Our observations that (i) osimertinib–BAY-293 synergy was only observed in 3D spheroids but not in adherent (2D) cultures and (ii) synergy between RTK-signaling intermediates and osimertinib was not broadly applicable to EGFR downstream signaling components but was limited to proteins upstream of RAS reveal novel insights into pharmacologic studies assessing therapeutics designed to treat NSCLC. The gene discussed is EGFR; the disease is non-small cell lung carcinoma.