The evidence supporting this protocol is provided by a phase III, open label, multicentre, international randomised trial to compare survival without grade 3 or 4 toxicity between treatment arms in 260 chemotherapy naïve patients with locally advanced or metastatic (stage IIIB or IV) non-squamous NSCLC and an ECOG 0 to 2.r
Between October 2007 and April 2009, 260 patients were randomised to receive pemetrexed 500 mg/m2 and carboplatin AUC = 5 on day 1 every 3 weeks (n = 128) or docetaxel 75 mg/m2 plus carboplatin AUC = 5 on day 1 every 3 weeks (n = 132) for up to six cycles.
The primary end point was survival without treatment emergent grade 3 or 4 toxicity (SWT) in the qualified intention to treat population.
Secondary endpoints included overall survival (OS), progression free survival (PFS), objective response rate (ORR), duration of response (DoR), survival without treatment-emergent grade 4 toxicity, survival without treatment-emergent clinically important grade 3 or 4 toxicity and safety.
Optimal chemotherapy doublet
The predictive influence of histological subtypes on outcomes has been shown in recent studies. In a combined analysis of individual patient data from three phase III trials in first line treatment of NSCLC, Treat et al demonstrated a difference in overall survival between patients with non-squamous and squamous histology to different chemotherapy combinations.r In patients with non-squamous histology, pemetrexed/cisplatin conferred superior median overall survival (11 months) compared with other regimens including gemcitabine/carboplatin (8.3 months). However, in patients with squamous histology, vinorelbine/cisplatin conferred the best median overall survival outcome and gemcitabine/cisplatin was superior to pemetrexed/cisplatin.
Cisplatin vs carboplatin
A meta-analysis by Griesinger et al compared the results of 12 trials involving 4139 patients between cisplatin based combination chemotherapy (2304 patients) against carboplatin based chemotherapy (1830 patients) in the first line treatment of NSCLC.r A small effect on ORR favouring cisplatin was detected (RR 0.88; 95% CI: 0.79-0.99), however there was no significant difference in OS (HR 1.08; 95% CI: 0.96-1.21). The risk of nausea/vomiting was 47% higher with cisplatin than carboplatin (RR 0.53; 95% CI: 0.38-0.73). Thrombocytopenia occurred more frequently in the carboplatin-based regimens (RR 2.46; 95% CI: 1.49-4.04).
After a median follow up of 23.9 months, median survival without grade 3 or 4 toxicity was significantly longer in the pemetrexed and carboplatin group (3.2 months) than in the docetaxel and carboplatin group (0.7 months), HR 0.45 (95% CI: 0.34-0.60).r
There were no statistically significant differences in OS, PFS, DoR or ORR between the treatment groups.
N = 105
|SWT emergent Grade 3/4 toxicity
Kaplan-Meier curve for survival without toxicity (A), overall survival (B) and progression free survival (C)r
© J Thorac Oncol 2011
Overall, there were lower rates of drug-related grade 3 or 4 neutropenia, febrile neutropenia, and leukopenia, and higher rates of drug-related anaemia and thrombocytopenia in the pemetrexed and carboplatin group than in the docetaxel and carboplatin group.r
Fewer patients in the pemetrexed and carboplatin group than in the docetaxel and carboplatin group experienced at least one drug-related treatment-emergent adverse event of grade 3 or 4 toxicity (47.2% v 71.4%). There were three treatment related deaths in each treatment arm.
Grade 3 or 4 adverse events in the safety populationr
© J Thorac Oncol 2011