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Being molecular in the molecular age.

We congratulate the authors for completion of this large study, LUX Lung 5, to address an important question of the role of afatinib in combination with chemotherapy after progression of lung cancer on afatinib alone. In this phase III randomized study of patients with advanced nonsmall-cell lung cancer (NSCLC) treated with one or more lines of chemotherapy followed by an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) and afatinib, the authors show that continuing afatinib beyond progression in combination with paclitaxel resulted in a 2.5-fold increase in overall response rate and a doubling of progression-free survival (PFS) compared with investigator choice chemotherapy [1]. No significant improvement in overall survival was seen. This is a positive study that has met its primary end point of improvement in PFS. The challenge is to translate this finding into clinical practice. For this, we should ask two basic questions, ‘Who may benefit?’ and ‘Why should there be a benefit?’ Afatinib is an irreversible ErbB blocker. Preclinical data show that it is a more potent blocker of EGFR and human epidermal growth factor receptor (HER) signaling compared with the firstgeneration EGFR TKIs and has efficacy in lung cancer cells with resistance to EGFR TKIs due to development of the T790M exon 20 mutation or upregulation of the HER signaling pathway [2]. In the LUX Lung 3 and LUX Lung 6 trials, afatinib has demonstrated clinical efficacy as first-line treatment in patients with advanced NSCLC molecularly selected for activating EGFR mutation [3, 4]. However, its efficacy in clinically selected patients who have progressed on EGFR TKIs has been modest. In the LUX Lung 1, phase IIb/III study of advanced NSCLC patients progressing after chemotherapy and ‘clinically enriched’ for EGFR TKI response, the response rate to afatinib monotherapy was only 7%–11%. About 50% of patients had stable disease for 8 weeks [5]. Similar response rates were also seen in the phase II Lux Lung 4 trial where patients received afatinib after initial clinical benefit from EGFR TKI, although no prior chemotherapy was given [6]. In both of these studies, as in current study (LUX Lung 5), progression after disease control for ≥12 weeks with gefitinib/erlotinib was used as a surrogate for acquired resistance to EGFR TKIs. We must understand that this ‘clinically enriched’ population is a heterogeneous group that comprises wild-type and mutated EGFR (with or without concurrent exon 20 T790M) [7]. According to the TAILOR study that compared docetaxel with erlotinib in patients with wild-type EGFR, ∼30% of patients were progression-free after 12 weeks on erlotinib and these patients would have been eligible for LUX Lung 5 [8]. It may not be appropriate to use the word ‘acquired resistance’ for this population as it is unlikely that these patients were having a true response to EGFR TKI [9]. In LUX Lung 5, the patients who met the modified ‘higher clinical enrichment criteria’ of complete remission/partial remission to EGFR TKI or ≥48 weeks of disease control were more likely, but not exclusively, to be representative of an EGFR mutant population [7, 10]. The benefit of paclitaxel plus afatinib beyond progression was statistically significant for the subgroup with positive ‘higher clinical enrichment criteria’ [hazard ratio (HR): 0.56 (0.36–0.87)] while the benefit was more marginal [HR: 0.65 (0.39–1.08)] for the negative subgroup. Thus, we should explore the potential reasons for the benefit of the combination independently in both EGFR mutation-positive and -negative population. Patients with an EGFR mutation can be genuinely considered as ‘oncogene addicted’. The concept of treatment beyond RECIST progression in EGFR mutant patients with advanced NSCLC was explored in the ASPIRATION study and in the IMPRESS study [11, 12]. In the ASPIRATION study, erlotinib was continued as a single agent beyond RECIST progression and showed an improvement in PFS by 3.1 months. Exploratory analyses suggested that the benefit of continuation was best seen in those with good initial response to erlotinib. The IMPRESS study showed no significant benefit of gefitinib beyond progression in combination with platinum-based chemotherapy compared with chemotherapy alone. However, subgroup analysis suggested that the combination may benefit T790M mutation-negative patients with improvement in PFS from 5.4 to 6.7 months (HR 0.67, 95% confidence interval 0.43–1.03, P = 0.0745) [13]. With the recent approval of osimertinib (third-generation EGFR TKI) for patients with T790M, there will be no role for combination of paclitaxel plus afatinib in this population. The combination, plausibly, may be worthy of consideration in the T790M-negative patients. Afatinib resistance in the T790M-negative population may be related to upregulation of the extracellular-regulated kinase and v-Akt murine thymoma viral oncogene/mammalian target of rapamycin (mTOR) signaling pathways, bypassing EGFR [14]. Paclitaxel, in preclinical studies, has been shown to inhibit the mTOR signaling pathway and also phosphorylate the downstream target of mTOR, p70 S6 kinase [15, 16]. Afatinib in combination with paclitaxel has demonstrated preclinical synergy in solid tumor cell lines and xenografts and has been studied in the phase I setting. In the phase I study including different solid tumor patients, nine patients with NSCLC were treated, three obtained clinical benefit and one of these patients had a wildtype EGFR [16, 17]. It is possible that afatinib and paclitaxel may have synergistic effect in the T790M-negative population. Potentially, authors may study the T790M status of patients from LUX Lung 5 if plasma cfDNA is available. Benefit of the combination in patients with predominantly wild-type EGFR remains a challenge to explain. PFS benefit of ed ito ria ls editorials Annals of Oncology 27: 367–368, 2016 doi:10.1093/annonc/mdw002