Background: M2698 is a potent and selective dual inhibitor of p70S6K and AKT1/3 in the PAM pathway. M2698 has the advantages of being an oral, brain penetrant, PAM pathway inhibitor, which can mitigate the effects of the AKT feedback loop, a potential escape mechanism in tumors resistant to standard therapies. Methods: Patients (pts) with advanced cancer received once-daily oral M2698 (15–380 mg; 9 dose levels) in 21-day cycles. The 3+3 dose escalation [DE] design was followed by an expansion phase (240 mg/day) in a pt population enriched with tumors that have PAM molecular alterations (PAM+). PAM+ profiles, potential resistance markers (RM), including EGFR, KRAS and Akt2, safety and efficacy were investigated (cut-off Nov 2017). Results: From 12/2013 to 3/2017, of 66 pts screened, 50 received M2698 (DE [n = 40] and expansion [n = 10]); 18 men, 32 women, 78% were < 65 years old. Of these 50 pts, 44 were PAM+ (37 without RM, 7 with RM). M2698 was well tolerated. Adverse events were transient. The maximum tolerated dose was not reached at the maximum dose tested. Efficacy outcomes are shown in the table. In addition, 5 pts in the PAM+ without RM subgroup had tumor control > 6 months (mo; range, 6.9–15.2 mo), whereas no pts in the PAM+ with RM subgroup had such prolonged tumor control. Clinical trial information: NCT01971515 PFS, progression free survival; SD, stable disease. Conclusions: M2698 was well tolerated. PAM+ pts without RM were more likely to have sustained tumor control. Molecular characterization of tumor resistance signals may help identify patients who are likely to benefit from M2698.