PS01.04 International Tailored Chemotherapy Adjuvant Trial : ITACA Trial. Final Results


      Adjuvant platinum-based chemotherapy in early stage non-small cell lung cancer confers a modest 5% overall survival benefit. Different strategies have been investigated to improve these results. mRNA expression of some genes was correlated with the sensitivity or resistance to specific anticancer agents. We aimed to evaluate the predictive utility of the mRNA expression levels of molecular markers ERCC1 and TS.


      An open label, randomized, comparative phase III investigator-initiated study (EudraCT 2008-001764-36) of adult patients (aged ≥ 18 years), with an ECOG performance status of 0 or 1 and with a completely resected stage II-III NSCLC according to the 6th edition of the TNM staging System was planned. We enrolled patients from 17 Italian centers and 13 German Centers within 6-12 weeks after radical surgery. Genomic analyses were performed soon after surgery and then patients were randomly assigned in each of the 4 genomic subgroups to investigator’s choice of platinum-based chemotherapy (C1-2-3-4) or chemotherapy defined by the molecular markers. In the tailored arm patients with tumors that had high ERCC1 and high TS received single-agent docetaxel (T1); patients with high ERCC1 and low TS received single-agent pemetrexed (T2); patients with low ERCC1 and high TS received cisplatin and gemcitabine (T3); finally, patients with low ERCC1 and low TS received cisplatin and pemetrexed (T4). All anticancer drugs were administered according to standard doses and schedules. We randomly allocated patients with 1:1 ratio centrally using permuted blocks sizes and stratified by stage and smoking status. The primary end point of the study was overall survival according to an intent to treat analysis. For the final statistical analysis all the control arms were grouped in one (control arm) and all tailored chemotherapies in another one (experimental arm).


      Between December 2008 and August 2014, 773 patients were enrolled and randomly assigned to the treatment groups: 389 to arms C and 384 to arms T (T1, n=148, T2, n=43, T3, N=101, T4, N=92). Six hundred and ninety patients were included in the intent to treat analysis. In the control arm the following regimens were used: cisplatin /gemcitabine (n=159, 50.0%), cisplatin /viborelbine (n=123, 38.7%), cisplatin/docetaxel (n=23, 7.2%), platinum/pemetrexed (n=5, 1.6%), others (n=8, 2.5%). At a median follow up of 28.2 months (IQR: 9.9-55.8 months), 86 (24.9%) and 68 (19.8%) patients were deceased in arms C and T, respectively. The estimated median overall survival in arm C was 83.5 months (95%CI: 60.1-not defined) and in arm T was 96.4 months (95%CI: 81.8-not defined; hazard ratio (group T vs. group C) was 0.76 (95%CI: 0.55-1.04; p=0.091). Grade 3-5 toxicities that were reported more frequently in arm C (control) than in arm T (tailored) were neutropenia (18.9% vs 13.4%), leukopenia (13.3% vs 3.9%), thrombocytopenia (7.7% vs 3.3%) and anaemia (2.7% vs 0.9%).


      In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy on the basis of the mRNA expression of selected genes do not confer a statistically significant survival advantage in terms of overall survival and relapse-free survival and toxicity was less commonly reported in the customization arms.


      Completely resected stage II-III NSCLC, adjuvant pharmacogenomic-driven chemotherapy, mRNA expression