Abstract CT060: Efficacy, safety and tolerability of dasatinib combined with afatinib: a phase I trial in patients with epidermal growth factor receptor mutant (EGFRm) advanced non-small-cell lung cancer (NSCLC) after acquired tyrosine kinase inhibitor (TKI) resistance

Abstract

Abstract Background: Combining the Src family kinase inhibitor dasatinib and irreversible EGFR inhibitor afatinib results in enhanced antitumor activity in proliferation and apoptosis assays with EGFRm, TKI-resistant cell lines. Moreover, this combination results in higher tumor regression than either drug alone in PC9GR xenograft studies. We hypothesized that this drug combination would arrest progression in EGFRm NSCLC with acquired resistance. Therefore, we initiated a phase I open-label trial (NCT01999985) to evaluate dasatinib in combination with afatinib for patients (pts) with EGFRm advanced NSCLC who had progressed on previous EGFR TKIs. Methods: A phase I dose-escalation cohort with 3+3 design included patients (pts) with refractory NSCLC and ECOG performance status (PS) ? 1. Pts received continuous oral afatinib daily followed by addition of continuous oral dasatinib daily beginning on Day 8. After determination of maximum tolerated dose (MTD), a phase I cohort was expanded to include only pts with activating EGFR mutation who had acquired resistance to previous EGFR TKI. Safety, median progression-free survival (PFS), and tumor response were investigated. Plasma before and during treatment was collected for sequencing of circulating cell-free tumor DNA. Cox regression was performed. All statistical tests were 2-sided. Interim results are reported. Results: Of 31 pts screened, 25 were treated. Characteristics: 63% were female, median age was 66.8 years (range 53 - 81), and 72% were ECOG PS 1. Race: 75% Caucasian, 16% African-american. Median prior lines of therapy was 3. For EGFRm pts (n = 16), 56% had exon 19 deletion, 43% exon 21 mutation. In addition, 31% also had T790M detected in tumor prior to treatment. No significant interactions were observed with dasatinib and afatinib. Dose escalation halted at 40 mg afatinib and 100 mg dasatinib when 2 patients at this level experienced grade 2 or 3 diarrhea despite optimal supportive care. The most common drug-related adverse events of any grade from dose escalation included 63% diarrhea, 45% rash, 27% nausea, 18% oral mucositis, and fatigue. The MTD was 30 mg afatinib with 100 mg dasatinib. The PFS for EGFRm pts was 5.5 months (95% confidence interval 2.6 - 8.5). A trend toward more favorable PFS for T790M was observed (7.0 vs. 2.8 months, p = 0.06) in evaluable subjects. No confirmed partial or complete responses have been observed. Conclusions: Afatinib plus dasatinib was acceptably tolerated in pts with NSCLC in the escalation phase. Clinical benefit has been observed in the expansion phase, although without objective radiologic responses. Preliminary data support continued evaluation of afatinib 30 mg plus dasatinib 100 mg as the expansion phase dose in pts with EGFRm NSCLC with acquired TKI resistance. Citation Format: Ben Creelan, Jhanelle Gray, Diana Lima, Scott Antonia, Alberto Chiappori, Tawee Tanvetyanon, Rebecca DeVane, Charles Williams, Eric Haura. Efficacy, safety and tolerability of dasatinib combined with afatinib: a phase I trial in patients with epidermal growth factor receptor mutant (EGFRm) advanced non-small-cell lung cancer (NSCLC) after acquired tyrosine kinase inhibitor (TKI) resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT060.