Second-line treatment options for advanced non-small cell lung cancer (NSCLC) patients have substantially expanded in the past few years. Docetaxel- or pemetrexed-based chemotherapy and erlotinib were the only three drugs approved in our setting until year 2014, achieving an approximate 8–10% of response rates (RRs), median 4 months of progression-free survival (PFS) and 8–10 months of overall survival (OS) (1). Recently, antiangiogenics [ramucirumab (2), nintedanib (3), and bevacizumab (4)] and particularly PD-1/PD-L1 inhibitors [nivolumab (5, 6), pembrolizumab (7), and atezolizumab (8)] have shown to prolong survival in pretreated patients, transforming the standardization of second-line NSCLC treatment.

In the absence of significant differences in terms of efficacy, the choice between pemetrexed- or docetaxel-based second-line chemotherapy is largely driven by three factors: histology, as pemetrexed is restricted to non-squamous tumors, type of platinum doublet used during first-line treatment, with pemetrexed being increasingly incorporated into the first-line or maintenance treatments, and differences in toxicity profiles. On the other hand, when deciding between chemotherapy and erlotinib, apart from clinical factors, EGFR mutation status is the main biomarker that determines treatment selection.

The IPASS trial definitely demonstrated that the clinical activity of EGFR tyrosine-kinase inhibitors (TKIs) in treatment-naïve patients was restricted to those with EGFR-mutant tumors (EGFR-sensitizing mutations). As the clinical activity of EGFR TKIs in TKI-naïve, EGFR-mutant tumors is comparable between treatment-naïve or platinum-pretreated patients (9), first- or second-generation EGFR TKIs are the preferred treatment options in patients with EGFR-mutant tumors. On the contrary, in patients with EGFR wild-type (WT) cancers, RRs and survival were significantly lower with gefitinib- compared to platinum-based chemotherapy in the IPASS study (10). However, whether this was also true in the second-line setting, a clinical context in which the efficacy of docetaxel- or pemetrexed-based chemotherapy hardly reaches 10% of RRs, has been a matter of extensive debate in the past few years. Some molecularly unselected randomized trials, initiated at a time where no definitive predictive biomarkers for the benefit or EGFR TKIs were discovered yet, initially suggested similar efficacy outcomes between erlotinib and second-line chemotherapy (11–13). More recent data, including molecularly selected or molecularly stratified randomized trials and large meta-analysis, have confirmed that second-line chemotherapy is superior to EGFR TKIs in patients with EGFR WT tumors, at least in terms of RRs and PFS. OS differences did not reach statistical significance (14–16).

In this therapeutic scenario, and considering that EGFR pathway activation might hypothetically contribute to cancer progression even in tumors with no EGFR activating mutations (17), to investigate if a more potent pan-HER inhibition with dacomitinib would add any clinical benefit seemed a rational approach, either from a biological or a clinical perspective. In addition, as the majority of patients with EGFR-mutant tumors treated with first-generation EGFR TKIs develop acquired resistance by ERBB-dependent mechanisms (18), and considering that dacomitinib showed activity in gefitinib-resistant preclinical lung cancer models (19), it was also rational to test its clinical activity in patients with EGFR-mutant, TKI-resistant cancers. Herein, we will succinctly discuss the potential role of second-line dacomitinib in EGFR WT and EGFR-mutant NSCLC.

Dacomitinib is a second-generation, irreversible, covalent-binding pan-HER TKI. As compared to first-generation EGFR TKIs, it has comparable inhibitory activity against the WT EGFR kinase in vitro. However, dacomitinib is more potent than gefitinib against cell lines harboring common EGFR-sensitizing mutations (del19, L858R). Moreover, it has inhibitory activity against gefitinib-resistant exon 20 insertions and acquired resistance exon 20 T790M mutations in preclinical lung cancer models. Unlike gefitinib or other first-generation TKIs, dacomitinib, as a pan-ERBB inhibitor, also inhibits the activity of both WT and mutant HER2 kinase (19, 20).

Three phase I trials, conducted both in Western and Asian patients, established that the maximum tolerated dose of dacomitinib was 45 mg daily, and this dose level was selected for further clinical evaluation. The most frequent dose-limiting drug-related adverse events were skin and gastrointestinal toxicities (21–23). The three trials consistently demonstrated that plasma concentrations and other pharmacokinetic parameters proportionally increased with increasing doses of oral dacomitinib (21–23), with no apparent food effect (21). Dacomitinib’s half-life was estimated at 59–85 h in the phase I trial conducted in the United States (21). A modest preliminary clinical activity was observed in small cohorts of NSCLC patients previously treated with first-generation EGFR TKIs and/or chemotherapy. No objective responses were seen in EGFR TKI-resistant patients whose tumors harbored EGFR T790M mutations (21–23).

Dacomitinib has failed to improve overall outcomes in pretreated NSCLC patients. An irreversible pan-HER inhibition is not superior to erlotinib in patients with no EGFR-sensitizing mutations and does not prolong OS compared to placebo in heavily pretreated patients either. Also, dacomitinib does not overcome EGFR T790M-mediated acquired resistance in EGFR-mutant NSCLCs at tolerable doses in humans. In non-T790M-mediated resistance, in which functional activation of HER pathway or acquired HER2 activating mutations have been described in some cases (18, 33), no reliable clinical data are available, but a robust activity in this clinical setting seems unlikely. With these clinical data, together with recent regulatory approvals of third-generation, EGFR-mutant selective TKIs (e.g., osimertinib) with potent activity against the T790M mutation (34), current development of dacomitinib is focused to TKI treatment-naïve, molecularly selected patients with EGFR-mutant and HER2-mutant lung cancers. In a small phase II trial including a total of 45 treatment-naïve patients with tumors harboring common EGFR-sensitizing mutations, dacomitinib achieved an overall RR of 75.6% and a median PFS of 18.2 months (30).

In this regard, whether second-generation EGFR TKIs in TKI-naïve patients are superior to first-generation TKIs in EGFR-mutant NSCLCs is not fully answered to date. In the LUX-Lung 7 trial, afatinib significantly increased RRs (70 vs. 56%; p = 0.0083), median PFS (11 vs. 10.9 months; HR 0.73, CI 95% 0.57–0.95; p = 0.0195), and median time to treatment failure (13.7 vs. 11.5 months; HR 0.73, CI 95% 0.58–0.92; p = 0.0073) over gefinitib. However, there were no OS differences among treatment arms in this phase IIb trial (n = 319). Pre-specified subgroup analysis according to mutation type (exon 19 deletions vs. L858R mutations) did no show significant differences in OS either. Overall, treatment-related adverse events (mainly skin rash and diarrhea) and serious adverse events were more common with afatinib (33). Therefore, this trial suggests that the emergence of acquired resistance might be delayed with second-generation compared to first-generation TKIs, but whether these modest differences are clinically relevant for patients is arguable for many physicians. The ARCHER 1050 trial (NCT01774721) comparing first-line dacomitinb vs. gefitinib has recently completed accrual and will hopefully give a definitive answer in this regard, establishing the true role of front-line dacomitinib in EGFR-mutant NSCLCs.

All authors contributed equally to this work.

LP-A has received advisory honoraria from Roche, Lilly, MSD, Novartis, BMS, Clovis, Amgen, Boehringer Ing., Astra Zeneca, and Pfizer, not related to this work. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.