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 [11
], 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 [12
] and gefinitib [13
], Phase III studies were undertaken, which initially failed to identify a benefit of these agents in unselected patient populations [14
]. However, with the gained clinical experience, subclasses of patients likely to benefit from these therapies were identified [17
], and subsequent studies performed in enriched patient populations have indeed identified a clinical niche for these molecularly targeted agents [9
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 [20
] or EGFR inhibition, and initial clinical studies investigating such combinations have shown promise [21
]. Thus, the study by Johnson et al.
] represents an early chapter in the story of SFK inhibition in NSCLC.