External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer

• Published in: ESMO open 2022-08, Vol.7 (4), p.100551-100551, Article 100551
• Main Authors: Rolfo, C., Hess, L.M., Jen, M.-H., Peterson, P., Li, X., Liu, H., Lai, Y., Sugihara, T., Kiiskinen, U., Vickers, A., Summers, Y.
• Format: Article
• Language: English
• Subjects: clinical trial; external control; Original Research; real-world data; RET fusion; synthetic control
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2022.100551

Data for selpercatinib [a selective REarranged during Transfection (RET) inhibitor] from a single-arm trial (LIBRETTO-001, NCT03157128) in RET-fusion-positive advanced/metastatic non-small-cell lung cancer (NSCLC) were used in combination with external data sources to estimate comparative efficacy [objective response rate (ORR), progression-free survival, and overall survival (OS)] in first- and second-line treatment settings. Patient-level data were obtained from a de-identified real-world database. Patients diagnosed with advanced/metastatic NSCLC with no prior exposure to a RET inhibitor and one or more prior line of therapy were eligible. Additionally, individual patient-level data (IPD) were obtained from the pemetrexed + platinum arm of KEYNOTE-189 (NCT03950674, first line) and the docetaxel arm of REVEL (NCT01168973, post-progression). Patients were matched using entropy balancing, doubly robust method, and propensity score approaches. For patients with unknown/negative RET status, adjustment was made using a model fitted to IPD from a real-world database. In first-line unadjusted analyses of the real-world control, ORR was 87.2% for LIBRETTO-001 versus 66.7% for those with RET-positive NSCLC (P = 0.06). After adjustment for unknown RET status and other patient characteristics, selpercatinib remained significantly superior versus the real-world control for all outcomes (all P < 0.001 except unadjusted RET-fusion-positive cohort). Similarly, outcomes were significantly improved versus clinical trial controls (all P < 0.05). Findings suggest improvement in outcomes associated with selpercatinib treatment versus the multiple external control cohorts, but should be interpreted with caution. Data were limited by the rarity of RET, lack of mature OS data, and uncertainty from assumptions to create control arms from external data. •Single-arm trials are limited by the lack of a comparison arm, and external controls are needed.•Multiple methodological approaches with various external control arms evaluated the comparative efficacy of selpercatinib.•Findings suggest that selpercatinib is associated with significantly improved clinical outcomes versus standard therapies.•Results should be considered exploratory and hypothesis generating due to the limitations of this study.