Beer, Tomasz M.

3010 Background: PATHFINDER (NCT04241796) is an interventional, prospective study evaluating implementation of a blood-based multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA analysis to detect multiple cancer types and simultaneously predict cancer signal origin (CSO). We present a prespecified interim analysis of PATHFINDER evaluating an MCED test in a clinical setting. Methods: Participants (pts; ≥50y) were enrolled into 2 risk cohorts: non-elevated and elevated (smoking history, prior cancer [ > 3y post treatment], or genetic predisposition). MCED test results (cancer signal detected/not detected) were returned to investigators; pts with a signal detected also received a CSO prediction and underwent further diagnostic testing by their medical team. The primary objective was to assess the extent of diagnostic testing needed to achieve diagnostic resolution (eg, time to resolution, number/type of tests). Secondary endpoints included positive predictive value (PPV) and a measure of test satisfaction (following diagnostic resolution [signal detected] and post test [signal not detected]). Results: PATHFINDER consented 6796 pts before closing accrual on 12/4/20; as of October 6, 2020, 4086 consented, 4047 enrolled, and 4033 analyzable pts were included in the interim analysis (62.4% female, 92.1% white). Two study-related adverse events (anxiety of mild severity) were reported. Cancer signal was detected in 1.5% (62/4033) of pts; 40/62 reached diagnostic resolution to date. Kaplan-Meier estimate of median time to resolution was 78 (95% CI, 54-151) days. Among 40 pts that reached diagnostic resolution, ≥1 imaging test was performed in 93% (37/40); ≥1 invasive procedure was performed in 72% (13/18) versus 18% (4/22) of pts with diagnostic resolution of cancer versus no cancer, respectively. Based on results to date, PPV was 45% (95% CI, 30.7-60.2%; 18/40). Of 18 cancer diagnoses, 11 were solid tumors (3 stage IV, 6 stages I-III, 1 metastatic recurrence, 1 missing stage), and 7 were hematologic malignancies (1 stage IV, 4 stages I-III, 2 without AJCC stage). Accuracy of the top CSO prediction in true positives was 82.4% (95% CI, 59.0-93.8%; 14/17). Most pts were satisfied with the test (43.7% extremely satisfied, 30.7% very satisfied, 14.6% satisfied). Signal detection rate and test satisfaction were similar in the 2 risk cohorts; PPV tended to be higher in the elevated risk cohort, as expected. Conclusions: An interim analysis of this return of results study demonstrated promising MCED test results. Of 40 pts achieving diagnostic resolution, nearly half had a diagnostic workup confirming cancer; CSO was predicted with high accuracy for detected cancers. Taken together with the rarity of adverse events and high test satisfaction, these results support the feasibility of clinical implementation. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

Abstract Background: Early detection decreases patient mortality for many cancers, but prevailing paradigms focus on distinct screening modalities for each cancer type. A minimally invasive test that detects multiple tumor types could substantially reduce cancer mortality and improve screening efficiency. In preliminary studies, we showed that a targeted methylation cell-free DNA (cfDNA) test can detect cancer and determine the tissue of origin (TOO) of abnormally methylated cfDNA with high sensitivity and specificity; however, blood was collected at the time of diagnosis and results were not disclosed to inform care. The current study includes disclosure of results to the study investigator to understand the care pathways prompted by a “signal detected” test result, and the benefits, harms, and burdens associated with a multi-cancer detection test. Methods: PATHFINDER (NCT04241796) is a prospective, longitudinal, multi-center clinical study. Approximately 6,200 participants with varying levels of cancer risk will be enrolled at 5-10 clinical sites in the United States. Participants must be ≥50 years of age. If participants have at least 1 of the following–a smoking history of ≥100 cigarettes, a genetic cancer predisposition, or a history of invasive or hematologic malignancy with definitive treatment completed >3 years prior to enrollment–they are eligible for the Elevated Risk Cohort (n = 4340); otherwise, they are eligible for the Non-Elevated Risk Cohort (n = 1860). Individuals being evaluated for cancer or who have a history of invasive or hematologic malignancy within 3 years of enrollment will be excluded. Blood drawn at study sites will be analyzed at GRAIL, Inc. (Menlo Park, CA). Participants and study investigators will be informed of the test results. Participants with “signal not detected” results will be advised to continue routine clinical care, including age- and risk-based cancer screening. Those with “signal detected” test results will be informed of the predicted origin and undergo diagnostic evaluation. The primary study objective is to determine the extent of diagnostic testing required to achieve diagnostic resolution following a “signal detected” test result, defined as the date when the study investigator determines to end diagnostic evaluation triggered by a “signal detected” test result. Health resource utilization, the number and types of tests and time required to reach this point, is the primary endpoint. Secondary objectives include evaluation of test performance (specificity, positive predictive value, and TOO accuracy), and assessment of participants' perceptions about the test and changes in anxiety and health-related quality of life. Exploratory aims include assessment of the number and types of invasive cancer diagnoses among participants with “signal not detected” test results and changes in attitude toward adherence to guideline-recommended screening. Citation Format: Lincoln Nadauld, Charles H. McDonnell III, Minetta C. Liu, Eric Klein, Tomasz M. Beer, Deborah Schrag, Andrew G. Hudnut, Richard Whittington, Bruce Taylor, Joanna Tierney, Catherine Marinac, Jafi Lipson, Margarita Lopatin, Karen C. Chung, Eric Fung, Anne-Renee Hartman, Geoffrey R. Oxnard. The PATHFINDER Study: Assessment of the implementation of an investigational multi-cancer early detection test into clinical practice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT291.

