ASCO 2015. Abstract 8002. Overall survival (OS) analysis from the global phase III trial LUX-Lung 8 (LL8)

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American Society of Clinical Oncology 2015

ASCO 2015. Abstract 8002. Afatinib (A) vs erlotinib (E) as second-line therapy of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following platinum-based chemotherapy: Overall survival (OS) analysis from the global phase III trial LUX-Lung 8 (LL8).

Jean-Charles Soria, Enriqueta Felip, Manuel Cobo, Shun Lu, Konstantinos N. Syrigos, Ki Hyeong Lee, Erdem Goker, Vassilis Georgoulias, Wei Li, Dolores Isla, Salih Zeki Guclu, Alessandro Morabito, Young Joo Min, Andrea Ardizzoni, Shirish M. Gadgeel, Bushi Wang, Vikram K. Chand, Glenwood D. Goss, LUX-Lung 8 Investigators; Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France; Vall d'Hebron University Hospital, Barcelona, Spain; Hospital Carlos Haya, Malaga, Spain; Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Athens School of Medicine, Athens, Greece; Chungbuk National University College of Medicine, Cheongju, South Korea; Ege University Faculty of Medicine, Izmir, Turkey; Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece; First Hospital Affiliated to Jilin University, Jilin, China; Hospital Lozano Blesa, Zaragoza, Spain; Department of Chest Diseases, Izmir Chest Diseases Research Hospital, Izmir, Turkey; Istituto Nazionale Tumori “Fondazione G.Pascale"- IRCCS, Naples, Italy; Department of Medicine, Ulsan University Hospital, Ulsan, South Korea; University Hospital, Parma, Italy; Karmanos Cancer Center, Detroit, MI; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada

Background: Treatment options for pts with advanced SCC of the lung progressing after platinum-based chemotherapy are limited. Overexpression of EGFR, ErbB receptors and the dysregulation of their downstream pathways are implicated in SCC pathobiology. Primary analysis of LL8 (2nd line A, an irreversible ErbB family blocker vs E, a reversible EGFR tyrosine kinase inhibitor [TKI; only TKI approved in this setting], in pts with SCC of the lung) showed significantly better progression-free survival (PFS) with A. OS and updated PFS are reported here. 

Methods: Pts with stage IIIB/IV disease were randomized 1:1 to receive A (40 mg/day) or E (150 mg/day) until disease progression. Primary endpoint: PFS; key secondary endpoint: OS. Other endpoints: objective response (ORR), disease control (DCR), patient reported outcomes and safety. 632 events and a sample size of 800 pts was needed to detect a HR of 0.8 with 80% power for OS. 

Results: OS was significantly better with A (n = 398) vs E (n = 397), with a 19% reduced risk of death (median 7.9 vs 6.8 mos; HR [95% CI] 0.81 [0.69–0.95]; p = 0.008). Significant differences in OS were seen at 6 (63.6 vs 54.6%; p = 0.010), 12 (36.4 vs 28.2%; p = 0.016) and 18 (22.0 vs 14.4%; p = 0.013) mos. PFS (median 2.6 vs 1.9 mos; HR [95% CI] 0.81 [0.69–0.96]; p = 0.010), ORR (5.5 vs 2.8%; p = 0.055) and DCR (50.5 vs 39.5%; p = 0.002) were all better for A vs E. More pts had improved global health status/quality of life (35.7 vs 28.3%; p = 0.041), cough (43.4 vs 35.2%; p = 0.029) and dyspnea (51.3 vs 44.1%; p = 0.061) with A vs E. Adverse event (AE) profiles were comparable (G ≥ 3 AEs: 57.1 and 57.5% for A vs E) with a higher incidence of drug-related G3/4 diarrhea (9.9/0.5 vs 2.3/0.3%), G3 stomatitis (4.1 vs 0%) with A and a higher incidence of G3 rash/acne with E (5.9 vs 10.4%). Preliminary data from FoundationOne analysis of tumor blocks will be shown. 

Figure 1. Primary Analysis of Overall Survival

Conclusions: A significantly improved OS vs E in pts with SCC of the lung in a 2nd line setting. PFS and DCR were also significantly better. With a manageable AE profile, added QoL benefit, and symptom control seen in LL8, A should be preferred over E for these pts. Clinical trial information: NCT01523587

 

CARE Faculty Perspective:

LUX Lung 8 asked the question of which EGFR TKI fared better in squamous cell cancer of the lung (SCC) in the second line setting. At ESMO 2014, the primary outcome of PFS was presented with a HR of .82 p=0.0427.  Although it reached significance, the absolute benefit was small with PFS 2.43 months for afatinib and 1.94 months for erlotinib.

The discussant dismissed these results for any clinical meaningfulness and suggested that targeted drugs (EGFR TKI) should not be used in patients without a target (EGFR WT). This question has been under debate for many years in many parts of the world.

This year at ASCO, the overall survival was presented (see Figure 1). Importantly, this was a prespecified powered secondary endpoint. Patients on afatinib had an overall survival of 7.9 months versus 6.8 months for erlotinib HR 0.81 p = 0.008.

Never smokers made up of less than 1% of patients on the LUX Lung 8 trial. Thus, the rate of EGFR mutations in LUX Lung 8 would be negligible. Afatinib fared better in the second line setting of patients with squamous carcinoma of the lung. EGFR TKI’s have activity in the squamous carcinoma. If follows that EGFR TKI’s have activity in EGFR Wild type.

This is an important trial and likely practice changing in provinces and countries where EGFR inhibitors have been restricted to patients with an EGFR mutation. Afatinib is the better TKI in this setting.

LUX Lung 8 was a positive trial in PFS and now at ASCO 2015 OS! This confirms activity of EGFR TKI in particular afatinib in squamous carcinoma of the lung. We look forward to future studies exploring the biomarker or target being affected.  

- CARE Oncology Faculty

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