Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer

Mariacarmela Santarpia, Jessica Menis, Imane Chaib, Maria Gonzalez Cao & Rafael Rosell

To cite this article: Mariacarmela Santarpia, Jessica Menis, Imane Chaib, Maria Gonzalez Cao & Rafael Rosell (2019): Dacomitinib for the first-line treatment of patients with EGFR- mutated metastatic non-small cell lung cancer, Expert Review of Clinical Pharmacology, DOI: 10.1080/17512433.2019.1649136
To link to this article: https://doi.org/10.1080/17512433.2019.1649136

Accepted author version posted online: 29 Jul 2019.

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Publisher: Taylor & Francis

Journal: Expert Review of Clinical Pharmacology

DOI: 10.1080/17512433.2019.1649136
Drug Profile

Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer

Mariacarmela Santarpia 1*, Jessica Menis 2,3*, Imane Chaib 4, Maria Gonzalez Cao 5, Rafael Rosell4,5.

⦁ Medical Oncology Unit, AOU Policlinico “G. Martino”, Department of Human Pathology of Adult and Evolutive Age “G.Barresi”, University of Messina.
⦁ Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
⦁ Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
⦁ Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Spain.
⦁ Dr. Rosell Oncology Institute (IOR), Dexeus University Hospital, Barcelona, Spain.

* These authors equally contributed to the article.

Correspondence to:
Mariacarmela Santarpia
Medical Oncology Unit, AOU Policlinico “G. Martino”, Department of Human Pathology of Adult and Evolutive Age “G.Barresi”, University of Messina
Via Consolare Valeria, 1, 98122, Messina (Italy) [email protected]

Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first- line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first- generation TKI gefitinib and is the most recent inhibitor to be approved in this setting.
Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR- mutated NSCLC.
Expert opinion: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.

Article Highlights
⦁ Treatment landscape for advanced NSCLC patients with EGFR mutations has evolved during these last years
⦁ Beyond gefitinib, erlotinib, afatinib and osimertinib, dacomitinib has emerged as a novel therapeutic option for EGFR-mutated NSCLC
⦁ First-line dacomitinib has demonstrated to improve PFS compared to gefitinib, with acceptable toxicity
⦁ Dacomitinib is the first, irreversible EGFR TKI showing an OS improvement compared to a first-generation TKI in the first-line setting
⦁ The drug received approval by FDA on September 2018 and has been recently approved for clinical use also in Europe and Japan

⦁ Introduction
Lung cancer represents the leading cause of cancer-related deaths worldwide [1]. Patients with non- small cell lung cancer (NSCLC), the predominant form of lung cancer, are commonly diagnosed with locally advanced or metastatic disease, for which systemic treatment represents the standard of care. Therapeutic management of metastatic NSCLC has remarkably improved over the last few years due to the increasing number of molecularly targeted agents approved for treatment of patients whose tumors harbour specific oncogenic alterations, including mutations of EGFR or BRAF, and ALK or ROS1 rearrangements, mainly found in adenocarcinoma histology [2].
Additional targeted therapies are currently under evaluation in other oncogenic-driven subtypes of NSCLC. More recently, a number of immune checkpoint inhibitors, including monoclonal antibodies directed against the PD1-PD-L1 axis, has been introduced for clinical use due to demonstration of high efficacy in NSCLC patients with both squamous and non-squamous histologies [3,4]. Due to the number of therapeutic options currently available in the first-line setting of metastatic NSCLC patients, molecular profiling of tumors for targetable oncogenic alterations and for immuno-oncology therapy biomarker, PD-L1, is crucial to guide treatment decisions [5,6].
The discovery of somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene in 2004, and the development of specific kinase-inhibitor therapy, has marked the advent of the era of personalised medicine in NSCLC. These activating genetic mutations are predominant in adenocarcinoma and cluster around the adenosine triphosphate (ATP)-binding pocket of the kinase domain (exons 18–21) and induce constitutive activation of the receptor and downstream pathways, including phosphatidylinositol 3-kinase (PI3K)/AKT, RAS/RAF/mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways, involved in cell proliferation and survival.The most common, “classic” mutations are the in-frame exon 19 deletion and exon 21 missense mutation, accounting for about 90% of all mutations. EGFR mutations confer oncogenic properties to cells and a high susceptibility to EGFR tyrosine kinase inhibitors (TKIs) [7]. In a systematic review and meta-analysis, including 456 studies, the overall pooled prevalence for EGFR mutations in patients with NSCLC was found to be 32.3%, ranging from 38.4% in China to 14.1% in Europe [8].

