Inter-Ethnic Differences in the Efficacy and Safety of Tyrosine Kinase Inhibitors Used in Oncology: Insights From Phase 3 Clinical Trials

Abstract

Differences in the efficacy and safety of tyrosine kinase inhibitors (TKIs) have been observed across ethnic/ancestry subpopulations (previously reviewed to 2017). With an expanding number of TKIs approved since that time, an updated review of TKI response across ethnic/ancestry subpopulations in Phase 3 TKI clinical trials was conducted. A total of 73 population subgroup analyses (defined by participant race, ethnicity, ancestry or geographic region) of progression-free survival (PFS) and/or overall survival (OS) were identified by a literature search. Twelve (16%) of the analyses investigating the efficacy of afatinib, brigatinib, dacomitinib, gilteritinib, lorlatinib, neratinib, osimertinib, or pazopanib were assessed to report population differences in PFS and/or OS. For 28 (38%) of the analyses that showed suggestions of a potential efficacy difference across subpopulations, limitations in the data available precluded further assessment. There were 17 (23%) analyses assessed to report comparable efficacy outcomes across diverse subpopulations. The majority of clinical trials noted no clinically remarkable differences in safety between subpopulations; however, for brigatinib, crizotinib, pazopanib, and sunitinib, distinct patterns of adverse events were reported in the Asian and non-Asian subgroups. The underrepresentation of specific subpopulations, the grouping together of results of diverse subpopulations, as well as inconsistencies in the definition and reporting of participant ethnicity/ancestry are barriers to the meaningful exploration of inter-ethnic differences in TKI response. Therefore, further insight into the associations between ethnicity/ancestry and TKI response will require an increase in the diversity of clinical trial participants and appropriate analysis and reporting of subpopulation results.

Keywords: diversity; efficacy; ethnicity; geographic ancestry; inter‐ethnic differences; safety; tyrosine kinase inhibitors.

FIGURE 1

Intrinsic and Extrinsic Factors Contributing to Population Differences in Drug Pharmacokinetics and Pharmacodynamics. The figure was adapted from Ref. [4]. The figure was prepared using an illustration from Servier Medical Art (SMART, https://smart.servier.com).

FIGURE 2

Assessment of Population Subgroup Differences in Progression‐Free Survival and/or Overall Survival from Phase 3 Clinical Trials of TKIs Used in Oncology.

FIGURE 3

Progression Free Survival and/or Overall Survival Results for Clinical Trials with Strong Trends Indicating Population Subgroup Differences (Blue) or Similarities (Black). Additional population subgroup analyses for these clinical trials are reported in Figures S1, S2. (1) Afatinib + vinorelbine vs. trastuzumab + vinorelbine, (2) Compares maintenance erlotinib and erlotinib administered at disease progression, (3) Gilteritinib + azacitidine vs. azacitidine alone, (4) Neratinib + capecitabine vs. lapatinib + capecitabine, (5) Nintedanib + best supportive care vs. placebo + best supportive care, (6) Regorafenib + best supportive care vs. placebo + best supportive care. ALK, Anaplastic lymphoma kinase; AML, Acute myeloid leukemia; AUS, Australia; CLL, Chronic lymphocytic leukemia; CRC, Colorectal cancer; DFS, Disease‐free survival; EGFR, Epidermal growth factor receptor; FLT, FMS‐like tyrosine kinase; GIST, Gastrointestinal stromal tumor; HCC, Hepatocellular carcinoma; HER, Human epidermal growth factor receptor; HR [95% CI], Hazard ratio [95% confidence interval]; N. America, North America; NSCLC, Non‐small cell lung cancer; OS, Overall survival; PFS, Progression‐free survival; TKI, Tyrosine kinase inhibitor; RCC, Renal cell carcinoma; SLL, Small lymphocytic lymphoma; TKI, Tyrosine kinase inhibitor; W. Europe, Western Europe.