Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer
Mené sur 40 patients atteints d'un cancer avancé du poumon non à petites cellules (âge médian : 66 ans), cet essai de phase II évalue, du point de vue du taux de réponse globale, l'efficacité d'une chimiothérapie administrée en fonction de la présence de polymorphismes à simple nucléotide de deux gènes, ERCC1 et RRM1
Objectives: Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and Gemcitabine, in NSCLC. Material and Methods: We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118 T/C and 8092 C/A) and RRM1 (-37 C/A and -524 T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-resonder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to Gemcitabine non-responder. Four schedules were provided: Cisplatin + Gemcitabine, Cisplatin + Docetaxel, Gemcitabine + Docetaxel; Docetaxel + Vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population. Results: 42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95%CI = 15-26) and OS was 40.4 weeks (95%CI = 32-55). Treatment was well tolerated. Conclusion: We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.