⦁ Overview of the market
The first-generation, reversible, EGFR TKIs, gefitinib and erlotinib, are orally bioavailable synthetic 4< anilinoquinazoline derivatives designed to compete for ATP binding to the catalytic site of the receptor and, therefore, switch off prosurvival signals. The second-generation, also-

defined irreversible or covalent EGFR inhibitors, including afatinib and dacomitinib, have broader activity against other ErbB (HER) family members. In large randomized trials, gefitinib, erlotinib and afatinib have consistently demonstrated higher efficacy, in terms of progression-free survival (PFS) and objective responses, than platinum-based chemotherapy as first-line therapy of EGFR- mutated NSCLC patients [9-15]. Notably, in all studies the benefit of improvement in ORR and PFS was consistent across all subgroups of patients according to predefined baseline demographic characteristics, including race, genders, smoking status and performance status (PS). Also, EGFR TKIs have shown favourable toxicity profiles and to improve quality of life (QoL) compared to chemotherapy. These positive results have led to approval of these drugs as upfront therapies for patients with advanced NSCLC and sensitizing EGFR mutations. However, probably due to treatment crossover effects at progression, no overall survival (OS) difference was observed between EGFR-TKIs and chemotherapy across all of these studies. Only in a pooled OS analysis of patients included in two phase III trials, afatinib was associated with a significant OS benefit compared with chemotherapy in patients with exon 19 deletions, whereas the same OS difference was not seen in patients with L858R mutations [16]. However, in the randomized, phase IIb, LUX- Lung 7 study, comparing afatinib versus gefitinib, OS was not statistically different (HR 0.86; 95% CI 0.66-1.12; p= 0.258; median OS: 27.9 versus 24.5 months) between the two treatment arms, including those patients with EGFR exon 19 mutation, although a modest benefit in median PFS (HR 0.73, 95% CI 0.57-0.95; p= 0.017; median PFS: 11.0 v 10.9 months), ORR and time to treatment failure (TTF) was observed for afatinib [17,18]. However, the study had no specific statistical power for all co-primary endpoints.Until recently, geftinib, erlotinib and afatinib have been the standard of care and the only available therapeutic options for EGFR-mutated patients.
Despite the remarkable clinical benefit observed with these drugs, almost all patients inevitably progress due to development of acquired resistance, which presents a great challange to the durable efficacy of these agents [19, 20]. The most common mechanism of resistance is represented by a secondary mutation in exon 20 of EGFR, the T790M, which occurs at a conserved ‘gatekeeper’ threonine residue within the ATP binding pocket and is found in approximately 50-60% of patients with acquired resistance to early-generation EGFR TKIs [21-23]. Despite promising results of second-generation TKIs in inhibiting T790M kinase activity in preclinical studies, clinical data suggested a rather limited activity of these drugs in patients with acquired resistance to first generation TKIs. Therefore, third-generation, mutant-selective, wild-type-sparing, EGFR TKIs have been designed with preferential activity toward both sensitizing- and T790M-resistance mutations. Osimertinib was the first, third-generation, mutant EGFR-specific TKI to be granted US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for the treatment of patients with metastatic EGFR T790M-positive NSCLC in progression after EGFR TKI therapy [24].
In the phase III, randomized FLAURA trial, osimertinib demonstrated higher efficacy as first-line treatment of EGFR-mutated NSCLC patients compared to gefitinib or erlotinib, the standard of care when the study was started. Treatment with osimertinib resulted in a significantly prolonged PFS, with a 54% lower risk of disease progression or death compared to first-generation TKIs. The benefit was observed across all predefined subgroups of patients, including those with central nervous system (CNS) metastases. Overall survival data were not yet mature at the time of this analysis. Notably, a lower rate of grade ≥3 adverse events (AEs) and of AEs leading to treatment discontinuation was reported in patients receiving osimertinib, suggesting a better tolerability profile compared to first-line EGFR-TKIs [25, 26]. Based on these positive results, osimertinib received FDA (April 2018) and EMA (June 2018) approval as first-line therapy of EGFR-mutant NSCLC patients.
Other therapeutic strategies have been tested in phase II and III trials in the first-line setting of EGFR-mutated NSCLC including the combination of EGFR TKIs with platinum-based chemotherapy [27] or antiangiogenic agents, which can represent additional treatment options to improve frontline treatment [28-31]. Cytotoxic chemotherapy may potentially induce apoptosis in

those cells that exhibit primary resistance to EGFR TKI therapy. The synergistic inibition of VEGF and EGFR pathways has been supported by pre-clinical data. The inhibition of the EGFR pathway blocks tumor cell growth and the synthesis of angiogenic proteins by tumor cells, while the use of antiangiogenic drugs, such as bevacizumab, prevents the activation of endothelial cells by VEGF. The combination of erlotinib with bevacizumab has already been approved by EMA based on promising PFS results [5].

⦁ Introduction to the drug

Dacomitinib (PF-00299804; Pfizer, New York, NY, USA) is an orally administered, highly selective ATP-competitive, second -generation pan-HER inhibitor that irreversibly binds to EGFR, HER2, and HER4 tyrosine kinases [32]. Preclinical studies have shown antitumour activity in NSCLC cancer cell lines with sensitive- and TKI resistant-EGFR mutations [32, 33].

⦁ Chemistry
Dacomitinib (chemical formula: [2E]-N-4- [piperidin-1-yl)but-2-enamide]) is a quinazoline-based pan-HER inhibitor that binds irreversibly to receptor tyrosine kinases of the HER family by alkylating a prominent cysteine residue (Cys) in each of the ATP-binding pockets of EGFR, HER-2 and HER-4 [34].

