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

Abstract

Background: Osimertinib is an effective first-line therapy option for EGFR-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.

Method: This is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-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).

Results: 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.

Conclusions: 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.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT02954523.

Keywords: EGFR; Src; dasatinib; lung cancer; osimertinib.

Conflict of interest statement

CK reports serving as a consultant or advisory board member for Novartis, Janssen, and PierianDx, and reports research funding (to institution) from AstraZeneca, Bristol-Myers Squibb, Novartis, Genentech, Regeneron, Spectrum, Mirati, Debiopharm, Karyopharm, and Janssen. SL reports serving as a consultant or advisory board member for Amgen, AstraZeneca, Beigene, Blueprint, Bristol-Myers Squibb, Daiichi Sankyo, G1 Therapeutics, Genentech, Guardant Health, Inivata, Janssen, Jazz Pharmaceuticals, Lilly, Merck, PharmaMar, Pfizer, Regeneron and Takeda and reports research funding (to institution) from Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Elevation Oncology, Genentech, Lilly, Lycera, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Spectrum, and Turning Point Therapeutics. VC reports research funding from Bayer. GE reports serving as a consultant for Novartis. DS is currently an employee and shareholder of AstraZeneca Plc. This study received funding from AstraZeneca. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. GG reports serving on advisory boards for Novartis and Daiichi, and research funding from Incyte and Karyopharm. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kim, Liu, Crawford, Torres, Chen, Thompson, Tan, Esposito, Subramaniam and Giaccone.

Figures

Figure 1

Waterfall plots are shown summarizing the best percentage change in target lesions. Each bar represents a patient.

Figure 2

Swimmer’s plots. Bar length indicates duration of treatment. Red circle indicates time when response was observed. Diamond indicates time when progression was noted. Arrowheads indicate ongoing study treatment.

Figure 3

Progression-free survival and overall survival. The Kaplan-Meier estimate for progression-free survival (A) and overall survival (B) is shown. Censored data are indicated by tick marks.

Figure 4

In patient ID 1, FDG-PET obtained after 1 cycle showed diffuse update in cervical lymph nodes (B), compared with baseline (A), which resolved at 4 months (C). The primary lung lesion continued to shrink with study treatment (D–F). In patient ID 2, a similar pattern was noted. FDG-PET obtained after 1 cycle showed diffuse update in cervical and inguinal lymph nodes (G), compared with baseline (H), which resolved at 4 months (I). The primary lung mass responded to study treatment (J–L).