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

C Rolfo, L M Hess, M-H Jen, P Peterson, X Li, H Liu, Y Lai, T Sugihara, U Kiiskinen, A Vickers, Y Summers, C Rolfo, L M Hess, M-H Jen, P Peterson, X Li, H Liu, Y Lai, T Sugihara, U Kiiskinen, A Vickers, Y Summers

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: RET fusion; clinical trial; external control; real-world data; synthetic control.

Conflict of interest statement

Disclosure LMH, MHJ, UK, YL, XIL, HL, and PP are employees of Eli Lilly and Company. TS and AV are employees of Syneos Health and RTI Inc., respectively. Both Syneos Health and RTI Inc. receive funding from Eli Lilly and Company for statistical and analytic support of outcomes research. YS reports advisory/educational activities for Abbvie, AstraZeneca, Amgen, BMS, EQRX, Eli Lilly and Co., MSD, Roche, Takeda, and Pfizer. CR reports current consulting for EMD Serono, Pfizer, Mirati, Eisai, Daiichi Sankyo, and Sanofi; stock ownership in Novartis; educational activities for AstraZeneca, Roche, and CORE2ED; and research grant funding from Pfizer. CR also serves on a safety advisory board for EMD Serono. Data sharing Lilly provides access to all individual participant data collected during a clinical trial, after anonymization, with the exception of pharmacokinetic or genetic data. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. The real-world data that support the findings of this study have been originated by Flatiron Health, Inc. These de-identified data may be made available upon request and are subject to a license agreement with Flatiron Health; interested researchers should contact DataAccess@flatiron.com to determine licensing terms.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

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