⦁ Pharmacodynamics
Dacomitinib obtained prolonged pharmacodynamic effects in vitro and in vivo when compared with reversible inhibitors, which is likely due to the irreversible nature of the compound caused by covalent interaction with a unique unpaired cysteine residue within the ATP binding pocket of the erbB family of receptor tyrosine kinases domains [33]. The higher potency of dacomitinib was also reflected in cell lines harboring EGFR-activating mutations (L858R, exon 19 deletions, A767_V769duspASV and EGFRvIII) by achieving lower IC50 values when compared with gefitinib. However, other enzymes that contain analogous cysteine residues in their ATP pocket (e.g., JAK3) were not inhibited [32].
The irreversible inhibition of the autophosphorylation of EGFR in cells led to potent antitumor activity (including complete tumor regression) in human tumor xenograft models expressing erbB family members [33]. Dacomitinib showed activity by complete inhibition of EGFR, Akt and ErbB3 phosphorylation in both EGFR TKI-sensitive and -resistant cell lines. Its activity against T790M mutations was reproducible in other in vivo studies in which dacomitinib was effective in inhibiting the H1975 xenograft models harboring T790M mutations [33].
In summary, dacomitinib showed excellent potency in in vitro cells, and a breadth of activity in a range of in vivo human xenograft models.

⦁ Pharmacokinetics and metabolism
Dacominitib has a favourable pharmacokinetic profile in all preclinical species (rat, dog, and monkey): in summary, high bioavailability (>50%), long half-life (t1/2: >12 hours), and a large volume of distribution (>17 L/kg) [33]. In vivo, dacomitinib is highly bound to plasma proteins (97–98 %) across species, including human, and shows a similar distribution between red blood cells and plasma in human blood. In order to well characterize the routes of elimination and metabolic profiles of dacomitinib in humans, six healthy, male volunteers (mean age 31.5 years) were recruited in a phase I trial and received a single 45-mg oral dose containing [14C] dacomitinib. Whole blood, urine, and fecal samples were collected throughout the study and analyzed for total radioactivity by liquid scintillation counting. Peak concentrations of dacomitinib in plasma occurred 12 h (median) after oral dosing. Mean terminal plasma half-life was 55 h for dacomitinib.
Dacomitinib underwent multiple pathways of metabolism (mainly oxidative and conjugative

metabolism) and was excreted in feces (78.8 %) and in urine (3.2 %). The formation of O- desmethyl dacomitinib, the major circulating metabolite, O-desmethyl dacomitinib, primarily involves CYP2D6. Another site of metabolism is the nitrogen side of the amide bond, resulting in the formation of M7. Other oxidative pathways appear to involve oxidation of the piperidine moiety, yielding M9, M10, M19, and M20. In addition, it is likely that dacomitinib underwent glutathione conjugation with subsequent hydrolysis to form the cysteine conjugate (M2). Overall, dacomitinib was well tolerated with no serious/severe adverse events or deaths during the study [35].
The impact of coadministration of paroxetine, a CYP2D6 inhibitor, on dacomitinib pharmacokinetics was investigated in a Phase I study with healthy volunteers who were extensive CYP2D6 metabolizers. CYP2D6 inactivation by paroxetine significantly inhibited the CYP2D6- mediated metabolism of a single dose of dacomitinib. However, the effect on dacomitinib’s exposure was modest and, thus, dacomitinib dose adjustment upon coadministration with a CYP2D6 inhibitor was not recommended. Drug–drug interaction may occur if dacomitinib is to be taken concomitantly with drugs that are metabolized by CYP2D6. Dacomitinib is a potent inhibitor of CYP2D6 with an IC50 of 60 nM in vitro. Its inhibitory effect was verified clinically in a Phase I study involving healthy volunteers with coadministration of dacomitinib and dextromethorphan (a CYP2D6 probe).
Finally, dacomitinib can be administered in a gastrostomy tube but half-live was shorter by 20 %, Cmax and AUC were reduced if compared to oral administration. Possible explanations could be loss of dacomitinib when the pills were dissolved or transferred: tubing or tube coating could potentially adsorb a portion of the active ingredient as well. This loss can be minimized by dissolving the drug in a syringe and by repeated flushing with a larger volume [36].

⦁ Clinical efficacy.
⦁ Phase I studies.
Several phase I studies aimed to assess the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) for this compound as well as pharmacokinetics and possible interactions [Table 1].
A phase I study of dacomitinib in 122 patients with advanced solid tumours (57 NSCLC) was conducted. The study included a first dose-escalation phase, ranging from 0.5 to 60 mg every day, according to the modified Fibonacci scheme followed by a series of expansion cohorts, so to assess also intermittent schedule, loading doses, gastric pH effect and food effect. At 60 mg, 3 of 6 patients experienced a dose limiting toxicity (DLT) (grade (G)3 stomatitis, G3 palmar–plantar erythema, and G3 dehydration). The next lowest dose, 30 mg, was then expanded and 1 patient experienced DLT (G3 oral mucositis). The dose was then escalated to 45 mg. At this dose, 1 patient experienced DLT (grade 3 rash), and the MTD was established at 45 mg.
The main reported adverse events for the group of patients that received a dose 33% higher than the continuously dosed MTD administered on an intermittent schedule (schedule B) were diarrhea (20% G3; 90% any grade), cutaneous rash (no G3; 60% any grade), fatigue (10% G3; 40% any grade), and nausea (10% G3; 40% any grade).
As sampling was insufficient in the dose escalation cohort, a full pharmacokinetic profile could only be assessed by including the expansion cohorts. In terms of activity, no complete responses were observed but 4 patients (3.6%), all with NSCLC, had a PR [37].
Another phase I open-label, dose-escalation study had the same objective to be investigated according to a traditional ‘3+3’ design in the Japanese population [38]. None of the thirteen enrolled patients experienced a DLT, so that the RP2D was defined at 45 mg once daily. Toxicities were manageable and similar in type to those observed in other studies: cutaneous rash (20% G3; 100% any grade), diarrhea (no G3; 92% any grade), stomatitis (no G3; 61.5% any grade) and fatigue (no G3; 46% any grade) being the most common ones. PK concentration parameters increased with dose over the range evaluated, no evidence of accumulation over time. Of 13

evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease [38].
A phase I/II, multicenter, open-label, dose-escalation study of Korean patients with pre-treated KRAS wild-type adenocarcinoma NSCLC enrolled twelve patients in the phase I, and 43 patients enrolled in the phase II part at the RP2D of 45 mg once daily [39]. In phase I, successive cohorts of six patients received escalating doses of oral dacomitinib, starting at 30mg QD. No DLTs were observed up to a dose of 45mg QD, which was then confirmed as the RP2D.
In the phase II part, PFS rate at 4 months was 47.2% (95% CI, 31.6–61.3; 1-sided p = 0.0007). Median PFS was 15.4 weeks and median OS 46.3 weeks; and the ORR was 17.1% (95% CI, 7.2– 32.1). Common treatment-related adverse events were dermatitis acneiform (81.8% any grade; 4.7% G3), diarrhea (78.2% any grade; 14% G3), paronychia (63.6% any grade; 9.3% G3) and stomatitis (45.5% any grade; no G3); there were no treatment-related grade 4 or 5 adverse events [39].
To further evaluate the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI), a specific phase I study was built. The study concluded that dacomitinib was generally well tolerated and could be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required [40].
Dacomitinib was also combined with other targeted agents, crizotinib and figitumumab, in two phase I trials. The combination with crizotinib was tested in a phase I trial in pretreated advanced NSCLC patients with the aim of targeting one of the resistance mechanism to EGFR TKi i.e. MET alteration. Overall seventy patients were treated in the dose- escalation (33) and expansion phases (37). Three patients had DLTs: G3 increased alanine aminotransferase level (at dacomitinib, 45 mg once daily, and crizotinib, 200 mg twice daily), G3 diarrhea (at dacomitinib, 45 mg once daily, and crizotinib, 200 mg twice daily), and G3 mucosal inflammation (at dacomitinib, 30 mg once daily, and crizotinib, 250 mg twice daily): all three DLTs resolved. Therefore, the MTD was defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%; 74% any grade), rash (7%; 33% any grade), and fatigue (6%; 37% any grade). In terms of activity, only one patient (1%) had a partial response, 46% had stable disease. Median PFS was 3.0 months (95% CI: 2.8-4.3) in the escalation phase and 2.1 months (95% CI: 1.4-3.5) in the expansion phase [41].
A multicenter, nonrandomized, open-label, single- arm phase I trial with a standard 3+3 dose- escalation/de-escalation design was utilized to assess the safety and tolerability of dacomitinib– figitumumab combination therapy in patients with advanced solid tumors in a phase I, open-label, single-arm trial. The rationale for testing this combination was to tackle another mechanism of resistance to EGFR TKIs represented by IGF receptor 1 (IGF-1R) activation, which has a crucial role in tumor cell proliferation. The starting doses were 20 mg/kg of intravenous figitumumab administered once every 3 weeks and once daily 30 mg oral administration of dacomitinib with a loading dose for both figitumumab and dacomitinib.
Dacomitinib and figitumumab were tolerable without any significant drug-drug interaction but with significant dose reductions. The most common treatment-related adverse events were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer [42]. A summary of the key ongoing phase 1 trials are listed in Table 2.

