Enrollment Barriers for Molecular Targeted Trials

Abstract

This quality improvement study examines the difficulties of patient accrual among patients with cancer and SETD2 variants.

A wide array of challenges may hamper patient accrual to molecular targeted trials, with inaccessibility to next-generation sequencing results through electronic medical records and point-of-care matching to a specific trial in large portfolios believed to be paramount factors.¹ Sequencing reports typically provide listings of relevant national clinical trials; however, availability of trials within patients’ travel radius and incomplete information on changing enrollment status of trials limit the listings’ usefulness.^2,3

Methods

We aimed to address these challenges in the context of a SETD2 variant–targeted trial⁴ that assessed AZD1775 response in 2 cohorts with advanced renal cell carcinoma (RCC) or other tumors. The University of Chicago Medical Center Institutional Review Board approved the study and waived the informed consent requirement because the study posed minimal risk to patients. We followed the SQUIRE reporting guideline.

Tempus, a company providing molecular testing services, was engaged to prospectively identify patients whose tumors carried relevant SETD2 molecular variants and who resided within 50 miles of the research institution or were receiving treatment at prespecified clinical sites that routinely referred patients to the institution. Tempus staff sent an initial notification of potential trial eligibility to ordering physicians via email, and multiple follow-up notifications were made via telephone to remind physicians of potential trials and provide contact information for referrals.

Descriptive statistics were reported using Microsoft Excel, version 16.16.22 (Microsoft Corp). Descriptive data were extracted from February 15 to March 6, 2022.

Results

Over 1 year (from September 24, 2020, to October 8, 2021), 38 potentially eligible patients were identified, none of whom were enrolled. Physicians received 0 to 1, 2 to 3, or 4 or more follow-up notifications regarding trial availability for 14, 19, or 5 patients, respectively. The Table shows the frequency of different tumor types, reasons for lack of enrollment, and distance from the trial site. Twenty-two patients without RCC who otherwise fulfilled eligibility criteria were not enrolled as the non-RCC cohort closed after initial SETD2 variant identification. Cohort closure occurred less than 2 months, 2 to 4 months, 4 to 6 months, or more than 6 months after identification of SETD2 variant in 5, 8, 2, or 7 patients, respectively (median [range], 4.0 [0.5-7.0] months).

Table. Frequency of Different Tumor Types, Reasons for Lack of Enrollment, and Distance From Trial Site Among Patients With SETD2 Variant.

Variable	Patients, No. (%)
No. of potentially eligible patients who were not enrolled	38 (100)
Tumor type (n = 38)
Non–small cell lung cancer	10 (26.3)
Clear cell–type RCC	7 (18.5)
Colorectal	4 (10.5)
Breast	4 (10.5)
Melanoma	3 (7.9)
Biliary tract	2 (5.3)
Endometrial	2 (5.3)
Glioblastoma	2 (5.3)
Sarcoma	1 (2.6)
Ovarian	1 (2.6)
Gastric	1 (2.6)
Bladder	1 (2.6)
No. of eligible patients without RCC who were not enrolled	31 (81.5)
Reasons for lack of enrollment
Cohort closure	22 (57.9)
Time from initial outreach to cohort closure, mo (n = 22)
<2	5 (22.7)
2-4	8 (36.4)
4-6	2 (9.1)
>6	7 (31.8)
Considering trial enrollment as future option	6 (15.8)
Lack of response from ordering physician	4 (10.5)
Presence of prohibitive comorbidities	3 (7.9)
Lack of patient interest	2 (5.3)
Patient death before enrollment	1 (2.6)
Distance from trial site, milesa
0-10	10 (26.3)
11-20	5 (13.2)
21-30	6 (15.8)
31-40	5 (13.2)
41-50	1 (2.6)
>50	9 (23.7)

Abbreviation: RCC, renal cell carcinoma.

SI conversion factor: To convert miles to kilometers, multiply by 1.6.

^a Distance from trial site unavailable for 2 patients.

Discussion

Inability to accrue patients in this study occurred despite the Clinical Laboratory Improvement Amendments certifying sequence variation detection as well as individual and repeated follow-up with treating physicians. While many patients likely had extenuating clinical circumstances precluding their trial participation, molecular testing is often performed to provide guidance for treatment in refractory scenarios. At least 10 patients in this study were likely never informed of trial availability since the treating physicians either did not respond to outreach or indicated only considering trial enrollment in the future. We made similar observations of limited accrual to the National Clinical Trials Network Molecular Analysis for Therapy Choice trial after treating physicians were provided with detailed enrollment information following identification of a qualifying sequence variation through the molecular testing platform at the University of Chicago Medical Center. These findings raise the hypothesis that the biggest barrier to enrollment, as in other settings, is motivation of treating physicians and that algorithms for identifying potential participants need to be aligned with patients’ treatment trajectory.^5,6

This study was limited by not addressing other relevant factors associated with patient enrollment, including financial barriers, availability of standard-of-care options, and socioeconomic factors such as travel barriers. Larger-than-anticipated target populations, better coordination between outreach efforts and enrollment status, and directed patient outreach may be necessary.

Supplement.

Data Sharing Statement