AUTHOR=Kim Chul , Liu Stephen V. , Crawford Jennifer , Torres Tisdrey , Chen Vincent , Thompson Jillian , Tan Ming , Esposito Giuseppe , Subramaniam Deepa S. , Giaccone Giuseppe 

TITLE=A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.728155

DOI=10.3389/fonc.2021.728155

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Osimertinib is an effective first-line therapy option for <italic>EGFR</italic>-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.</p></sec><sec><title>Method</title><p>This is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced <italic>EGFR</italic>-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).</p></sec><sec><title>Results</title><p>Ten patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.</p></sec><sec><title>Conclusions</title><p>The combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.</p></sec><sec><title>Clinical Trial Registration</title><p><uri xlink:href="https://clinicaltrials.gov/ct2/show/NCT02954523" xmlns:xlink="http://www.w3.org/1999/xlink">https://clinicaltrials.gov/ct2/show/NCT02954523</uri></p></sec>