Dataset Information

Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.

ABSTRACT:

Background

A trial of neoadjuvant gemcitabine and pemetrexed (GP) chemotherapy in patients with resectable non-small cell lung cancer was conducted. The goal was to achieve a disease response rate of 50% and to determine if the expression levels of genes associated with GP metabolism are predictive of response.

Methods

Patients had staging with a computed tomography scan, whole body F-18 fluorodeoxyglucose positron emission tomography, and mediastinoscopy. Four biweekly cycles of GP were given. Patients were restaged, and those with resectable stage IB-III disease had thoracotomy. Fresh frozen tumor specimens were collected before and after chemotherapy and the mRNA levels of 14 target genes determined by real-time reverse transcription polymerase chain reaction.

Results

Fifty-two patients started therapy. The radiographic disease response rate was 35% (95% confidence interval 21.7-49.6%), and the progression rate was 6%. Forty-six patients had a thoracotomy. The complete tumor resection rate was 77% (40/52). There were no perioperative deaths or deaths related to chemotherapy. Tumor response to chemotherapy was inversely correlated with the level of expression of RRM1 (p < 0.001; regulatory subunit of ribonucleotide reductase) and TS (p = 0.006; thymidylate synthase); i.e., the reduction in tumor size was greater in those with low levels of expression.

Conclusions

Neoadjuvant GP is well tolerated and produces an objective response rate of 35%. Tumoral RRM1 and TS mRNA levels are predictive of disease response and should be considered as parameters for treatment selection in future trials with this regimen.

SUBMITTER: Bepler G

PROVIDER: S-EPMC2639211 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Publications

Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.

Bepler Gerold G Sommers K Eric KE Cantor Alan A Li Xueli X Sharma Anupama A Williams Charles C Chiappori Alberto A Haura Eric E Antonia Scott S Tanvetyanon Tawee T Simon George G Obasaju Coleman C Robinson Lary A LA

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20081001 10

<h4>Background</h4>A trial of neoadjuvant gemcitabine and pemetrexed (GP) chemotherapy in patients with resectable non-small cell lung cancer was conducted. The goal was to achieve a disease response rate of 50% and to determine if the expression levels of genes associated with GP metabolism are predictive of response.<h4>Methods</h4>Patients had staging with a computed tomography scan, whole body F-18 fluorodeoxyglucose positron emission tomography, and mediastinoscopy. Four biweekly cycles of ...[more]

PMID: 18827606

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Project description:We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Dataset Information

Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.

Background

Methods

Results

Conclusions

Publications

Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.

Similar Datasets

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