Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced nonsmall cell lung cancer: evidence from an individual patient analysis.

BACKGROUND: Excision repair cross complementing 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) are molecular determinants that predict sensitivity or resistance to platinum agents and gemcitabine, respectively. Tailored therapy using these molecular determinants suggested patient benefit in a previously reported phase 2 trial. Here, we report an individual patient analysis of prospectively accrued patients who were treated with the "personalized therapy" approach versus other "standard," noncustomized approaches. METHODS: Patients who had nonsmall cell lung cancer (NSCLC) with extranodal metastatic disease and an Eastern Cooperative Oncology Group performance status of 0/1 were accrued to 4 phase 2 clinical trials conducted at the H. Lee Moffitt Cancer Center: Trial A (first-line carboplatin/gemcitabine followed by docetaxel), Trial B (docetaxel and gefitinib in patients aged ≥70 years), Trial C (combination therapy with carboplatin/paclitaxel/atrasentan), and Trial D (personalized therapy based on ERCC1 and RRM1 expression). Patients with low RRM1/low ERCC1 expression received gemcitabine/carboplatin, patients with low RRM1/high ERCC1 expression received gemcitabine/docetaxel, patients with high RRM1/low ERCC1 expression received docetaxel/carboplatin, and patients with high RRM1/high ERCC1 expression received vinorelbine/docetaxel. Patients who were treated on Trials A, B, and C were pooled together and analyzed as the "standard therapy" group. Patients accrued to Trial D were called the "personalized therapy" group. Individual patient data were updated as of February 8, 2011. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS: There were statistically significant improvements between the personalized therapy group versus the standard therapy group in response (44% vs 22%; P = .002), OS (median: 13.3 months vs 8.9 months; P = .016), and PFS (median: 7.0 months vs 4.3 months; P = .03). CONCLUSIONS: The results from individual patient analyses suggest that ERCC1 and RRM1/tailored selection of first-line therapy improved survival over standard treatment-selection approaches.

Setting the stage for tailored chemotherapy in the management of non-small cell lung cancer.

Random selection of a chemotherapy regimen improves responses and survival only modestly in patients with advanced non-small cell lung cancer. Chemotherapy that is selected based on the molecular determinants of the tumor may further augment response rates and survival. This requires an in-depth understanding of the prognostic and predictive significance of the molecular determinants. The ultimate clinical utility of these molecular determinants will depend on the feasibility and ease of estimating these parameters using, in primary tumors, techniques that are widely applicable and relatively inexpensive. Using our work with excision repair cross-complementation group 1 (EERC1) and ribonucleotide reductase M1 (RRM1) as a paradigm, we demonstrate the step-wise development of molecular determinants as tools to aid in the selection of chemotherapy. We show that molecular determinant-based selection of chemotherapy is both feasible in the clinical setting and suggests clinical benefit. These findings are currently being confirmed in a Phase III trial. This paradigm could be used for developing customized treatment strategies for other cancers with other chemotherapeutic and targeted agents. In the future, identifying a molecular determinant could be an integral part of drug development. Developing functional imaging techniques for widely used molecular determinants would also mitigate the need for repeated invasive biopsies, allowing us to evaluate the change in the status of molecular determinants in response to treatment.

Molecular analysis-based treatment strategies for non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. Improved understanding in the molecular biology and genetics of lung cancer has resulted in the identification of individual genes, gene expression profiles, and molecular pathways that may be useful for clinical management decisions. METHODS: We focused on recent molecules and platforms under evaluation for implementation into clinical decision making. RESULTS: Prognostic molecular parameters are defined as markers that impact overall outcome in terms of survival independent of therapeutic interventions. Predictive molecular parameters are defined as markers that impact therapeutic efficacy. CONCLUSIONS: Several molecules and profiles are emerging with promising utility as predictive and prognostic parameters in non-small cell lung cancer independent of the standard clinical parameters, such as stage, performance status, and gender. These include the genes ERCC1, RRM1, and BRCA1, which are involved in nucleotide metabolism and DNA damage repair, epidermal growth factor receptor, which is involved in cell proliferation and survival, and oligonucleotide expression array profiles, which are signatures of global gene expression associated with specific tumor phenotypes.

Phase 2 trial of docetaxel and gefitinib in the first-line treatment of patients with advanced nonsmall-cell lung cancer (NSCLC) who are 70 years of age or older.

BACKGROUND: This is a phase 2 study of chemotherapy-naive patients, 70 years of age or older, with nonsmall-cell lung cancer (NSCLC) who were treated with docetaxel and gefitinib. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS) and progression-free survival (PFS). METHODS: Eligible patients were treated with docetaxel 75 mg/m(2) every 3 weeks and gefitinib 250 mg orally, daily. Docetaxel and gefitinib were given for 2 cycles beyond maximal response. Gefitinib was continued until disease progression. Comorbidities and activities of daily living were assessed (IADL). RESULTS: Forty-four patients initiated therapy between March 2003 and May 2005. Seventeen patients (40%; 95% confidence interval [CI], 26%-57%) had a partial response and 48% had stable disease. The median PFS was 6.9 months (95% CI, 3.95-7.8 months). Median survival time was 9.6 months (95% CI, 4.6-16.3 months). On univariate analyses, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and Charlson comorbidities index (CCI) score were predictors of improved survival. On multivariate analyses female sex was a statistically significant predictor of survival. The median survivals were 22.8 months in women and 4.8 months in men. This regimen was well tolerated, with the most common adverse events being hyperglycemia, fatigue, and lymphopenia. CONCLUSIONS: Docetaxel combined with gefitinib is active and well tolerated in patients with advanced NSCLC who are 70 years of age and older. This paradigm of treatment merits further investigation as a first-line treatment strategy. Female sex-specific confirmatory clinical trials with this regimen may be warranted.