Abstract
Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D) is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C) ± D in NSQL. Eligibility criteria were untreated NSQL stage IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500 mg/m(2) and C at 75 mg/m(2) IV were given every 3 weeks. D was given at 10 mg/kg IV weekly on days 1, 8, and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every two cycles and were treated for a maximum of six cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs. PC + D. From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC + D. We observed two partial responses (PR), seven stable disease (SD), three progressive disease (PD), and two not evaluable (NE) in the PC arm. In comparison, for the PC + D arm, there were three PR, four SD, four PD, and one NE. The hematologic toxicity was similar in both groups. There was higher incidence of hyperglycemia in the experimental group; four cases with grade 3 and one case with grade 4. PC + D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL. NCT00799240, clinicaltrials.gov.
Highlights
Insulin-like growth factor 1 receptor (IGF-1R) is a tyrosine kinase receptor that regulates cell growth, proliferation, and apoptosis (1) (Figure 1)
High expression of IGF-1R is associated with poor survival in surgically resected stage I adenocarcinoma which along with never-smokers had a higher expression of IGF-1R compared to squamous histology or smokers (4)
We had 19 patients that did not enter in the trial due screen failure due a variety of reasons (7 patients declined to participate, 2 had recent surgery and did not recover, 1 due to physician decision, 1 had EGFR mutation positive and went to have treatment with EGFR TKI, 1 hospitalized due disease, 1 had insurance disapproval to participate in clinical trial, 1 due study termination) with 5 not meeting study criteria (2 had performance status >1, 1 due to creatinine clearance bellow 50 ml/ min, 1 had squamous histology on pathology review, and 1 did not have stage IV on PET scan)
Summary
Insulin-like growth factor 1 receptor (IGF-1R) is a tyrosine kinase receptor that regulates cell growth, proliferation, and apoptosis (1) (Figure 1). Several types of cancer, including non-small cell lung cancer, express IGF-1R and its ligand. Increased expression of IGFBP-3 is associated with improved outcome in resected stage I lung cancer (3). High expression of IGF-1R is associated with poor survival in surgically resected stage I adenocarcinoma which along with never-smokers had a higher expression of IGF-1R compared to squamous histology or smokers (4). Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C) ± D in NSQL
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