Advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations derive greater benefits from first-line treatment with afatinib than gefitinib, shows a head-to-head comparison of the second- and first-generation tyrosine kinase inhibitors (TKIs).
Keunchil Park, from Sungkyunkwan University School of Medicine in Seoul, Korea, presented the results of the phase IIb LUX-Lung 7 trial at the ESMO Asia 2015 Congress in Singapore.
The risk of progression and treatment failure were each significantly reduced by 27% for the 160 EGFR mutation-positive, treatment naive NSCLC patients with stage IIIb or IV disease given afatinib 40 mg/day compared with their 159 counterparts treated with gefitinib 250 mg/day. The corresponding median times were 11.0 versus 10.9 months for progression-free survival (HR 0.73; 27% at 18 months for afatinib and 15% for gefitinib, and 18% at 24 months for afatinib and 8% for gefitinib) and 13.7 versus 11.5 months for time to treatment failure.
The data for the third primary endpoint, overall survival, were not mature when the primary analysis was conducted at a median follow-up of 27.3 months, the presenter reported.
But the secondary endpoint of objective response rate was significantly higher in patients given the irreversible ErbB family blocker afatinib compared with those given the reversible EGFR inhibitor gefitinib (70 vs 56%) and the median duration of response was also longer (10.1 vs 8.4 months).
The presenter emphasised that afatinib treatment led to improved outcomes regardless of the mutation subtype, with benefits observed in participants harbouring the exon 19 deletion as well as in those with the L858R mutation.
Treatment-related serious adverse events occurred more frequently in afatinib- than in gefitinib-treated study participants (10.6 vs 4.4%), as did side effects resulting in dose reductions (41.9 vs 1.9%). But the proportion of patients who discontinued treatment as a result of associated adverse events was the same in both groups (6.3%).
Diarrhoea (11.9%) and rash or acne (9.4%) were the most frequently observed toxicities of grade 3 or worse in the afatinib arm while elevations in alanine aminotransferase levels were most common in the gefitinib group (7.5%).
“LUX-Lung 7 provides the first direct evidence that first-line afatinib significantly improves progression-free survival versus gefitinib in this patient population, also with consistent time to failure and objective response benefit without compromising tolerability”, concluded Keunchil Park.
He commented that these findings could lead to new guidelines for clinical decision making when choosing first-line EGFR TKIs.
Discussing the findings, Pasi Jänne, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, remarked that although afatinib remains an option for first-line treatment of EGFR-mutant NSCLC, he does not believe it to be the only choice.
The key, the discussant said, is to “balance efficacy and toxicity”, adding that he does not believe that the choice of first-line EGFR TKI has an effect on subsequent therapies. He cited recent results showing that the EGFR T790M mutation – one of the major causes of resistance to first-generation TKIs – also develops in afatinib-treated patients to support his belief.
“The therapeutic landscape in this field is evolving”, said the discussant, with the development and evaluation of structurally divergent EGFR inhibitors (such as osimertinib) as initial therapies and the use of combination regimens (such as the first-generation TKI erlotinib plus bevacizumab), which are also undergoing assessment for first-line use.
Pasi Jänne envisages changes in how clinicians will approach patients with advanced EGFR-mutant disease over the next several years, and concluded: “Our opportunity and challenge is to develop the most effective and tolerable strategy to prevent or delay resistance for as long as possible.”
Keunchil Park, Eng-Huat Tan, Li Zhang,et al.Afatinib versus gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer harboring activating EGFR mutations: LUX-Lung 7. Presented at: ESMO Asia 2015 Congress. Singapore; 18–21 December 2015; LBA2 PR