⦁ Phase II studies.
⦁ Dacomitinib in NSCLC patients with EGFR or HER2 alterations.
An open-label, phase 2 study enrolled patients from 25 centres in 5 countries with histologically confirmed advanced lung adenocarcinoma, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST version 1.0), who had not previously received systemic treatment for advanced disease [43]. The patient population was divided into two cohorts: the EGFR mutated and the HER-2 mutated cohorts. First the EGFR-mutated was published. Patients were originally selected based on clinical characteristics (i.e. smoking status) for being possibly EGFR-mutated but afterwards the protocol was amended to include only NSCLC with known EGFR mutation. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate organ function, treated brain metastases were allowed. Dacomitinib was given orally, once daily, in 28-day cycles: the planned dose was 45 mg per day but due to the toxicity experienced, the protocol was amended to begin dacomitinib at 30 mg per day with the option to escalate to 45 mg per day at 8 weeks if no adverse events more than grade 1 were experienced.
Among the 53 (60%) patients with a confirmed EGFR mutation, 45 (85%) had an activating EGFR mutation in exon 19 (25 [47%]) or exon 21 (20 [38%]), and eight (15%) had other types of EGFR mutation. One (1%) patient had a double mutation (Glu709Val and Leu861Gln) and was classified as having an activating mutation in exon 21. The primary endpoint was progression-free survival at 4 months, no central review of tumour response was performed. Progression-free survival at 4 months was 76.8%, rejecting the null hypothesis for PFS at 4 months of 50% or less (one-sided p<0.0001). The estimated median PFS was 11.5 months. The proportion of patients achieving an ORR was 53.9%. At the time of data cut-off, 61 (69%) of 89 patients had died. Estimated median OS was 29.5 months (95% CI 22.8–35.6). At the time of data cut-off, 24 (53%) of the 45 patients with activating EGFR mutations had died. Median PFS was 18.2 months (95% CI 12.8–23.8) and median OS was 40.2 months (95% CI 29·0–NR). For both PFS and OS, no appreciable difference between patients with mutations in EGFR exon 19 (16.6 months and 40.0 months, respectively) or exon 21 (18.3 months and 46.0 months, respectively) was identified.The ORR was 75.6% (95% CI 60.5–87.1), and the median duration of response was 17.2 months (95% CI 11.8–22.1). Twelve patients (14%) permanently discontinued study treatment as a result of adverse events, 28 (32%) had a dose reduction, and 50 (56%) interrupted treatment temporarily.
The most common treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients (Table 3). The most common treatment-related grade 3 or 4 adverse events were dermatitis acneiform (18%), diarrhoea (15%), stomatitis (4%), and paronychia (4%). Two (2%) patients had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No treatment- related deaths were recorded. The study was not powered to formally compare treatment doses of 30 mg of dacomitinib per day with 45 mg per day, although overall the incidence of the most frequently reported adverse events did not differ to any clinically meaningful extent between patients who started treatment at 30 mg per day and those in the full- dose group. A separated cohort of 30 patients with pathologically confirmed recurrent or de-novo HER-2 amplified or mutated NSCLC was enrolled. Half were women, 60% were never smokers, and all but two had stage IV disease. Dacomitinib was the first systemic therapy for 17% and 83% had received at least one prior i.v. cytotoxic chemotherapy; two patients (7%) were previously treated with trastuzumab. The overall response for the patients with HER2-mutant disease was 12% and 0% for the four patients with HER2-amplified tumors. For the HER2-mutant cohort, the median PFS was 3 months (95% CI 2–4 months), the median OS was 9 months [44]. Some diarrhea was seen in 90% and skin rash in 73%. There was one case of grade 4 diarrhea and no grade 4 rash. Rash and diarrhea resolved with either supportive measures or dacomitinib cessation. There was only one drug-related death by hepatic failure likely due to an interaction of mirtazapine and dacomitinib. Mirtazapine is metabolized by CYP2D6 and was started 6 days after the initiation of dacomitinib (strong inhibitor

of the same cytochrome). Pharmacokinetic evaluations after development of liver failure revealed plasma mirtazapine levels increased 26-fold over expected [44].

⦁ Dacomitinib in KRAS wild-type or EGFR mutated NSCLC patients.
Another multicenter, open-label, phase II trial included 66 patients with histologically or cytologically confirmed advanced KRAS wild-type or known EGFR-mutated NSCLC [45].
In the overall population, the ORR for response- evaluable patients was 5.2%; for patients with adenocarcinoma was 4.8%, 6.3% for patients with non-adenocarcinoma. Overall median PFS was 12 weeks with 54 (82%) patients reaching PFS events, and similar values in the adenocarcinoma and non-adenocarcinoma populations. Median PFS was 12 weeks in the adenocarcinoma group and 11 weeks in the non-adenocarcinoma group. At the time of data cut-off, 47 patients (71%) had died and median OS was 37 weeks in the overall population, 45 weeks in patients with adenocarcinoma, and 27 weeks in patients with non-adenocarcinoma. The majority of treatment-related AEs were of grade 1 or 2 severity and were manageable with standard supportive care. Common events included diarrhea (85%), dermatitis acneiform (68%), dry skin (38%), fatigue (38%), exfoliative rash (24%), stomatitis (24%), decreased appetite (23%), and pruritus (23%). One patient experienced treatment- related grade 4 AEs of dyspnea and pulmonary embolism, possibly related to study drug; 18 patients (27%) experienced treatment-related AEs with a maximum severity of grade 3. The majority of patients (67%) did not require a dose reduction. Twelve deaths occurred within 28 days following the last dose of dacomitinib; none was considered treatment-related. Patients with radiographic disease control reported improvement in lung cancer symptoms of dyspnea, cough, pain in chest, and pain in arm/shoulder relative to baseline scores [45].
⦁ Dacomitinib versus erlotinib.
Finally, dacomitinib was compared to erlotinib in global, multicenter, randomized, open-label, phase II trial in advanced NSCLC patients. Prior EGFR-targeted therapy, known leptomeningeal or symptomatic brain metastases, clinically significant gastrointestinal abnormalities, interstitial lung disease, or uncontrolled cardiovascular disease were excluded [46].
Patients were randomly assigned (1:1) to receive oral erlotinib (150 mg once daily) or oral dacomitinib (45 mg once daily) until disease progression, intolerance, patient withdrawal, or death, with stratification by smoking status (non vs ever smoker), race (Asian vs non-Asian), and histologic subtype of NSCLC (adenocarcinoma vs non-adenocarcinoma).
In 11 months 188 patients were randomly assigned to dacomitinib or erlotinib. Patient baseline characteristics were balanced between treatment arms, except for baseline ECOG PS 2 (dacomitinib, n = 19; erlotinib, n = 3), EGFR mutation (EGFR: dacomitinib, n = 19; erlotinib, n = 11), and number of patients receiving two prior chemotherapy regimens (dacomitinib, n = 40; erlotinib, n = 27).
Median PFS was 2.86 months for dacomitinib and 1.91 months for erlotinib, with a HR of 0.66, 95% CI, 0.47 to 0.91, and two-sided p = 0.012.
The overall improvement in PFS seen with dacomitinib was noted across most clinical and molecular sub- sets assessed, including patients with tumors confirmed as KRAS wild-type/EGFR any status (including mutant; median PFS, 3.71 months for dacomitinib, 1.91 months for erlotinib; HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = 0.006), KRAS wild-type/EGFR wild-type (median
PFS, 2.21 months for dacomitinib, 1.84 months for erlotinib; HR = 0.61; 95% CI, 0.37 to 0.99; two- sided P = 0.043). For the EGFR mutant subset, median PFS was 7.44 months for both dacomitinib and erlotinib (HR = 0.46; 95% CI, 0.18 to 1.18; two-sided P = 0.098). The ORR for dacomitinib was 17.0%, with one complete response, and 5.3% for erlotinib (two-sided P = 0.011). The median duration of response was 16.56 months (range, 3.15 to 23.95) for dacomitinib and 9.23 months (range, 5.69 to 16.58) for erlotinib, respectively. OS was analyzed after 150 deaths (80%) had occurred, showing a trend toward favorable OS with dacomitinib, despite not reaching statistical

