify communication factors associated with completion of mt-sDNA screening. Methods: Adults aged 45-75 years, with a US postal address, who received a valid order for mt-sDNA and whose kit was shipped between 5/21-9/21 were eligible for sampling. The survey was administered by RTI International between 3/22-6/22. Participants could complete electronic or paper surveys. We fit a multivariable logistic regression to identify patient-provider communication factors associated with mt-sDNA test completion. Results: 2,973 respondents completed the survey (response rate = 21.7%). The majority (77.3%) completed the mt-sDNA test and said they would be ‘very likely’ (76.8%) to complete Cologuard in the future. The proportion of respondents who had conversations with their healthcare provider about Cologuard, and the specific content of those conversations, was significantly different between completers and non-completers and between respondents who said they were ‘very likely’ to complete Cologuard in the future compared to respondents who were not. Results from a binary logistic regression suggested that discussions with a healthcare provider related to step-by-step instructions for completing Cologuard (OR = 1.62) and needing to have a colonoscopy follow-up (OR = 1.93), as well as feeling included ‘a great deal’ in the decision-process with respondents’ healthcare provider (compared to ‘somewhat’ or ‘not at all’) increase the odds of kit completion. Additionally, healthcare provider discussions relating to test cost (OR = 1.47) and performance (OR = 1.72), as well as feeling included ‘a great deal’ in the decision-process was positively associated with respondents indicating they were ‘very likely’ to use Cologuard in the future. Provider discussions about the cost of a follow-up colonoscopy was negatively associated with a ‘very likely’ future user (OR = 0.52). Conclusions: Healthcare providers play a key role in patient adherence to CRC screening and must be appropriately prepared and resourced to educate and to engage patients in shared decision-making about CRC screening.

e22500 Background: Oncologists are change agents to improve tobacco cessation among patients. As part of the National Cancer Institute Cancer Center Cessation Initiative, we established an electronic health record (EHR, Epic)-based "opt-out" approach to refer patients to tobacco treatment specialist without active involvement by oncologists. However, the role of oncologists in contributing to the “opt-out” approach to patients has not been explored. We tested the hypothesis that a multi-component educational program for oncologists would increase the proportion of patients who completed tobacco treatment appointments. Methods: As a quality improvement initiative, oncology providers at the Rochester Mayo Clinic Cancer Center were educated using a multimodal academic detailing approach with group and individual educational sessions. Its effectiveness was tested using a modified step-wedge implementation design. The primary outcomes were patient behaviors that could plausibly be changed by conversations with their provider: the rate at which cancer patients identified as current tobacco users scheduled an appointment in the Nicotine Dependence Center (NDC) (which required active patient involvement), and the rate at which patients scheduled for a NDC appointment completed their appointment. Comparisons were made before, during, and after the education period (from July through Dec 2019) and with a separate group of providers who did not complete education (results examined over a similar time period). Results: Education did not improve outcomes in providers who received education; indeed, the rate of appointment scheduling decreased, although this may reflect other concurrent changes in the referral process (Table). Outcomes were similar between providers who did and did not receive education. Conclusions: Tobacco cessation efforts should be routinely integrated into cancer care to improve outcomes. The “opt-out” program resulted in approximately 1 in 5 cancer patients being seen for tobacco use, but an academic detailing approach designed to equip oncology providers to encourage their patients to complete appointments was not effective. Other approaches are needed to increase the uptake of tobacco treatment in these patients. [Table: see text]

10585 Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2 or ATM PV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts < age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( < 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts < age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( < 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients < 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS. [Table: see text]

10580 Background: Blood-based tests are an emerging option for non-invasive colorectal cancer (CRC) screening for which the Centers for Medicare & Medicaid Services (CMS) has proposed coverage every 3 years for average-risk individuals. Analyses with the CRC-AIM microsimulation model demonstrated that triennial screening with blood-based tests with CMS minimum performance often yields inferior outcomes to stool-based CRC screening (fecal immunochemical test [FIT] and multi-target stool DNA [mt-sDNA]). CRC-AIM was used to explore the impact of blood-based screening intervals, using reported performance characteristics from the ECLIPSE study (Guardant Health, Inc.)1, on estimated clinical outcomes vs FIT and mt-sDNA screening. Methods: Outcomes were simulated for average-risk individuals screened between ages 45-75 years. Intervals were set at 1, 2, or 3 years for blood-based, 3 years for mt-sDNA and annually for FIT screening. The blood-based test was modeled at 83% CRC sensitivity, 13% advanced adenoma sensitivity, and 90% specificity. Perfect adherence (100%) was modeled for blood-based tests and real-world adherence rates used for CRC initial screening tests (mt-sDNA=65.6%; FIT=42.6%) and follow-up colonoscopy (mt-sDNA=72.1%; FIT=46.0%). Primary outcomes were life-years gained (LYG) and colonoscopies (COL) per 1000 individuals for blood-based screening compared to mt-sDNA and FIT. As a secondary analysis, estimates were generated with perfect (100%) adherence assumed for initial screening and follow-up colonoscopy for mt-sDNA and FIT as well. Results: Blood-based testing at a 3-year interval with 100% adherence led to 11% fewer LYG than mt-sDNA at RWE adherence (240 vs 270, respectively), and 9% more COL (1402/1000 vs 1288/1000). Meanwhile, blood-based testing at a 1-year interval and perfect adherence (best case scenario) resulted in the lowest LYG per COL ratio across all scenarios (16% more LYG and 87% more COL compared to mt-sDNA at RWE adherence). Blood-based test results showed similar trends when compared to FIT. Conclusions: Outcomes for blood-based screening every 3 years based on reported test performance characteristics and unrealistic perfect adherence demonstrate fewer LYG as compared to either mt-sDNA or FIT. When compared to real-world adherence for mt-sDNA and FIT, blood-based tests with 1- and 2-year intervals and perfect adherence had higher LYG with the tradeoff of a greater number of diagnostic colonoscopies. [Table: see text]

