ESMO 2014-AFATINIB BETTER THAN ERLOTINIB

Progression-free survival was statistically significantly better in patients treated with afatinib than in those treated with erlotinib 

• Date: 27 Sep 2014
• Topic: Lung and other thoracic tumours /  Anticancer agents & Biologic therapy

In the LUX-Lung 8, global, randomised, phase III study the progression-free survival (PFS) and disease control rate (DCR) were significantly better in patients with relapsed/refractorysquamous cell carcinoma of the lung treated with afatinib than in those treated with erlotinib. The study was presented by Prof. Glenwood Goss of the Division Of Medical Oncology, University of Ottawa, Ottawa, Canada during the Proffered Paper session on metastatic non-small cell lung cancer (NSCLC) at ESMO Congress 2014, in Madrid, Spain.

Squamous histology represents approximately 30% of NSCLC cases. Limited progress and therapeutic options exist for these patients in second-line setting. Targetable oncogenic alterations are limited and have not yet translated to a therapeutic paradigm. In addition, patients often have extensive comorbidities.

Erlotinib is the last drug approved (in 2005) based on efficacy vs placebo in second-/third-line setting. Survival benefit is confirmed in subset analysis of male, ever-smokers with squamous cell carcinoma.

Afatinib is an irreversible ErbB-family blocker that inhibits all kinase-active members (EGFR, HER2 and HER4). Proof of concept in squamous histology was observed in various trials in lung and head and neck cancer. It is approved in the major International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use regions of USA, EU and Japan for the treatment of patients with NSCLC harbouring distinct types of epidermal growth factor receptor (EGFR)-activating mutations.

The LUX-Lung 8 study is a randomised, open-label, prospective phase III trial in patients with squamous cell carcinoma of the lung following failure of first-line chemotherapy. It compared afatinib with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor.

Afatinib vs erlotinib in relapsed/refractory setting

Progression-free survival by independent review in the LUX-Lung 8 study. © Glenwood Goss

Eligible patients with stage IIIB/IV squamous cell carcinoma of the lung and ECOG performance status 0 and 1 were randomised 1:1 to receive afatinib or erlotinib until disease progression. All patients had progressed after ≥4 cycles of platinum-based doublet chemotherapy and had not received prior EGFR tyrosine kinase inhibitors (EGFR TKI). Patients were stratified based on race (eastern Asian vs. other).

The trial was powered for PFS and overall survival (OS). The primary endpoint was PFS acoording to RECIST 1.1 criteria as assessed by independent radiological review (IRR). Secondary endpoints included overall survival (OS) planned at 632 events, objective response rate (ORR), DCR, safety and health-related quality of life.

An interim futility analysis was performed by an independent data monitoring committee and the trial was allowed to accrue to the planned 800 patients. Overall 795 patients were recruited between March 2012 and January 2014. Planned primary analysis was based on 414 PFS events by IRR in the first 669 patients randomised (afatinib = 335, erlotinib: 334) while recruitment was ongoing.  

Baseline characteristics were well balanced between arms. Median age was 65 years, 85% of patients were male; eastern Asian counted 22% of the study population; and never smokers 5%.

Median PFS was significantly higher for afatinib than erlotinib, both by IRR (2.4 vs 1.9 months; p=0.0427) and investigator review (2.7 vs 1.9 months; p=0.0053).

Objective response by independent review in the LUX-Lung 8 study. © Glenwood Goss

The ORR was 4.8% vs. 3.0% (p=0.233), but DCR (45.7% vs 36.8%; p=0.020) was significantly higher with afatinib vs erlotinib.

Overall adverse event profile was comparable and consistent with the mechanistic profile of EGFR inhibition (patients with ≥ grade 3 adverse events: 50.2% and 49.1% for afatinib and erlotinib with higher incidence of drug-related ≥ grade 3 diarrhoea (9.7% vs 2.4%) and grade 3 stomatitis (3.3% vs 0.0%) with afatinib and higher incidence of grade 3 rash/acne with erlotinib (5.5% vs 9.0%).

Conclusion

The authors concluded that LUX-Lung 8 is the largest prospective trial to compare EGFR TKIs in patients with relapsed/refractory squamous cell carcinoma of the lung. The PFS was statistically significantly better for afatinib than erlotinib. Tumour shrinkage was greater, response rate higher, and disease control rate significantly higher in the afatinib arm compared to the erlotinib arm. Overall adverse event profile was consistent with mechanistic profile of EGFR inhibition and was manageable. Patient-reported outcomes favoured afatinib versus erlotinib. The OS data are awaited.

Dr Pasi Janne, in his discussion entitled “Who should be treated with EGFR TKI”, said that the clinical implications of LUX-Lung 8 study are marginal benefit of afatinib over erlotinib and increased toxicity. EGFR-inhibitors are used less (if at all) in squamous cell lung cancer, chemotherapy is generally more effective in this disease and more than 99% of EGFR mutations actually occur in adenocarcinoma. New therapies are emerging for squamous cell cancer in particular anti-PD 1, PD-1 and anti-PD-L1 inhibitors.