Interim results of PATHFINDER, a clinical use study using a methylation-based multi-cancer early detection test.

Abstract

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.

Circulating Tumor DNA Allele Fraction

“…52 The interventional PATHFINDER study has shown the ability of a targeted methylation-based MCED test to detect cancer before clinical presentation. 55 This evidence also disproves models that estimate the feasibility of cancer detection from tumor volume alone, 16 as these cannot sufficiently reflect the heterogeneity, varying detectability, and varying clinical significance of neoplasms of the same volume. Such models do not agree with empirical evidence, including prospective interventional studies.…”

“…The ability to detect cancer before clinical presentation using this targeted methylation-based MCED test has been demonstrated in the interventional PATHFINDER Q17 study. 55 In addition, in the exploratory prospective, interventional study, Detecting Cancers Earlier through Elective Mutation-Based Blood Collection and Testing, 26 preclinical cancers in z10,000 women, aged 65 to 75 years, with no personal history of cancer and with high adherence to standard-of-care screening were detected using a cfDNA-based MCED test and protein biomarkers. 56 Notably, the ability to detect low cTAF cancer cases overcomes issues associated with low ctDNA yield in blood samples for early-stage cancers.…”

Circulating cell-free DNA for cancer early detection

“…The interim results showed that cancer signals were detected in 1.4% of all analyzable participants, and nearly half with diagnostic resolution had confirmed cancer, with an estimated 45% positive predictive value (PPV). 152 Another multi-cancer detection based on cfDNA methylation yielded a sensitivity of 80.6% in six types of cancers at specificity of 98.3% in the validation group, and the TOO accuracy was 87.0% for top-two organ localization. 94 …”

“…Thus, current early detection tests of multi-cancers cannot fully replace SOC screening tests; instead, they can be a complement. In PATHFINDER and DETECT-A studies, 92 , 152 participants are all encouraged to stick to SOC screening tests, even with a negative test result to rule out the possibility of false-negative results.…”

Regulation of Laboratory-Developed Tests in Preventive Oncology: Emerging Needs and Opportunities

“…[50][51][52][53][54][55][56] For one methylation-based ctDNA LDT, the positive predictive value, the proportion of actual cancers found after an abnormal test in an asymptomatic population, ranged from , 10% to 45%, depending on how the calculation was performed. 55 These inconsistent metrics are due to differing methodologic assumptions regarding incident rather than prevalent cancer rates in asymptomatic populations, lower test sensitivities in earlier-stage disease, and the presence of noncancer conditions affecting specificity, [53][54][55][56] underscoring the need for clinicians and regulators to have access to reproducible metrics of clinical validity. For presymptomatic cancer LDTs, a predictive value of a positive test that is , 50% will have substantial safety implications in terms of risks of resulting invasive diagnostic procedures.…”