A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.

Abstract

8107 Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “3+3” design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline & d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n=6), 100 mg/d (n=6), 80 mg 5d on 2d off (5/2, n=3), with gef 250 mg/d. Gp A (n=9, 1 CNS), B (n=6, 1 CNS), F:M (9:6), median age 63 (47-73) and majority >3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%), mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea. MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80 5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax (>25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12 PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1 MET amp) had clinical responses, including slight tumor shrinkage and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed. Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted. A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

“…Further studies of buparlisib in combination with chemotherapy were similarly negative, 64 whilst it has also been studied in combination with gefitinib. 65 Pilaralisib has also been assessed as monotherapy in phase I trials, with one partial response in a patient with NSCLC. 66 Another phase I trial in combination with erlotinib established its safety profile although similarly exhibited only one partial response.…”

“…The primary objective for efficacy based on 12‐week PFS, was not met. Further studies of buparlisib in combination with chemotherapy were similarly negative, whilst it has also been studied in combination with gefitinib . Pilaralisib has also been assessed as monotherapy in phase I trials, with one partial response in a patient with NSCLC .…”

PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

“…Preliminary results of a Phase IB study of buparlisib and gefitinib demonstrated potential antitumor activity in EGFR TKI-resistant NSCLC (NCT01570296). 31 A nonselective, mandatory tissue collection approach will therefore be employed in a Phase II study of buparlisib and erlotinib in advanced NSCLC that was previously sensitive to erlotinib (NCT01487265). Exploratory biomarker analyses will examine interactions between the two pathways.…”

Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

“…A recent neoadjuvant phase II study of paclitaxel plus trastuzumab, with and without buparlisib (Neo-PHOEBE) in HER2-overexpressing breast cancer patients is also accruing. Though buparlisib in combination with geftinib was found to be safe, high frequency of severe late toxicities, including rash and diarrhea was noted in patients with EGFR TKI-resistant NSCLC in a phase IB study, and alternative dosing schedules are thus warranted in subsequent studies [ 109 ].…”