4*Cisplatin in addition to single-agent first-line chemotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC): efficacy results of a joint analysis of the multicentre, randomized phase 3 MILES-3 and MILES-4 studies

Annals of Oncology(2017)

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Background: The role of platinum in first line treatment of elderly patients with advanced NSCLC is still debated. We tested its efficacy in two parallel phase 3 trials. Patients and methods: Advanced NSCLC patients, >70 years, ECOG performance status 0-1, were eligible. In MILES-3 patients with any tumor histology were randomly assigned 1:1 to cisplatin/gemcitabine (Cis 60 mg/m2 d1, Gem 1000mg/m2 dd1,8) or gemcitabine (Gem 1200 mg/m2 dd1,8). In MILES-4 patients with non-squamous histology were randomly assigned 1:1:1:1 to CG, G, cisplatin/pemetrexed (Cis 60 mg/m2 d1, Pem 500 mg/m2 d1) or pemetrexed (Pem 500 mg/m2 d1). Six cycles were planned. In each trial, to have 80% power in detecting a HR of death 0.75 (corresponding to 3-month prolongation of median survival), with 0.05 two-tailed α, 382 events were required. The trials were closed prematurely because of slow accrual, but a joint analysis allowed to properly perform the final analysis, according to IDMC advice. Analysis was based on intention-to treat and adjusted by trial, histotype, companion drug, stage, PS, gender, age and size of centre. Results: From Mar 2011 to Aug 2016, 531 patients (MILES-3: 299, MILES-4: 232) were assigned to Cis-doublet (n = 263) or single-agent chemotherapy (n = 268). Median age was 75, 79% were male, 70% had non-squamous histology. Median number of cycles was 4 and 3 with and without Cis, respectively. With a median follow-up of 2 years, 384 deaths and 448 progression-free survival (PFS) events were reported. With and without Cis, median OS was 9.6 vs 7.5 months (HR 0.86, 95% CI: 0.70-1.04, p = 0.14); median PFS was 4.6 vs 3.0 months (HR 0.76, 95% CI: 0.63-0.92, p = 0.005); objective response rate was 15.5% vs 8.5% (p = 0.02). Significantly more severe hematologic toxicity, fatigue and anorexia, were found with Cis. Toxic deaths were 3 (1.1%) and 2 (0.7%), with and without Cis. QoL was not improved with Cis in the joint analysis at the common time-points (cycles 1 and 2), but in MILES-4, with a longer time of observation (cycles 1 to 6), a significant prolongation of the time to global QOL deterioration (items 29/30) was found with Cis (HR 0.53, 95% CI: 0.29-0.97). Conclusion: Addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival of elderly patients with advanced NSCLC. However, there is significant improvement in PFS, response rate and time to global QoL deterioration. Partially supported by AIFA (grant FARM8KAJZK) and Eli Lilly.
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Key words
cisplatin,lung cancer,chemotherapy,single-agent,first-line,non-small-cell
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