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Published on: June 26, 2019
A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung
Chul Kim1, Stephen V Liu1, Jennifer Crawford1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States.
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://clinicaltrials.gov/ct2/show/NCT02954523.
Insights
This study combined dasatinib and osimertinib for EGFR-mutant NSCLC, showing anticancer activity but limited by dasatinib toxicity. Future research should explore Src inhibitors with better safety profiles for improved co-inhibition therapy.
Area of Science:
- Oncology
- Pharmacology
Background:
- Osimertinib is a first-line therapy for EGFR-mutant NSCLC, but resistance is common.
- CRIPTO-mediated Src activation contributes to resistance against EGFR tyrosine kinase inhibitors (EGFR-TKIs).
- Dasatinib, a Src inhibitor, shows preclinical synergy with EGFR-TKIs.
Purpose of the Study:
- To evaluate the safety and efficacy of combining osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC.
- To determine the recommended phase II dose (RP2D) of the combination therapy.
Main Methods:
- A single-arm phase I/II trial (NCT02954523) enrolled 10 patients.
- Phase I used a 3+3 design to establish the RP2D.
- Osimertinib 80 mg QD was combined with varying doses of dasatinib (70 mg BID, 50 mg BID, 70 mg QD, 50 mg QD).
Main Results:
- Nine out of ten patients achieved a partial response (90%).
- Median progression-free survival (PFS) was 19.4 months and median overall survival (OS) was 36.1 months.
- Common toxicities included pleural effusion, diarrhea, rash, and cytopenias, largely attributed to dasatinib.
Conclusions:
- The combination of dasatinib and osimertinib demonstrated significant anticancer activity in EGFR-mutant NSCLC.
- Treatment was limited by chronic toxicities, primarily from dasatinib.
- Future studies should investigate Src inhibitors with improved safety profiles for EGFR and Src co-inhibition.
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