Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung

Ahroom Youk, Mercer University College of Pharmacy

The American Cancer Society remarks that lung cancer is by far the leading cause of death due to cancer, attributing it with almost 27% of overall cancer mortality.  They estimate that approximately 158,040 patients will die from lung cancer this year alone.  Among the various types of lung cancer, the American Cancer Society states that squamous cell carcinomas – a type of non-small cell lung cancer (NSCLC) – account for 25-30% of all lung cancers.  They further explain that this type of cancer begins in the squamous cells lining the inside of the airways in the lungs, and that it is commonly associated with a history of smoking.1

In patients with advanced or recurrent squamous cell carcinomas and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1, the National Comprehensive Cancer Network (NCCN) recommends a platinum-based doublet as first-line therapy.  If the disease progresses during or after first-line therapy, the NCCN states that nivolumab, docetaxel ± ramucirumab, erlotinib, or gemcitabine may be initiated as second-line therapy, depending on patient-specific criteria.  Additionally, the NCCN considers either erlotinib or afatinib as first-line treatment options in NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) mutations, such as Exon19del (deletions in exon 19) and L858R (a mutation in exon 21).2

The Food and Drug Administration (FDA)-approved indication for both afatinib and erlotinib is the first-line treatment of patients with metastatic NSCLC and EGFR exon 19 deletions or exon 21 substitution mutations as detected by an FDA-approved test.  However, erlotinib is also indicated in three other scenarios: for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy, for the treatment of locally advanced or metastatic NSCLC after failure of one or more prior chemotherapy regimen(s), and for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine.3,4

Title: Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomized controlled phase 3 trial5
Design Open-label randomized controlled trial; N= 795
Objective To compare afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung
Study Groups Patients with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based chemotherapy were assigned to receive either afatinib 40 mg by mouth once daily (n= 398) or erlotinib 150 mg by mouth once daily (n= 397).
Methods Computed tomography (CT) or Magnetic Resonance Imaging (MRI) was used to assess the tumors at baseline and at week eight, 12, 16, and every eight weeks thereafter.  Adverse events were graded using the Common Terminology Criteria for Adverse Events.  Laboratory assessments for safety were completed at the time of screening, on the first day of each treatment course, and at the end of the treatment.  Patients completed the European Organization for the Research and Treatment of Cancer questionnaire and its lung cancer module at the first visit of each treatment course to report their symptoms and overall well-being.
Duration March 30, 2012 – October 7, 2013
Primary Outcome Measure Progression-free survival
Baseline Characteristics Afatinib (n= 398) Erlotinib (n= 397)
          Male 335 (84%) 331 (83%)
          Female 63 (16%) 66 (17%)
Median age, years (range) 65.0 (36-84) 64.0 (35-88)
Age group
          < 65 years 189 (47%) 210 (53%)
          > 65 years 209 (53%) 187 (47%)
Baseline ECOG PS
          0 126 (32%) 134 (34%)
          1 269 (68%) 262 (66%)
          2 * 3 (< 1%) 1 (< 1%)
Ethnic origin
          Non-eastern Asian 312 (78%) 311 (78%)
          Eastern Asian 86 (22%) 86 (22%)
Smoking status
          Never smoker 26 (7%) 18 (5%)
          Light ex-smoker † 11 (3%) 12 (3%)
          Current and other ex-smoker ‡ 361 (91%) 367 (92%)
Median time since diagnosis (years, range) 0.8 (0.2-9.3) 0.7 (0.2-13.5)
Tumor histology §
          Squamous 381 (96%) 382 (96%)
          Mixed 17 (4%) 15 (4%)
Previous platinum doublet
          Carboplatin-based 249 (63%) 229 (58%)
          Cisplatin-based 163 (41%) 198 (50%)
          Other 5 (1%) 8 (2%)
Clinical stage at screening
          IIIA 1 (< 1%) 4 (1%)
          IIIB 48 (12%) 48 (12%)
          IV 349 (88%) 345 (87%)
Best response to chemotherapy ¶
          CR or PR 186 (47%) 185 (47%)
          SD 161 (40%) 167 (42%)
          Unknown 47 (12%) 42 (11%)
Data are n (%), unless stated otherwise.  ECOG PS = Eastern Cooperative Oncology Group performance status.  CR = complete response.  PR = partial response.  SD = stable disease.

* Protocol violations

† < 15 pack-years and stopped > 1 year before diagnosis

‡ 71 (18%) versus 85 (21%) were current smokers.

§ Three patients in the erlotinib group had undifferentiated tumor histology but were considered to be squamous by the treating investigator.

¶ Seven patients (four in the afatinib group and three in the erlotinib group) had a best response of progressive disease on chemotherapy.

Results There was an improvement in progression-free survival with afatinib (median 2.4 months [95% CI 1.9-2.9]) compared with erlotinib (median 1.9 months [95% CI 1.9-2.2]), with the hazard ratio as 0.82 [95% CI 0.68-1.00] and p = 0.0427.
Adverse Events Common Adverse Events:

Afatinib: diarrhea, rash or acne, fatigue, stomatitis

Erlotinib: rash or acne, diarrhea, fatigue, pruritus

The rates of treatment-related grade 3 diarrhea and grade 3 stomatitis were higher in the afatinib group than the erlotinib group, while the incidence of grade 3 rash or acne was higher in the erlotinib group than the afatinib group.

Serious Adverse Events:

Treatment-related serious adverse events included diarrhea (15 [4%]), dehydration (seven [2%]), and acute renal failure (four [1%]) in the afatinib group, and diarrhea (six [2%]) in the erlotinib group.

Percentage that Discontinued due to Adverse Events:

Afatinib group: 79 (20%) total; death (six [2%]), diarrhea (16 [4%]), rash or acne (10 [3%])

Erlotinib group: 67 (17%) total; death (five [1%]), diarrhea (six [2%]), rash or acne (eight [2%])

Study Author Conclusions The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung.

A secondary endpoint that the LUX-Lung 8 authors additionally analyzed was the median overall survival.  They determined that afatinib significantly improved overall survival compared with erlotinib (7.9 months [95% CI 7.2-8.7] versus 6.8 months [95% CI 5.9-7.8], respectively).  However, the study authors also mentioned that the 1.1 month improvement in overall survival may or may not be clinically significant.  Another analysis from this study depicted an improved overall health-related quality-of-life in patients treated with afatinib versus erlotinib (121/339 [36%] versus 96/339 [28%]; p = 0.041).  Furthermore, the authors reported that the adverse events seen in this trial were expected and manageable; therefore, it was suggested that afatinib could be used to treat patients with squamous cell carcinoma of the lung.5


  1. Lung Cancer – Non-Small Cell. American Cancer Society, Inc. Accessed August 17, 2015.
  2. Non-Small Cell Lung Cancer Guidelines Version 7.2015. National Comprehensive Cancer Network. Accessed August 17, 2015.
  3. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim International HmbH; 2013.
  4. Tarceva [package insert]. San Francisco, CA: Astellas Pharmas US, Inc., and Genentech Inc.; 2004.
  5. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897-907. doi: 10.1016/S1470-2045(15)00006-6.

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