Monoclonal antibodies versus tyrosine kinase inhibitors concurrent with chemotherapy in non-small-cell lung cancer: exploring divergent results.

On February 18, 2008, a press release from Bayer and Onyx Pharmaceuticals reported that their large, randomized phase III trial evaluating the multitargeted tyrosine kinase inhibitor (TKI) sorafenib in patients with advanced non–small-cell lung cancer (NSCLC) was stopped. This was after the independent Data Monitoring Committee (DMC) concluded that the study would not meet its primary endpoint of improved overall survival (OS).1 This trial, widely known as ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC), tested the standard first-line doublet of carboplatin plus paclitaxel with or without sorafenib. Interestingly, the same report stated that higher mortality was seen in the subset of patients with squamous cell carcinoma treated in the sorafenib arm. These trial results are summarized in the Meeting Highlights of this issue. Shortly thereafter, AstraZeneca issued a press release announcing the early closure of its own phase II/III trial in patients with advanced NSCLC combining the vascular endothelial growth factor receptor (VEGFR)–targeted TKI cediranib with carboplatin and paclitaxel.2 According to the release, following a planned efficacy and tolerability analysis by the study’s DMC at the end of the phase II stage, “there appeared to be an imbalance in toxicity...therefore the study was considered not to have met the predefined criteria for automatic continuation into phase III.” These results highlight a series of failed randomized trials of chemotherapy with or without TKIs, directed either toward the epidermal growth factor receptor (EGFR) or VEGFR, in the first-line therapy of advanced NSCLC. Early this century, the entire research community was disappointed by the results of the 4 large, randomized trials of the EGFR TKIs gefitinib or erlotinib in combination with platinum-based doublets. In sum, these 4 trials (INTACT I, INTACT II, TRIBUTE, and TALENT) collectively accrued > 4000 patients with chemotherapy-naive NSCLC and found no benefit for the concurrent use of either EGFR-targeted TKI with platinum-based therapy.3-6 In contrast, phase III trials combining chemotherapy with monoclonal antibodies (MoAbs) have demonstrated modest improvements in efficacy. The first positive result was from the Eastern Cooperative Oncology Group (ECOG) 4599 study, a trial of carboplatin/paclitaxel with or without the VEGF-targeted antibody bevacizumab, which showed significant improvements in tumor response, progression-free survival (PFS), and OS.7 Subsequently, a phase III study of cisplatin/gemcitabine with or without 2 different doses of bevacizumab showed a modest improvement in the primary endpoint of PFS in the bevacizumab arms, although there was no improvement in OS.8,9 As expected, both trials also showed enhanced toxicity with the addition of bevacizumab. More recently, Merck KGaA issued a press release (September 11, 2007) announcing the positive survival results of its large, randomized, multinational trial, known as FLEX (First-Line Treatment for Patients with EGFR-Expressing Advanced NSCLC). This study treated patients with EGFR-overexpressing tumors with cisplatin/vinorelbine alone or in combination with cetuximab, a MoAb against the EGFR.10 The definition of EGFR positivity was very lenient, as patients with ≥ 1 EGFR-expressing cell in their tumor by immunohistochemistry (IHC) were deemed eligible. Although this trial had not yet been formally presented as of this writing, the press release noted that FLEX met its primary endpoint of a 25% increase in survival in favor of the cetuximab arm. Indeed, with the exception of lapatinib in combination with capecitabine in advanced breast cancer (and arguably, erlotinib plus gemcitabine in pancreatic cancer, which was only marginally positive), there have been few chemotherapy-plus-TKI trials that have yielded any substantial changes in oncologic community practice. On the other hand, chemotherapy-plus-MoAb (eg, rituximab, trastuzumab, and bevacizumab) combinations are now established as standard of care in hematologic malignancies and/or solid tumors such as colorectal, breast, and lung cancer. Why is there an apparent divergence in the results of trials of concurrent chemotherapy plus TKIs or MoAbs? Although editorial