Biomarker-directed chemotherapy detrimental in NSCLC
medwireNews: Treating non-small-cell lung cancer (NSCLC) patients with chemotherapy customised according to expression of BRCA1 and receptor-associated protein 80 (RAP80) does not improve progression-free survival (PFS) compared with nonselected, cisplatin-based chemotherapy, show study findings.
In fact, the researchers observed a detrimental effect in the biomarker-directed arm and the trial was prematurely closed.
“[O]ur unexpected negative findings highlight the importance of close clinical validation of preclinical findings before undertaking a major randomized clinical trial”, say Rafael Rosell (Catalan Institute of Oncology, Badalona, Spain) and colleagues.
In a previous phase II study, the combination of BRCA1 and RAP80 expression was significantly associated with outcome in Caucasian patients with NSCLC. The team therefore conducted a phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customised according to BRCA1 and RAP80 expression.
A total of 279 patients were randomly assigned in a 1:1 ratio to receive docetaxel and cisplatin or the biomarker-directed experimental arm. In the experimental arm, patients with low RAP80 expression received gemcitabine and cisplatin, those with intermediate or high RAP80 expression and low or intermediate BRCA1 expression received docetaxel and cisplatin, and those with intermediate or high RAP80 expression and high BRCA1 expression received docetaxel alone.
As reported in the Annals of Oncology, PFS was 5.49 months in the control arm compared with 4.38 months in the experimental arm (adjusted hazard ratio [HR]=1.35). The detrimental effect observed in the experimental arm was particularly noted in the patients who received single agent docetaxel (adjusted HR=2.65).
“[W]e can speculate that the detrimental effect in the experimental arm may well have been partly due to the use of single-agent docetaxel”, say Rosell et al. “This potential harmful effect of monotherapy should be kept in mind when designing future clinical trials.”
An analogous phase II trial was carried out in China at the same time to evaluate the effect of BRCA1/RAP80 expression in 124 Asian patients who were randomly assigned in a 1:3 ratio to receive the control or the experimental arm.
Analysis revealed that PFS was 4.74 months for participants in the control arm and 3.78 months for those in the experimental arm, with an HR of HR 0.95.
The researchers say that these studies provide “proof of concept that an international, nonindustry, biomarker-directed trial is feasible.”
They conclude: “Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to elucidate DNA repair mechanisms will help define novel therapeutic approaches.”
medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2014
By Nikki Withers, medwireNews Reporter