10567 Background: Average-risk screening for colorectal cancer (CRC) is effective and recommended. The U.S. Preventive Services Task Force issued grade A and B recommendations for screening ages 50-75 and 45-49, respectively, however the recommendation for the older population (ages 76-85) is grade C (moderate certainty that the net benefit is small). With emerging blood-based CRC screening, we evaluated the benefits of screening the older population with continued multi-target stool DNA (mt-sDNA) or FIT strategies and/or with a modality shift to blood-based tests after age 75. Methods: Using the validated CRC-AIM microsimulation model, triennial mt-sDNA and annual FIT screening (ages 45-75) followed by four strategies for ages 76-85 (no screening, continued mt-sDNA/FIT, or a modality shift to blood-based screening using either CMS criteria [CMS] or recently reported blood test data from the ECLIPSE study1 [BT; Guardant Health, Inc.] were considered. For CMS criteria and BT, CRC sensitivity were set at 74% and 83%; and adenoma sensitivity was set to 20%, and 13%; and CRC specificity was set to 90% for both tests. Real-world (RWE) adherence for initial screening was set to 80% (CMS, BT), 65.6% (mt-sDNA), and 42.6% (FIT). Adherence for follow-up colonoscopy was set to 72.1% (mt-sDNA, CMS, BT) and 46.0% (FIT). Results: Screening among the population aged 45-85 resulted in 281 life years gained (LYG) with continued mt-sDNA as compared to 193 with continued FIT. Furthermore, mt-sDNA reduced CRC mortality by 70% as compared to 49% by FIT (Table). When screening modality was shifted to CMS (76-85 year olds), mt-sDNA/CMS resulted in 279 LYG as compared to 196 for FIT/CMS. CRC incidence was reduced by 59% (mt-sDNA/CMS) as compared to 38% (FIT/CMS), and mortality declined by 69% (mt-sDNA/CMS) as compared to 51% (FIT/CMS). Reductions in disease burden were lower when modality was switched to BT after age 75 due to reduced test performance. Conclusions: Extending CRC screening to the older population with continued mt-sDNA demonstrated the best health outcomes compared to other modalities. A modality shift after age 75 to blood-based testing resulted in greater LYG as compared to no screening, with performance at CMS criteria yielding better results than BT. Therefore, despite inferior performance, blood-based tests may offer a CRC screening option for older patients who are unable to complete stool testing. [Table: see text]

10520 Background: PATHFINDER (NCT04241796) was a prospective, interventional return of results study that enrolled 6,662 participants (pts) from 7 US institutions to assess clinical implementation of a blood-based multi-cancer early detection (MCED) test. Test results for those with a cancer signal detected also included a cancer signal origin prediction designed to help guide diagnostic evaluations. We analyzed whether the diagnostic evaluations in PATHFINDER were appropriately directed by cancer signal origin predictions, assessed the residual risk of cancer after negative initial evaluation, and examined the role of whole-body imaging (WBI, defined as PET/CT or CT chest/abdomen/pelvis) in diagnostic evaluation. Methods: Analysis included pts with a cancer signal detected result from the two different versions of an MCED test evaluated in PATHFINDER. Prespecified criteria blinded to study results were used to define expected diagnostic evaluations by cancer signal origin prediction. These criteria were then used to judge concordance between cancer signal origin predictions and the diagnostic evaluation actually performed. Definitive cancer or no cancer diagnosis (cancer status at end of study [EOS]) was assessed at 12 months after enrollment (EOS). Results: 39 pts had cancer signal detected results by both test versions. Diagnostic evaluations were consistent with cancer signal origin in 30/39 (77%) cases. Diagnostic resolution was achieved in 32/39 (82%) pts after initial evaluation, while 7/39 (18%) required additional workup. 25 of the 32 (78%) pts who achieved diagnostic resolution after initial evaluation had a cancer signal origin-guided workup. Additional evaluation of the 7 pts not achieving initial diagnostic resolution was based on persistent clinical suspicion of cancer due to prior cancer history (n = 1) or abnormal/equivocal findings on initial evaluation (n = 6). Additional workup led to diagnostic resolution in all 7 cases (3 with cancer and 4 with no cancer confirmed at EOS). WBI was ordered in 27 cases, of whom 9 had a prior cancer history, 10 had non-localizing cancer signal origin (hematologic or indeterminate), and 1 had both. WBI was equivocal or had no impact on diagnostic resolution in 8/27 (30%) cases. Conclusions: Most cases resulted in diagnostic resolution after cancer signal origin-directed diagnostic workup. In pts with a cancer history and negative initial evaluations, and those with equivocal initial evaluations, there was still a risk of cancer, suggesting the need for additional evaluation. WBI was used mostly in those with a cancer history or non-localizing cancer signal origins, and had no impact on diagnosis in almost one-third of pts. Clinical trial information: NCT04241796 .