A Phase I/II Trial of Dasatinib and Osimertinib in TKI Naive Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

Background: EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard of care in patients with EGFR-mutant NSCLC. However, a fraction of patients do not respond to EGFR-TKI therapy or have short duration of response. In addition, virtually all patients develop resistance. In a preclinical study, we have shown that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of resistance to EGFR-TKI therapy through the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically. Method: This is an open-label, single-arm phase I/II trial of osimertinib and dasatinib, a Src inhibitor, in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02954523). Patients with pleural or pericardial effusions were excluded. The primary endpoint of the phase I portion was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation includes 2 dose levels (DLs) (DL1: osimertinib 80 mg QD, dasatinib 50 mg BID, DL2: osimertinib 80 mg QD, dasatinib 70 mg BID). 2 DLs below the starting dose level (DL-1: osimertinib 80 mg QD, dasatinib 70 mg QD; DL-2: osimertinib 80 mg QD, dasatinib 50 mg QD) could be explored if necessary. Adverse events (AEs) were assessed per CTCAE 4.03. Result: 10 patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. None of the patients enrolled at DL2 had dose limiting toxicities (DLTs) but given the frequent dose reductions required and toxicities beyond the DLT period, DL1 was further assessed. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches and body pain, grade 3 neutropenia, grade 3 rash, one each). One patient was enrolled at DL -1 and did not have a DLT. The most common treatment-related adverse events (TRAEs) included pleural effusion (n=9), diarrhea (n=8), rash (n=7), AST elevation (n=6), ALT elevation (n=6), most of which were grade 1 or 2. 4/4/1 patients had grade 1/2/3 pleural effusion, respectively. 7 (70%) patients had grade 3 TRAEs. No grade 4 or 5 toxicities were observed. Eight (80%) patients had a partial response (including 1 unconfirmed partial response) and 2 had stable disease. Median PFS was 27.2 months; median OS was not reached. The recommended phase II dose was determined as osimertinib 80 mg QD and dasatinib 70 mg QD. Pharmacokinetics (PK) analysis is being performed and will be presented. Due to slow accrual after approval of osimertinib in first-line, the trial was closed to enrollment. Conclusion: The combination of dasatinib and osimertinib demonstrated encouraging anticancer activity. Median PFS is longer than what is historically reported with osimertinib alone in first-line setting, although definitive conclusions cannot be drawn given the small sample size. The tolerability of the combination was limited by TRAEs, but they were generally manageable with dasatinib dose reductions and supportive measures. Keywords: EGFR-mutant NSCLC, resistance, Osimertinib dasatinib