significance (median OS, 9.53 months for dacomitinib vs 7.44 months for erlotinib; HR = 0.80, 95% CI, 0.56 to 1.13, and two-sided P = 0.205 based on a stratified log-rank test with EGFR mutation status, KRAS mutation status, and baseline ECOG PS as stratification factors). After discontinuation, 84 patients (46%) overall received subsequent therapy, more among patients receiving erlotinib (47 of 94, 50%) than patients receiving dacomitinib (37 of 88, 42%). Frequently reported AEs included diarrhea (G3 11.8%; 73.1% any grade for dacomitinib vs G3 4.3%; 47.9% any grade for, erlotinib), acneiform dermatitis (G3 10.8%; 64.5% any grade for dacomitinib vs G3 6.4%; 57.4% any grade for, erlotinib), stomatitis (G3 1.1%; 29.0% any grade for dacomitinib vs G3 1.1%; 10.6% any grade for, erlotinib), mucosal inflammation (G3 2.2%; 24.7% any grade for dacomitinib vs no G3; 6.4% any grade for, erlotinib), and paronychia (G3 3.2%; 25.8% any grade for dacomitinib vs G3 1.1%; 8.5% any grade for, erlotinib); the majority of events were of grade 1 or 2 severity and manageable with standard supportive care [46].
A summary of the key phase II trials published in reported in Table 3.

⦁ Phase III studies.
Dacomitinib was tested in phase III studies including unselected NSCLC patients. In the double- blind, randomised, placebo-controlled, phase 3 trial BR.26, dacomitinib efficacy was assessed in patients with advanced or metastatic NSCLC pretreated with chemotherapy and a first-generation EGFR TKI, either gefitinib or erlotinib. The primary endpoint was OS in the intention-to-treat (ITT) population; secondary outcomes included OS in predefined molecular subgroups, PFS, ORR, safety and QoL [47]. The trial failed to achieve its primary endpoint. Dacomitinib did not improve OS compared to placebo (median 6.83 vs 6.31 months, HR 1.00 ,95% CI 0.83–1.21, p=0.506) but it was associated with longer PFS, higher ORR and longer time to deterioration of symptoms, including cough, dyspnoea, and pain, compared to placebo. Among the different molecular subgroups, the effect of dacomitinib on OS compared to placebo seemed similar in patients with EGFR mutation-positive (HR 0.98, 95% CI 0.67–1.44) and EGFR wild-type tumours (HR 0.93, 0.71–1.21; p=0.69) while it was noted qualitative differences in the effect of dacomitinib on OS for patients with KRAS mutation-positive tumours (HR 2.10, 1.05-4.22) and those with KRAS wild- type tumours (HR 0.79, 0.61–1.03; p=0.08) [47]. A phase II study demonstrated longer PFS for dacomitinib than erlotinib in locally advanced or metastatic NSCLC patients in progression after up to 2 previous regimens of chemotherapy, especially in those patients with KRAS wild-type tumours; based on these positive results, a phase III, randomised, double-blind trial (ARCHER 1009) was conducted [48]. The coprimary endpoints were PFS, based on independent radiological assessment, for all randomly assigned patients (intention-to-treat population), and PFS for the subgroup of KRAS wild-type patients. Overall, 878 patients were enrolled and 439 randomly assigned to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. The trial failed its coprimary endpoints and dacomitinib showed similar efficacy than erlotinib. Indeed, median PFS was 2.6 months in both the dacomitinib and erlotinib arm (HR 0.941, 95% CI 0.802– 1.104, p=0.229) in the overall unselected population and also in the subgroup of patients with KRAS wild-type tumours (HR 1.022, 95% CI 0.834–1.253, p=0.587). Grade 3-4 AEs, including diarrhea, rash and stomatitis were more frequent for dacomitinib compared to erlotinib, as were serious adverse events (SAEs)(12% vs 9%, respectively) [48].
Overall, we can conclude that these two trials failed to show better clinical efficacy of dacomitinib compared to placebo or first-generation EGFR TKIs, while being associated with more toxicities. In the subgroup of EGFR-mutated patients of the ARCHER 1009 study, representing 10-11% of all patients, dacomitinib and erlotinib had similar efficacy in terms of PFS and objective responses. A pooled subset analysis of patients with activating EGFR mutations in the ARCHER 1009 and the phase II A7471028 trials also suggested that dacomitinib had comparable efficacy to erlotinib in the EGFR-mutated patients [49].

