Randomized Phase III Trial of Gemcitabine-Based Chemotherapy With In Situ RRM1 and ERCC1 Protein Levels for Response Prediction in Non–Small-Cell Lung Cancer

Abstract

Purpose We evaluated the efficacy of gemcitabine versus gemcitabine and carboplatin in patients with advanced non–small-cell lung cancer (NSCLC) and a performance status (PS) of 2 and assessed if tumoral RRM1 and ERCC1 protein levels are predictive of response to therapy. Patients and Methods A randomized phase III trial was conducted in community-based oncology practices. Tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression levels by an automated quantitative immunofluorescent-based technology. Results One hundred seventy patients were randomly assigned. Overall median survival was 5.1 months for gemcitabine and 6.7 months for gemcitabine and carboplatin (P = .24). RRM1 (range, 5.3 to 105.6; median, 34.1) and ERCC1 (range, 5.2 to 131.3; median, 34.7) values were significantly and inversely correlated with disease response (r = −0.41; P = .001 for RRM1; r = −0.39; P = .003 for ERCC1; ie, response was better for patients with low levels of expression). A model for response prediction that included RRM1, ERCC1, and treatment arm, was highly predictive of the treatment response observed (P = .0005). We did not find statistically significant associations between survival and RRM1 or ERCC1 levels. Conclusion Single-agent chemotherapy remains the standard of care for patients with advanced NSCLC and poor PS. Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens in community oncology practices is predictive of response to gemcitabine and gemcitabine and carboplatin therapy. Oncologists should consider including in situ expression analysis for these proteins into their therapeutic decisions.

What can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis

“…Five publications [18,19,[21][22][23] are about randomized phase III trials and one was a randomized phase II trial [24]. Four studies [18,19,21,24] were specifically devoted to PS2 patients, while two trials [22,25] reported subgroup analysis for PS2 patients (18 and 20%, respectively) within larger randomized phase III trials.…”

“…Four studies [18,19,21,24] were specifically devoted to PS2 patients, while two trials [22,25] reported subgroup analysis for PS2 patients (18 and 20%, respectively) within larger randomized phase III trials. All trials compared a platinumbased doublet with single-agent chemotherapy; four of these [18,21,22,24] compared carboplatin-based doublet with single agent chemotherapy: carboplatin plus pemetrexed vs pemetrexed alone [18], carboplatin plus gemcitabine vs gemcitabine alone [21,24], carboplatin plus paclitaxel vs paclitaxel alone [22,25]; the other two trials compared cisplatin plus gemcitabine with gemcitabine alone [19] and cisplatin plus vinorelbine or vindesine with vinorelbine alone [23]. In nearly every trial characteristics were well balanced between two arms.…”

“…The extracted data, including number of patients, PS, age, histology, stage, chemotherapy regimens, and outcomes, were reported in Table 2. Data about ORR [18,19,21,22,24] and 1y-SR [18,[21][22][23][24] were available from five studies. Finally, data about toxicity were available from 4 trials [18,19,21,24].…”

“…Some included studies were specifically devoted to PS2 patients [18,19,21,24], 2 studies were not exclusively devoted to this subset of patients [22,23]. The CALGB trial [22] compared carboplatin-paclitaxel with paclitaxel alone in 584 patients with advanced NSCLC.…”

“…Another point of discussion regards the various treatment regimens in the included studies. In most studies included in our meta-analysis [18,21,22,24] patients received carboplatin-based regimen, while only in two [19,23] cisplatin-based chemotherapy was administered. It is well known that platinum-based regimens represent the standard treatment of advanced NSCLC patients without activating EGFR or ALK mutations [6].…”