The PI3K/AKT pathway is a promising target in NSCLC, especially in squamous (sq) tumors which show high frequencies of PI3K mutations and PTEN deletions. Epidermal growth factor receptor (EGFR) is also expressed in sq NSCLC tumors, and when treated with EGFR inhibitors, PI3K/AKT is up-regulated. In a sq NSCLC xenograft model, combination therapy with the EGFR monoclonal antibody, Necitumumab (Neci), and the PI3K/mTOR dual inhibitor, LY3023414 (LY), causes synergistic tumor regression. We initiated a phase 2 study evaluating these agents in pts with sq NSCLC. Here we report the first-in-human lead-in portion of the study.
Patients (pts) with metastatic sq NSCLC after platinum-containing therapy for advanced disease were eligible. Prior immunotherapy was allowed. Pts who developed venous thromboembolism within 3 months prior to screening or had uncontrolled diabetes were excluded. Pts received LY 200 mg PO BID on days (d) 1-21 and Neci 800 mg IV d1 and d8 of a 21 d cycle until disease progression or intolerable toxicity. Tumor assessments were performed every 6 weeks. Pts who had received ≥ 75% of the 1st cycle of treatment (tx) were considered evaluable for safety.
Fifteen pts were treated in the safety lead-in. Median age was 66, 86 % (13 pts) were male, 73 % (11 pts) were current or former smokers, and all had ECOG performance status 0-1. Seven pts were evaluable for safety. There were no dose-limiting toxicities and no serious tx-related adverse events (TRAEs). Common TRAEs are summarized in Table 1. Single-agent toxicity was not synergistic. Median duration of tx was 5 weeks (range 1-19+ weeks). Six pts remain on tx.
|TRAE in ≥10% of pts, n (%)||Grade 1-2||Grade 3-4||Total|
|Acneiform Rash||7 (47%)||1 (7%)||8 (53%)|
|Fatigue||4 (27%)||1 (7%)||5 (33%)|
|Nausea||4 (27%)||0||4 (27%)|
|Dehydration||3 (20%)||0||3 (20%)|
|Headache||3 (20%)||0||3 (20%)|
|Elevated ALT||1 (7%)||1 (7%)||2 (13%)|
|Anorexia||2 (13%)||0||2 (13%)|
|Chills||2 (13%)||0||2 (13%)|
|Hypomagnesemia||2 (13%)||0||2 (13%)|
|Mucositis||1 (7%)||1 (7%)||2 (13%)|
|Vomiting||2 (13%)||0||2 (13%)|
|Weakness||2 (13%)||0||2 (13%)|
|Weight Loss||2 (13%)||0||2 (13%)|
The combination of Neci and LY in sq NSCLC has preclinical rationale, appears to be safe and tolerable in patients, and is without over-lapping toxicities. Enrollment of the post lead-in cohort to determine efficacy in a total of 48 pts is on-going.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
V. Wacheck: Eli Lilly- Employee and Stock Ownership. D. Waterhouse: Lilly-speaker's fee. M. Gil: Lilly-employee and stock ownership. All other authors have declared no conflicts of interest.