Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study

Abstract

PURPOSE This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Paclitaxel (200 mg/m(2)) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS < or = 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity +/- NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively. CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.

Genomics of Squamous Cell Lung Cancer

“…The phase II analysis revealed a higher response rate for cediranib versus placebo (38 vs. 16%; p Ͻ .001) and hazard ratio (HR) for PFS of 0.77 (99% CI: 0.56 -1.08) [45]. However, patients in the cediranib arm had more reported toxicities, including hypertension, hypothyroidism, and gastrointestinal toxicity.…”

Vascular normalization: a real benefit?

“…It appears that bevacizumab can be a component of an effective combination therapy approach to colorectal cancer, non-small-cell-lung cancer (NSCLC), and breast cancer [3][4][5]. Encouraging results have also been obtained when chemotherapy has been used in combination with an anti-VEGF receptor-2 (VEGFR-2) monoclonal antibody (cediranib) [6] and an oral tyrosine kinase inhibitor of VEGFRs and epidermal growth factor receptor (EGFR) (vandetanib) [7,8]. The observation that combining chemotherapy with angiogenesis inhibitors causes increased apoptosis in tumors in vivo [9,10] suggest that angiogenesis inhibitors may have an additive effect when administered in combination with chemotherapy.…”

“…Blockade of VEGFR-2 has been shown to increase total pericyte vasculature. In fact, blockade of VEGF signaling promotes pericyte recruitment in Lewis lung carcinomas, RIP- 6 Tag-2 tumors [31] and other tumor models [21,32], by triggering increased tumor production of angiopoietin-1 (Ang-1) [23]. Surviving blood vessels of RIP-Tag-2 tumors treated with anti-VEGF agents have a reduced expression of VEGFR-2 and VEGFR-3 in addition to a more normal caliber [29].…”

Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

“…Although these agents have proven to be quite effective in treating certain tumor types, in others, such as ovarian and lung cancer, clinical success has been more variable. In particular, patients harboring advanced nonsmall cell lung cancer (NSCLC) generally respond poorly to aggressive chemotherapy, with median survival times commonly falling short of a year (1). In light of studies showing that nearly half of the patient population presents with advanced (stage IV) disease, it is not surprising that the 5-y survival rate for all NSCLC in the United States is less than 20%.…”

“…is a guest editor invited by the Editorial Board. 1 To whom correspondence should be addressed. E-mail: hemann@mit.edu.…”