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The phase III PRONOUNCE study compared a doublet of pemetrexed plus carboplatin followed by maintenance pemetrexed to a triplet of paclitaxel, carboplatin, and bevacizumab with maintenance bevacizumab as a treatment for patients with advanced nonsquamous non-small cell lung cancer (NSCLC). The trial had an unusual primary endpoint that assessed progression-free survival without grade 4 toxicity (G4PFS), explains Corey J. Langer, MD.
The question that the PRONOUNCE trial sought to answer is important, since these regimens are commonly used and demonstrated similar efficacy in separate trials, says Everett E. Vokes, MD. However, the PRONOUNCE trial fell short of answering this question, since a statistically significant difference in survival was not observed. Additionally, Vokes notes, the primary endpoint of G4PFS seemed engineered to favor pemetrexed. Despite the pemetrexed-containing doublet having a numerical advantage for G4PFS, this benefit was not statistically significant.
The primary endpoint of G4PFS has not been validated, notes Anne S. Tsao, MD. As such, it is not typically seen in clinical trials and may have limited utility. Adding to this criticism, Langer remarks that the G4PFS endpoint failed to include neuropathy, taxane-based toxicity, or lower grade events, which are more common. Had this endpoint included these factors, the trial may have been positive, Langer speculates.