In the single-arm phase 2 ARCHER 1017 study of dacomitinib as first-line therapy in clinically and molecularly selected patients with advanced NSCLC, PFS at 4 months was 76.8% (95% CI 66.4- 84.4) in the as-enrolled population, and 95.5% (95% CI 83.2-98.9) in the EGFR-mutant population. In patients with EGFR mutations, the ORR was 75.6% and median PFS 18.2 months [43]. Based on these findings, the ARCHER 1050 was specifically designed to head-to-head compare a second- generation TKI, dacomitinib, with a first-generation TKI, gefitinib, as first-line therapy of advanced or metastatic NSCLC patients with EGFR activating mutations (exon 19 del or exon 21 L858R substitution mutations). This was an international, multicentre, randomised, open-label, phase 3 study enrolling patients with newly diagnosed stage IIIB/IV or recurrent NSCLC, with at least one target lesion measurable according to RECIST version 1.1 criteria and one EGFR activating mutation (exon 19 deletion or Leu858Arg) [50]. Patients who had received prior systemic therapy for locally advanced or metastatic disease or who had CNS metastases were excluded. Patients were randomised 1:1 to receive oral dacomitinib (45 mg) or gefitinib (250 mg) once daily until disease progression or other discontinuation criteria, including initiation of new anticancer therapy, unacceptable toxicities, non-compliance, withdrawal of consent, or death. The primary endpoint was PFS assessed by masked independent review (IRC) in the ITT population. Secondary objectives included investigator-based PFS, ORR and duration of response (DoR) based on both masked IRC review and investigator assessment, OS, time to treatment failure (TTF), safety and patient-reported outcomes (PROs). Overall, demographics and baseline disease characteristics were well balanced between treatment groups, although the proportion of female patients was higher in the dacomitinib group than in the gefitinib group as was the proportion of patients with ECOG PS of 0. After a median follow-up for PFS of 22.1 months, PFS by IRC was 14.7 (95% CI 11.1-16.6) months in the dacomitinib group (n=227 patients) and 9.2 (95% CI 9.1-11.0) months in the gefitinib group (n=225 patients) (HR 0.59, 95% CI 0.47-0.74; p<0.0001). Subgroup analyses of PFS based on IRC review were conducted in patient subgroups according to prespecified baseline characteristics; the findings were generally consistent with the main analysis. Progression-free survival based on investigator assessment was also improved with dacomitinib and consistent with that of IRC review. Objective response rate by IRC was similar between the two groups (75% versus 72% for dacomitinib and gefitinib, respectively), however the DoR in responders significantly favors the irreversible TKI (14.8 versus 8.3 months for dacomitinib and gefitinib, respectively; HR 0.40, 95% CI 0.31–0.53; p<0.0001). The longer PFS with dacomitinib than with gefitinib could be explained by the greater reduction in tumour size with dacomitinib treatment than with gefitinib treatment. Moreover, patients in the dacomitinib group remained longer on study treatment than did those in the gefitinib group (median TTF: 11.1 versus 9.2 months, in the dacomitinib and gefitinib group, respectively; HR 0.67, 95% CI 0.54–0.83, p=0.0001). At the time of this report, OS data were not yet mature and were presented subsequently [51]. After a median follow-up time of 31.3 months, dacomitinib was associated wth a significantly longer OS compared to gefitinib (34.1 versus 26.8 months for dacomitinib compared with gefitinib; HR 0.760, 95% CI 0.582-0.993; p=0.044). Overall survival at 30 months was 56.2% in the dacomitinib group and 46.3% in the gefitinib group. The OS benefit was consistent across all prespecified patient subgroups. Of note, althoug patients with brain metastases were excluded from the study, the brain was the primary site of progression in one patient in the dacomitinib arm and 11 patients in the gefitinib arm. After study treatment discontinuation the proportion of patients receiving a subsequent therapy was 49.8% in the dacomitinib arm and 62.2% in the gefitinib arm.
Chemotherapy was the most common first subsequent therapy, received in a slightly higher proportion of patients in the gefitinib arm (35.6%) than in dacomitinib arm (27.8%), while third- generation EGFR TKIs were administered in a smaller fraction of patients (9.7% and 11.1% in the dacomitinib and gefitinib arm, respectively). Despite this small number of patients, interestingly, those who received dacomitinib followed by a third-generation EGFR TKI had the longest median OS (36.7 months). Overall survival was 29.5 months for patients receiving chemotherapy and 34.7

months for those who had EGFR TKI as subsequent treatment. A summary of the key phase III trials published are reported in Table 4.

