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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously
S Sugawara1, S Oizumi2, K Minato3
1Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai.
Background:
The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation.
Patients And Methods:
Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety.
Results:
All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients).
Conclusion:
This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study.
Clinical Trials Registration:
University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).
Insights
The concurrent administration of gefitinib and chemotherapy showed improved overall survival in patients with EGFR-mutant non-small cell lung cancer (NSCLC) compared to sequential treatment. This combination is being further evaluated in phase III trials.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Limited data exist on combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC).
- A randomized phase II study was conducted to determine the optimal combination regimen for further phase III investigation.
Purpose of the Study:
- To evaluate the efficacy and safety of concurrent versus sequential alternating gefitinib plus carboplatin/pemetrexed in chemotherapy-naïve patients with advanced EGFR-mutant NSCLC.
- To select a combination regimen for a phase III study.
Main Methods:
- Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomized to receive either concurrent or sequential alternating gefitinib (250 mg) with carboplatin/pemetrexed (AUC=6, 500 mg/m² every 3 weeks).
- Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and safety.
- 80 patients were enrolled and assessed for efficacy.
Main Results:
- Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential regimen (HR 0.71, P=0.20).
- Median OS was 41.9 months for concurrent and 30.7 months for sequential regimens (HR 0.51, P=0.042), though OS data were immature.
- Response rates were high and similar in both groups (87.8% concurrent vs. 84.6% sequential).
- Adverse events were common but manageable; interstitial lung disease occurred in 5% of patients in both groups and was not fatal.
Conclusions:
- This is the first randomized study comparing concurrent and sequential EGFR-TKI and chemotherapy in EGFR-mutated NSCLC.
- Both regimens demonstrated promising efficacy with acceptable toxicity.
- The concurrent regimen showed a potential survival benefit and was selected for further phase III evaluation against gefitinib monotherapy.
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