Broad versus limited gene panels to guide treatment in patients with advanced solid tumors: a randomized controlled trial

Abstract

Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs). Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with an MBRT identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to MBRT identification, the number of patients with and without MBRTs initiated, progression-free survival, best overall response, duration of response and safety. Among the 741 patients screened, 45.7% had quality-checked tumor samples. MBRTs were identified with F1CDX in 175 (51.6%) patients and with CTL in 125 (36.9%) patients, translating to a significant increase of 14.8 percentage points (P < 0.001) with the more comprehensive gene panel versus the more limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations. These findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded MBRTs. ClinicalTrials.gov registration: NCT03163732 .

Fig. 1. Trial profile.

Patients with tumor sample available (ITT population, n = 339) were allocated to randomization to F1CDX (n = 171) or CTL (n = 168). Molecular profile analysis failed in 13 patients for both panels (F1CDX: n = 5, CTL: n = 8), and 17 patients had a molecular profile achieved from a single panel (F1CDX: n = 10, CTL: n = 7). Molecular profiles achieved with both panels were available for 309 patients (per protocol population). Two gene panels were used: F1CDX (324 genes) and a home-based limited panel (CTL) (87 genes). At patient progression, the MTB reviewed genomic alterations matching with at least one MBRT based on the first panel as defined per randomization. In the case of failure (no MBRT identified with the first panel), the second panel was disclosed. Among the 339 patients, an MBRT was identified in 192 (56.6%) patients and an MBRT was initiated in 51 (15%) patients. Of note, 17 deaths occurred during screening, and tumor samples were not collected from these patients. A total of 58 patients died after randomization and before MTB review. However, their molecular profiles had been considered for MTB review at the date of data cutoff, and MBRTs were recorded (no MBRT: n = 25 (F1CDX: 12, CTL: 13); MBRTs: n = 33 (F1CDX: 19, CTL: 14)). A total of 233 deaths occurred during the study period.

Fig. 2. Progression free survival (PFS).

a,b, PFS in patients with subsequent treatment line (n = 163; F1CDX: 79, CTL: 84) (a), and in patients with MBRT initiated after MTB#1 (n = 43; F1CDX: 24, CTL: 19) (b). PFS was estimated from first molecular tumor board (MTB#1). PFS was set to 0 in patients with no MBRT (F1CDX: 30; CTL: 43). KM est., Kaplan–Meier estimate.

Extended Data Fig. 1. Trial design.

R: randomization; F1CDX panel (Foundation One, Inc); CTL: Control panel; MBRT: Molecular based recommended therapy. MTB: Molecular Tumor Board.

Extended Data Fig. 2. Paired analysis including prespecified sensitivity analysis.

Two gene panels were used F1CDX (324 genes), Home-based limited panel (CTL) (87 genes). ‡ At patient progression, the MTB reviewed genomic alterations matching with at least one MBRT, based on the first panel as defined per randomization. In the case of failure (no MBRT identification with the first panel), the second panel was disclosed.

Extended Data Fig. 3. Patients with molecular based treatment recommendation (MBRT) and MBRT initiated using F1CDX® or CTL panel (N = 339).

a) Patients with ≥1 molecular based treatment recommendation (MBRT) according to pathway (N = 192), b) Patients with ≥1 MBRT initiated, according to molecular pathway-based recommendations (N = 51), using F1CDX^® or CTL panel (N = 339).

Extended Data Fig. 4. Number of patients with MBRT initiated (all MBRTs) according to disease localization (N = 51).

Number of treatments initiated by tumor types.