Pertuzumab Plus Trastuzumab for Treatment-Refractory HER2-Amplified Metastatic Colorectal Cancer: Comparison of the MyPathway Trial With a Real-World External Control Arm

Abstract

PURPOSE We compared overall survival (OS) in patients with human epidermal growth factor receptor 2 ( HER2)–amplified, treatment-refractory metastatic colorectal cancer (mCRC) receiving pertuzumab plus trastuzumab (PER-HER) in the phase IIa MyPathway multibasket study (ClinicalTrials.gov identifier: NCT02091141 ) with OS in those receiving routine clinical care in an electronic health record–derived external control arm. METHODS A noninterventional study was conducted using patient-level data from MyPathway participants receiving PER-HER and real-world patients with HER2-amplified treatment-refractory mCRC receiving routine clinical care. This study used a deidentified US-based clinico-genomic database (CGDB). For patients in the CGDB who met study eligibility criteria at multiple index dates (treatment initiation dates in the treatment-refractory setting), all eligible index dates were used for the analysis. Standardized mortality ratio weighting on the basis of propensity score derived a pseudopopulation (postweighting population) balancing key prognostic variables between arms. Multivariate Cox proportional hazards models were used for estimation of the hazard ratio (HR) in the primary OS analysis. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis. RESULTS The PER-HER arm comprised 57 patients enrolled in the MyPathway study by August 1, 2017 (data cutoff); the external control arm comprised 18 patients (27 index dates) with HER2-amplified mCRC who met the major MyPathway eligibility criteria in CGDB collected between 2011 and 2019. The estimated HR for OS from the multivariate Cox proportional hazards model in the postweighting population was 0.729 (95% CI, 0.184 to 3.900). The results of sensitivity analyses were consistent with the primary analysis in terms of the point estimate of HR. CONCLUSION Despite a small sample size, these findings suggest that PER-HER could have a potential OS benefit for this population.

Examining external control arms in oncology: A scoping review of applications to date

“…The earliest study reported was by Onishi et al 33 . in 1996, while the most recent studies took place in 2022 26,34–36 (Table 1). During the 1990s, a total of 9% (2/23) of included studies were published 33,37 .…”

“…[38][39][40] The most notable growth in publications occurred in the 2010s, as demonstrated by the 10 studies published during that period, accounting for 43% (10/23). [41][42][43][44][45][46][47][48][49] This trend appears to continue into the 2020s, with 35% (8/23) studies already completed in the first few years of the decade 26,28,[34][35][36][50][51][52][53] (Table 1).…”

“…In this compilation of studies, we observed an increasing application of ECAs for oncology research in recent years. The earliest study reported was by Onishi et al 33 in 1996, while the most recent studies took place in 2022 26,[34][35][36] (Table 1). During the 1990s, a total of 9% (2/23) of included studies were published.…”

“…Pooled data from past trials were the primary data sources used in constructing the ECAs, featured in 30% (7/23) of the studies. 26,41,45,46,48,51,53 Administrative health databases 28,38,39,47 and electronic medical records 34,36,44,49 T A B L E 1 (Continued) from registries 37,50,52 , and 4% (1/23) did not specify the data source. 42 Moreover, 13% (3/23) drew from external databases, 33,35,43 while an equal percentage 4% (1/23) collected from both administrative health databases and registries 40 (Table 1).…”

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours

“…Chemotherapy plus trastuzumab is also the recommended first-line therapy according to the ToGA trial 5 , 6 . Moreover, growing evidence justifies the application of anti-HER2 therapy in HER2-positive colorectal cancer 7 , 8 .…”