Afatinib Extends OS by Approximately 1 Year in Subgroup of NSCLC

Lecia V. Sequist, MD

First-line afatinib (Gilotrif) improved overall survival (OS) by about 1 year in patients with advanced non—small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 19 deletions according to results from the LUX-Lung 3 and the LUX-Lung 6 phase III randomized trials. The data were presented at the 2014 Multidisciplinary Symposium in Thoracic Oncology.

The study authors believe that these survival data warrant a major shift among clinicians. “In our opinion, first-line afatinib should become the standard of care for EGFR Del19 patients,” lead author Lecia V. Sequist, MD, said at the symposium. “The questions have been answered regarding its effectiveness for this mutation,” added Sequist, medical oncologist, associate professor, Massachusetts General Hospital, Harvard Medical School.

Afatinib is approved in many countries globally, including the United States, where it is indicated for previously untreated patients with metastatic NSCLC harboring common EGFR mutations (Del19 and L858R).

Both the LUX-Lung 3 and the LUX-Lung 6 trials shared the same design and methodology. Following testing for an EGFR mutation, patients with stage IIIB/IV EGFR-positive NSCLC were randomized 2:1 to receive oral afatinib (40 mg daily) or up to six cycles of chemotherapy. LUX-Lung 3 chemotherapy was pemetrexed/cisplatin and LUX-Lung 6 chemotherapy was gemcitabine/cisplatin. Randomization was stratified by mutation type (Del19/L858R/other) for both trials, with 89% of patients in each trial having either Del19 or L858R. Only 11% of patients had uncommon mutations.

The LUX-Lung 3 also stratified patients (n = 345) by race (Asian/non-Asian). Non-Asian patients were recruited mainly from Europe, South America and Australia. LUX-Lung 6 (n = 364) consisted of Asian patients, primarily Chinese.

The primary endpoint of both studies was progression-free survival, which previously reported data showed both trials met. OS, disease control rate (DCR), patient reported outcomes (PRO) and objective response rate (ORR) were secondary endpoints for both studies.

Median follow up for OS was 40.9 months in LUX-Lung 3 and 33.7 months in LUX-Lung 6. The hazard ratios (HR) for OS were 0.78 (95% CI 0.58-1.06; P = .109) versus pemetrexed/cisplatin and 0.83 (95% CI, 0.63-1.09; P = .176) versus gemcitabine/cisplatin. Results within the mutation subgroups were consistent between both trials.

In the analysis of common mutations, OS improved in EGFR Del19 patients regardless of their race. The afatinib versus chemotherapy data by population group are as follows:

• LUX-Lung 3, global population: median of 33.3 months with afatinib versus 21.1 months with chemotherapy (HR = 0.54; 95% CI, 0.36-0.79)
• LUX-Lung 6, Asian population: median of 31.4 months with afatinib versus 18.4 months with chemotherapy (HR = 0.64; 95% CI, 0.44-0.94)
• LUX-Lung 3, Non-Asian population: median of 33.6 months with afatinib versus 20.0 months with chemotherapy (HR = 0.45; 95% CI, 0.21-0.95; P = .03)

However, there was no significant difference in the OS of patients who had L858R mutations between afatinib and chemotherapy. Sequist and her colleagues believe that, despite the lack of clear differentiating factors between the regimens, afatinib remains a treatment option for EGFR L858R patients.

Sequist et al also drew another important conclusion from the LUX-Lung 3 and LUX-Lung 6 trials: “We also believe that, going forward, we can no longer look at patients with these two mutations together [in the same study]. We need to look at them separately because the Del19 and L858R mutations react quite differently.”

Sequist L, Wu Y, Schuler M, et al. Overall survival (OS) with afatinib versus chemotherapy in patients (Pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): results of LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6). Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract 9.

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