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Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2
James Chih-Hsin Yang1, Jin-Yuan Shih, Wu-Chou Su
1Graduate Institute of Oncology and Cancer Research Centre, College of Medicine, National Taiwan University, Taipei, Taiwan.
Background:
Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations.
Methods:
In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148.
Findings:
129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease).
Interpretation:
Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC.
Funding:
Boehringer Ingelheim Inc.
Insights
Afatinib demonstrated efficacy in treating advanced lung adenocarcinoma with EGFR mutations, particularly deletion 19 or L858R. A 40 mg daily dose showed improved tolerability compared to 50 mg.
Area of Science:
- Oncology
- Pharmacology
Background:
- Afatinib is an irreversible ErbB-family blocker with demonstrated preclinical activity in non-small-cell lung cancer (NSCLC) harboring EGFR mutations.
- Lung adenocarcinoma with specific EGFR mutations represents a target for novel therapeutic agents.
Purpose of the Study:
- To assess the efficacy and tolerability of afatinib in patients with advanced lung adenocarcinoma and EGFR mutations.
- To compare two starting doses of afatinib (50 mg and 40 mg daily) to optimize treatment outcomes.
Main Methods:
- Phase 2, multi-center study enrolling 129 patients with advanced lung adenocarcinoma and EGFR mutations.
- Patients received afatinib at a starting dose of 50 mg daily, with a dose reduction to 40 mg daily for some.
- Primary endpoint was confirmed objective response rate based on RECIST 1.0 criteria.
Main Results:
- An objective response rate of 61% (79/129) was observed across all patients.
- Patients with common EGFR mutations (deletion 19 or L858R) showed a higher response rate (66%) compared to those with uncommon mutations (39%).
- The 40 mg starting dose demonstrated improved tolerability with fewer grade 3 adverse events (diarrhea, rash/acne) and serious adverse events compared to the 50 mg starting dose.
Conclusions:
- Afatinib exhibits significant activity in advanced lung adenocarcinoma with EGFR mutations, particularly common activating mutations.
- The 40 mg daily dose of afatinib appears to offer a better tolerability profile while maintaining anti-tumor activity.
- Further comparative studies of afatinib 40 mg against chemotherapy or other EGFR TKIs in EGFR-mutation-positive NSCLC are warranted.
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