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A Phase II study of the Src family kinase (SFK) inhibitor dasatinib was recently reported in molecularly unselected patients with metastatic NSCLC. SFK inhibition has a strong rationale as a clinical strategy in NSCLC. The reviewed study unfortunately showed disappointing activity as monotherapy in this molecularly unselected patient cohort and toxicity in terms of pleural effusion was problematic. Therefore, dasatinib as monotherapy in this setting does not appear promising. Nonetheless, the reviewed study may be used in conjunction with other studies of dasatinib in NSCLC to identify patients more likely to benefit from dasatinib either as monotherapy or in combination with other agents. Future studies of dasatinib in NSCLC should examine the agent in combination with EGFR inhibitors and/or cytotoxic chemotherapies.
Based on preclinical work suggesting the importance of the Src family kinases (SFKs), in NSCLC , a recent Phase II study of the SFK inhibitor dasatinib has been conducted in patients with metastatic NSCLC . SFKs have been demonstrated to have an important role in many oncologic functions in human tumors, including proliferation, motility, migration, survival and angiogenesis . In particular, in preclinical studies, an interaction between SFK inhibition and cell survival has been noted in EGFR-dependent NSCLC cell lines [4–6]. The recent identification of new promising targets in NSCLC that can be manipulated via targeted therapy, such as EML4-ALK , has further demonstrated that targeted therapy, in properly selected patients, can result in impressive clinical efficacy [8,9], with minimal toxicity as compared to traditional cytotoxic chemotherapy. Johnson et al. , therefore, sought to examine the efficacy of dasatinib in a molecularly unselected group of metastatic NSCLC patients, while attempting to identify biomarkers that could help to refine a patient population that may benefit from SFK inhibition.
The primary objective of the trial was to determine the efficacy of dasatinib in metastatic NSCLC, as measured by progression-free survival at 12 weeks. Thirty-four patients with radiographically measurable, metastatic NSCLC and an Eastern Cooperative Oncology Group performance status of 0 – 1 were included. Any patient who had previously received cytotoxic chemotherapy for metastatic disease was not allowed to enroll. Patients received oral dasatinib daily until disease progression or unacceptable toxicity was observed. Secondary objectives included the novel end point of metabolic response, as measured by 6- and 12-week positron emission tomography (PET)-CT standardized uptake value (SUV) as compared to baseline PET-CT SUV. Disease response was also measured as Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and partial response (PR) plus stable disease (SD) at 12 weeks was deemed to represent the disease control rate. Relationships between clinical response to dasatinib and biomarkers were also analyzed, including EGFR mutational status, activated SFK expression, EGFR copy number, changes in serum cytokines and phosphorylated Src levels in platelets.
The highlighted study was an ambitious endeavor that deserves credit for its thoughtful design. By studying the Src inhibitor dasatinib in patients with newly diagnosed metastatic NSCLC, the investigators were able to perform many correlative studies that may have not been feasible in a more advanced group of patients who had previously progressed through cytotoxic chemotherapy. Furthermore, tissue biologic parameters had been collected in close temporal fashion to dasatinib administration. It is well known that NSCLC tumor biology can change following administration of cytotoxic chemotherapies, and this confounder was, therefore, avoided in their correlative analyses. Additionally, the use of metabolic response via PET-CT, while not standard via the recently updated RECIST criteria , allowed for an assessment of therapeutic efficacy that may be more sensitive than standard response criteria. This approach may warrant incorporation into future studies investigating molecularly targeted therapies, where cytostatic effects may predominate (as opposed to cytotoxic effects).
While the clinical activity of dasatinib was disappointing and correlative studies in this small cohort were not able to identify a patient subpopulation for potential future studies, dasatinib has strong rationale for study in NSCLC. In considering its future, a brief review of the timeline of EGFR inhibitors in NSCLC may be considered, as it illuminates the challenges, and ultimate successes, in developing molecularly targeted therapies in NSCLC. Based on promising Phase II studies of erlotinib  and gefinitib , Phase III studies were undertaken, which initially failed to identify a benefit of these agents in unselected patient populations [14–16]. However, with the gained clinical experience, subclasses of patients likely to benefit from these therapies were identified [17,18], and subsequent studies performed in enriched patient populations have indeed identified a clinical niche for these molecularly targeted agents [9,19].
It is premature to conclude whether dasatinib (and SFK inhibition) may or may not experience a similar trajectory in NSCLC therapy. Preclinical studies suggest that the utility of SFK inhibition is magnified in the presence of cytotoxic chemotherapy  or EGFR inhibition, and initial clinical studies investigating such combinations have shown promise . Thus, the study by Johnson et al.  represents an early chapter in the story of SFK inhibition in NSCLC.
Declaration of interest
The laboratory of DLW has held a sponsored research agreement with Bristol-Myers Squibb. TJK and AMT state no conflict of interest and DLW, TJK and AMT received no payment in preparation of this manuscript. This project was supported, in part, by grant P30CA014520 from the National Cancer Institute, grant 1UL1RR025011 from the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health (DLW) and by grant RSG-10 - 193-01-TBG from the American Cancer Society (DLW).