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.
Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425-6350, USA. simong@musc.edu
George R
GR
Simon
Michael J
MJ
Schell
Mubeena
M
Begum
Jongphil
J
Kim
Alberto
A
Chiappori
Eric
E
Haura
Scott
S
Antonia
Gerold
G
Bepler
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012262:Ribonucleoside Diphosphate Reductase; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases