COMMENTARY

Comparing First-Line TKI Options for EGFR-Positive NSCLC

H. Jack West, MD

Disclosures

February 10, 2016

Over the past 6 years, multiple clinical trials in patients with an activating mutation of the epidermal growth factor receptor (EGFR) gene have compared different first- or second-generation oral EGFR tyrosine kinase inhibitors (TKIs) to conventional platinum doublet chemotherapy.[1] These have demonstrated strikingly superior efficacy, at least in terms of progression-free survival (PFS) and objective response rate (ORR), whether the EGFR TKI was gefitinib, erlotinib, or afatinib. Until the LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) trials tested afatinib vs chemotherapy in EGFR mutation–positive patients, however, these studies have not demonstrated an improvement in overall survival (OS), which in turn was only observed in patients with an exon 19 deletion.[2] Whether the OS benefit of afatinib is truly specific to afatinib or is a function of the gefitinib and erlotinib studies being smaller (and often stopped early due to marked differences at early time points) or more likely to have crossover from chemotherapy to EGFR TKI therapy, or other factors, has remained an open question; we are left inferring differences by comparing trials. To truly answer the question of how different EGFR TKIs compare as first-line therapy for patients with an activating EGFR mutation, we need a randomized trial of one EGFR TKI compared directly with another. We now have the early results of one such trial: LUX-Lung 7 (LL7).[3]

The randomized phase 2 LL7 trial screened 571 patients from Asia, Europe, Canada, and Australia to ultimately assign 319 previously untreated patients with advanced non-small cell lung cancer (NSCLC) with an activating EGFR mutation to either afatinib 40 mg orally daily or gefitinib 150 mg orally daily; co-primary endpoints were PFS, time to treatment failure (TTF, which measures duration of time on treatment before discontinuing due to side effects, and includes continuation of therapy if it appeared to continue providing benefit), and ORR.

LUX-Lung 7 Results

Approximately two thirds of the patients were never-smokers, 58% had an exon 19 deletion, the remaining 42% had L858R substitution, and nearly 60% were Asian. The early data on this study, as presented by Dr Keunchil Park[3] at ESMO Asia, revealed a significantly superior PFS (by independent review) that was not reflected by the essentially equivalent median PFS values (11.0 vs 10.9 months for afatinib and gefitinib, respectively). Instead, the benefit (hazard ratio [HR] 0.73; P = .0165) was seen in patients who progressed after the median PFS had been reached. Landmark analysis of PFS at 24 months was 18% vs 8% (P = .0184) for afatinib and gefitinib, respectively. Of note, all subgroups, whether by specific EGFR mutation, performance status, patient sex, race, or smoking history, showed very similar trends of significantly or nonsignificantly longer PFS with afatinib.

Looking at the other efficacy endpoints, afatinib was also superior in TTF (median 13.7 vs 11.5 months; HR 0.73; P = .0073) and ORR (70% vs 56%; P = .0083). Median duration of response was 10.1 vs 8.4 months for afatinib and gefitinib, respectively. Not surprisingly, for a population of patients typically demonstrating a survival of several years, the data on OS are immature, but a current HR of 0.87 favoring afatinib (nonsignificant) was noted.

 
should modest improvements in time-limited efficacy endpoints, arguably ameliorated by several more challenging side effects, lead us to conclude that afatinib is now the EGFR TKI of choice?
 

One of the potential limitations to the broader use of afatinib has been concern that its side-effect profile is considerably more challenging. The data from LL7 reveal a higher rate of drug-related serious adverse events (AEs) with afatinib (10.6% vs 4.4%) and a considerably greater rate of diarrhea (90% vs 61% for all grades, 11.9% vs 1.3% for grade 3) and stomatitis (64.4% vs 23.9% for all grades, 4.4% vs 0% for grade 3), but a higher rate of elevated liver function tests with gefitinib (23.9% vs 9.4% for all grades, 7.5% vs 0% for grade 3 ALT elevation). Although far more patients assigned to afatinib experienced AEs leading to dose reduction (41.9% vs 1.9%), the rate of drug-related AEs leading to discontinuation of therapy was actually the same (6.3%) for both agents.

Clinical Implications

What are the clinical implications of these data? To me, the key finding is that there is an arguably clinically significant difference in efficacy between two EGFR TKIs in EGFR mutation–positive patients, and this was true with multiple endpoints, in patients with either common activating mutation, and in all clinically defined subgroups. In addition, although afatinib is associated with several side effects that are both more common and more severe, the rate of discontinuation due to toxicity was identical between afatinib and gefitinib. But in the absence of a survival benefit, should modest improvements in time-limited efficacy endpoints, arguably ameliorated by several more challenging side effects, lead us to conclude that afatinib is now the EGFR TKI of choice? Some may argue that afatinib can only be concluded to be superior in efficacy to gefitinib, but not erlotinib, leaving us to our biases to surmise how recipients of erlotinib would fare in a similar comparison. It is also notable that the prevailing standard of care in EGFR mutation–positive patients has not shifted to erlotinib/bevacizumab as a result of the JO25567 trial[4] that compared this combination with erlotinib alone and revealed a highly significant improvement in PFS with this combination, as well as a similarly nonsignificant trend toward superior OS, based on preliminary data. Although the LL7 trial is larger, I would argue that the difference is more compelling for the combination of erlotinib/bevacizumab with a single-agent EGFR TKI as a comparator.

Taken together, these findings leave me with a view that, in the absence of a significant survival benefit, and with tolerability and cost also relevant factors, there is still room for physician judgment and individualization of treatment based on the priorities of a particular patient. We hope to learn more as these preliminary OS data mature and as additional treatment options, such as the third-generation EGFR TKIs, are also tested as first-line treatment for EGFR mutation–positive patients.

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