Novel Agents in the
Treatment of Lung Cancer
New Approaches to First-Line Therapies
A Monoclonal Antibody Against the IGF-IR for the Treatment of NSCLC
IGF-IR as a Target in Lung Cancer
The growth hormone (GH) and insulin like growth factor (IGF) system is comprised of GH, IGF ligands (IGF 1 and IGF 2), IGF binding proteins (IGFBPs 1 to 6), cell surface receptors IGF IR and IGF 2R, and adaptor proteins that allow signal transduction to the ERK/MEK and PI3K/AKT pathways.53-55 All of the IGFBPs have growth inhibitory effects that are mediated in part through competitive binding to IGFs, thus preventing their association with the IGF IR (Figure 1).
Epidemiological data, pathologic series, and genetic and pharmacological models have all implicated the IGF-IR in the initiation and progression of tumors.56,57 In lung cancer, high IGF-1 and low IGFBP3 levels have been associated with higher disease incidence and severity.58 Deregulation of the IGF IR pathway may be of particular significance in patients with squamous cell carcinoma where expression of IGFBP 3 (a good prognostic marker) is decreased.59 Also, IMP 1, an IGF2 mRNA binding protein associated with poor prognosis in NSCLC, is expressed in 77% and 75% of squamous cell and large cell tumors, respectively, compared with 36% of adenocarcinomas.60 IGF IR has been shown to be most prominently expressed in squamous cell carcinoma relative to other histologies.61
Anti-IGF-IR Antibody CP 751,871 (Figitumumab)
A strategy to inhibit the function of IGF IR in cancer cells is to employ anti–IGF IR antibodies that bind to the extra-cellular domain of the receptor and inhibit its activation. CP-751,871 (figitumumab) was developed as a potent and specific anti-IGF-IR antibody for use in cancer therapy. The mechanism of action appears to include both receptor blockade and downregulation through receptor internalization and degradation. CP-751,871 caused a dose-dependent inhibition of tumor growth in xenograft models with an ED50 of 13 µg/mL. As a single agent, CP 751,871 significantly inhibited the growth of human squamous cell xenografts and other sensitive tumors, and enhanced antitumor activity was seen in combination with a variety of anticancer therapies.62
A phase I dose-escalation study of CP-751,871 in combination with standard doses of paclitaxel and carboplatin showed that it was well tolerated.63 Toxicities included hyperglycemia, anorexia, nausea, and liver function test elevations. Pharmacokinetic (PK) analysis revealed an effective half-life (t1/2) of approximately 20 days at the 20 mg/kg dose, similar to that of endogenous IgG2. There was a substantial, sustained, dose-dependent increase in circulating IGF-I levels with CP-751,871 therapy. GH levels increased more than twofold over baseline, indicating the loss of IGF-1 negative regulatory feedback through pituitary IGF-IR. Significant increases in fasting insulin levels were observed in patients with disease stabilization, suggesting insulin as a biomarker of IGF-IR activity.64
Proof of Concept
Based on initial signs of antitumor activity, phase II testing of CP-751,871 was undertaken in combination with paclitaxel and carboplatin in previously untreated patients with NSCLC and inoperable stage IIIB, IV, or recurrent disease and ECOG performance status of 0 or 1. The study had a primary objective of response rate, assuming a 28% response (null hypothesis) for paclitaxel and carboplatin in first-line NSCLC.65 Patients (N=156) were randomized 2:1 to receive paclitaxel (200 mg/m2), carboplatin (AUC of 6), and CP-751,871 (10–20 mg/kg), or paclitaxel and carboplatin alone every 3 weeks for up to 6 cycles. Those receiving the combination of CP-751,871 and chemotherapy who had a PR or stable disease (SD) were eligible to continue CP-751,871 as a single agent upon chemotherapy discontinuation until disease progression. Patients receiving chemotherapy alone who experienced disease progression were eligible to receive CP-751,871 as a single agent or in combination with the chemotherapy at the discretion of the investigator.
Ninety-eight of these patients received the combination of chemotherapy and CP-751,871. Forty-eight patients received CP-751,871 at a dose of 10 mg/kg and 50 at 20 mg/kg. Fifty-three patients received the chemotherapy alone. The majority of patients were male (72%), less than 70 years of age (80%), and had stage IV disease (82%). The most common tumor histology was adenocarcinoma (46%). Eighteen percent of tumors were of squamous histology. The median number of chemotherapy cycles given in combination was 4, with 38% and 28% of patients receiving single-agent CP-751,871 at cycles 5 and 6, respectively.
The combination regimen was well tolerated. All-causality grade 3/4 toxicities were similar in both treatment arms with the exception of hyperglycemia, which was higher in those patients receiving CP-751,871 (15% versus 8%). Objective responses as assessed by the investigators were reported in 53 of 98 patients receiving combination therapy (54%, 95% CI 44-64%) and 22 of 53 patients (41%) receiving chemotherapy alone. The response rate of patients with squamous cell tumors receiving paclitaxel, carboplatin, and CP-751,871 at the dose of 20 mg/kg every 3 weeks was numerically the highest (78%).
Upon completion of the randomized portion of the study, 30 additional patients who did not have adenocarcinoma were also enrolled in a single-arm nonrandomized cohort. Using RECIST criteria, 11 of 14 patients (78%) with squamous histology responded to the combination treatment, including 9 responses in bulky disease and a reversal of a superior vena cava obstruction (See Figure 2).66 Objective responses were also observed in 2 patients with squamous tumors who received single-agent CP-751,871 upon paclitaxel and carboplatin discontinuation. Publication of survival data is anticipated in 2010.
