PI3K/AKT ACTIVATION AND RESPONSE IN PHASE IB: AKT INHIBITOR GDC-0068 WITH DOCETAXEL (D) OR MFOLFOX6 (F) IN REFRACTORY SOLID TUMORS

Activation of PI3K/Akt signaling in cancers by mutations (mut) of PIK3CA or AKT1 or decrease/loss of PTEN may increase chemoresistance. GDC-0068, a potent ATP-competitive small molecule inhibitor of Akt, synergistically combines with D or F in preclinical models and may abrogate chemoresistance. This phase Ib examined safety and efficacy of GDC-0068 combined with D or F and its relationship with PI3K/Akt activation. Pts with metastatic solid tumors, treated with ≤ 3 regimens, received GDC-0068 daily (QD) at 100-600 mg on days 1-14 with D (75 mg/m2) every 21 days (arm A) or days 1-7 with F (bolus 5-FU 400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2 on day 1, infusional 5-FU 2400 mg/m2 for 46 hours) every 14 days (arm B). Archival tumors were analyzed for PIK3CA and AKT1 mut by RT-PCR and PTEN by immunohistochemistry. 61 pts enrolled: arm A (n = 27), arm B (n = 34); prior therapy in A: 96% (56% had taxanes), B: 91% (47% had 5-FU + platinum). PI3K/Akt was activated in 57% (n = 35): diagnostic-positive (Dx+) defined by PTEN-low (H-score ≤ 200, n = 27), PIK3CA mut (n = 2), AKT1 mut (n = 1), or combined PIK3CA mut/PTEN-low (n = 5). GDC-0068 was generally well-tolerated with D or F (no DLTs; grade 1-2 gastrointestinal toxicities); maximum administered dose was 600 mg QD with D or F. 6 pts had RECIST responses: n = 3 per arm (A: all had taxanes; B: 1 had FOLFOX, 2 had platinum); 4 were Dx + : PTEN-low (n = 1), AKT1 mut (n = 1), PIK3CA mut/PTEN-low (n = 2). 20 additional pts (A: n = 7, B: n = 13) had prolonged stable disease (≥ 120 days) and/or minor CT responses (≥ 20% but < 30%): PTEN-low (n = 11), PIK3CA mut (n = 2), PIK3CA mut/PTEN-low (n = 1), no mut (n = 2). PIK3CA mut suggested higher rate of response in both arms (71%, N = 7), followed by PTEN-low (47%, N = 32). KRAS mut did not predict resistance. GDC-0068 600 mg QD combined well with D or F. PI3K/Akt activation occurred in more pts with RECIST responses and prolonged SD than progressive disease. Phase II trials will address activity in Dx+ pts.