TPS5093 Background: Globally, docetaxel remains the standard of care for metastatic CRPC; however, its use may be delayed until pts develop symptoms. The presence of infiltrating leukocytes in CRPC tumors suggests a natural antitumor immune response is occurring. This is supported by an overall survival (OS) benefit reported in men with asymptomatic or minimally symptomatic metastatic CRPC who received sipuleucel-T. Ipi, a monoclonal antibody that binds CTLA-4, augments antitumoral activity of cytotoxic immune cells. Ipi demonstrated OS benefit in two phase III trials for advanced melanoma, with side effects that were managed using product-specific treatment guidelines. In phase I/II trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostate-specific antigen [PSA] declines and RECIST response) with a similar toxicity profile to that observed in melanoma. This global (149 sites in 24 countries) phase III study (ClinicalTrials.gov identifier: NCT01057810) evaluates Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The study is designed to detect a 9.3-month median difference (HR=0.7) in OS with 90% power and 0.05 two-sided significance. Pts are randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo as induction therapy. Eligible pts will receive maintenance therapy of blinded study drug every 12 weeks. The accrual goal is 600 pts randomized. Clinical trial information: NCT01057810. [Table: see text] [Table: see text]

9021 Background: Physician-reported performance status (PS) is an important prognostic factor in advanced malignancies and is a commonly used stratification variable in cancer clinical trials. However, the extent, predictors, and prognostic importance of disagreement in PS assessment between physicians and patients have not been examined. Methods: Using NCCTG clinical trials from 1987–1990 (J Clin Oncol 19(15):3539–3546, 2001), we analyzed the difference and agreement of PS (ECOG and Karnofsky [KPS]) and nutritional status assessments reported by physicians and patients individually. The degree of disagreement was analyzed using paired t-test. Overall mortality was estimated by Kaplan-Meier method. The effect of disagreement on overall survival was analyzed by Cox regression. Independent predictors of disagreement were identified by logistic regression. Results: 1,636 patients with advanced lung and colorectal cancer had a median survival of 9.8 months (95% CI, 9.4 to 10.4). Percent agreement between patients and physicians about KPS, ECOG PS, and appetite/nutritional status was 32.9%, 43.4% and 42.0% respectively. Physicians were more likely to rate patients better than individual patients were to rate themselves: ECOG (Mean 0.91 vs 1.30, p<.0001), KPS (Mean 83.3 vs. 81.7, p<0.0001), appetite/nutritional status (Mean 1.6 vs. 2.1, p<0.0001). Inability to work, depression and less than a high school education were independently associated with disagreement. An increased risk of death was observed for patient and physician disagreement on KPS (HR=1.15, 95% CI, 1.03 to 1.27 p=0.01) and appetite/nutritional status (HR=1.39, 95% CI, 1.26 to 1.54 p<0.0001). Conclusions: Patients and physicians frequently disagree about patient PS, with physicians tending to rate patients higher than patients do themselves. Baseline patient demographic factors that independently predict disagreement have been identified. Disagreement confers an increased risk of death in the setting of advanced malignancies. These findings illustrate limitations of physician-only assessed PS. No significant financial relationships to disclose.

52 Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]

2 Background: The CA184-043 phase 3 study did not reach statistical significance for its primary endpoint of OS (HR=0.85, p=0.053). However, antitumor activity was observed in other efficacy endpoints, including progression-free survival. Prespecified subset analyses were performed to understand if any prognostic features may identify mCRPC patients (pts) more likely to benefit from Ipi treatment. Methods: 799 pts were randomized to receive a single dose of radiotherapy (RT) followed by either Ipi (N=399) or Pbo (N=400). Prespecified subset analyses based on Kaplan-Meier/Cox methodology were performed using known prognostic factors for OS in mCRPC. Results: Prespecified subset analyses suggested that Ipi may be more active in pts with favorable prognostic factors, including no visceral disease, alkaline phosphatase <1.5 ULN, and hemoglobin ≥11 g/dL (Table). The safety profile in this study was consistent with previous reports of Ipi. Conclusions: Based on these subset analyses, Ipi added to RT appears to have greater activity than RT alone in pts with a favorable prognostic profile. These results support continued investigation of Ipi in the ongoing CA184-095 study in chemotherapy-naive mCRPC pts. Clinical trial information: NCT00861614. [Table: see text]

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.