⦁ Safety of dacomitinib as first-line therapy of EGFR-mutated NSCLC.
In the ARCHER 1050, the most common reported AEs of any grade (incidence ≥ 30%) in the dacomitinib arm were diarrhoea, paronychia, dermatitis acneiform, stomatitis and decreased appetite. Grade 3 and 4 events were more common in patients in the dacomitinib group (53%) compared to gefitinib (32%) [50]. The most common grade 3–4 adverse events in the dacomitinib group were dermatitis acneiform (14%) and diarrhoea (8%). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). Dose reductions occurred in 66% of patients receiving dacomitinib and 8% of those receiving gefitinib, while permanent discontinuation due to drug-related AEs occurred in 10% of patients in the dacomitinib group (mainly due to skin and subcutaneous tissue disorders, gastrointestinal disorders and interstitial lung disease or pneumonitis) and in 7% of patients in the gefitinib group (mainly due to alanine aminotransferase or aspartate aminotransferase increase and interstitial lung disease or pneumonitis). In PROs, improvements from baseline in dyspnoea, cough, pain in arm or shoulder, and pain in other parts were similar in the two groups. In the dacomitinib group a significantly greater improvement of pain in chest compared with the gefitinib group was recorded. Despite clinically meaningful deteriorations in diarrhoea and sore mouth in dacomitinib-treated patients, global quality of life was maintained and the difference in global quality of life, although statistically significant in favour of gefitinib, was small.

⦁ Regulatory affairs.
Based on ARCHER 1050 results, on the 4th of April 2018, FDA granted priority review for dacomitinib for the first-line treatment of EGFR-mutant NSCLC patients and the 27 September 2018 dacomitinib received its first global approval, in the USA, for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test.
In April 2019, Dacomitinib received marketing authorization in the European Union (EU) for the first-line treatment of adult patients with EGFR-mutated NSCLC. Additionally, it is approved in Japan for EGFR gene mutation-positive, inoperable or recurrent NSCLC, and in Canada, for the first-line treatment of adult patients with unresectable locally advanced or metastatic NSCLC with confirmed EGFR exon 19 deletion or exon 21 L858R substitution mutations.

⦁ Conclusion.
In previously reported phase III trials including unselected NSCLC patients, dacomitinib failed to show an advantage in terms of PFS compared to placebo or first-generation EGFR TKIs, while causing more toxicities. In a subsequent phase III trial, the ARCHER 1050, in advanced, EGFR- mutated NSCLC, dacomitinib was associated with longer PFS and DoR in responders, compared to a first-generation EGFR TKI as upfront therapy. More importantly, dacomitinib was the first irreversible EGFR TKI to demonstrate an overall survival benefit compared to another EGFR TKI. Regarding its safety profile, dacomitinib treatment appears to be more toxic than the reversible inhibitors and dose reductions were required at higher frequency in the dacominitib arm to allow patients to remain on study treatment. However, despite the higher incidence of grade 3 and 4 adverse events, dacomitinib was associated with improvements in some baseline lung cancer symptoms, including chest pain. Moreover, the global quality of life was maintained in the

dacomitinib group, despite showing a statistically significant but not clinically meaningful improvement in the gefitinib group.

⦁ Expert opinion
Many advances have been made in the treatment of EGFR-mutated patients over the last few years. Currently, different EGFR TKIs, including gefitinib, erlotinib, afatinib and osimertinib, are used worldwide to treat patients with NSCLC and EGFR activating mutations in the first-line setting.
The negative results from initial trials of dacomitinib including unselected advanced NSCLC patients may have diminished the clinical relevance of dacomitinib and delayed its approval. In contrast, the phase III ARCHER 1050 definitively demonstrated that this irreversible EGFR TKI can be an effective option for the first-line therapy of EGFR-mutant NSCLC, thus further expanding the array of therapeutic strategies for this molecularly-defined subgroup of patients. However, the optimal sequencing of all available EGFR TKIs in advanced NSCLC with EGFR mutations still is under debate. Indeed, results from the FLAURA study strongly suggest the upfront use of the third generation TKI osimertinib, which has clinical activity against sensitizing- and T790M resistance-mutations, to be preferred to first-generation TKIs, erlotinib or gefitinib. The study was not designed to compare osimertinib with a second-generation TKI, although indirect comparison of PFS among first-line therapy studies seems to be in favour of osimertinib. However, final OS data from the FLAURA study are still missing and eagerly awaited within the next months. In contrast, OS data have already been reported with dacomitinib, and support its use over gefitinib in EGFR-mutant NSCLC patients. In contrast to the FLAURA study, patients with brain metastases were excluded from participation in the ARCHER 1050. However, brain metastases developed as primary site of progression for one patient in the dacomitinib arm and for 11 patients in the gefitinib arm. This difference might have contributed to the improved survival outcome with the irreversible inhibitor, although CNS activity needs to be further explored in larger studies.
Interestingly, in the ARCHER 1050 study, the subgroup of patients, although small, who received dacomitinib followed by a third-generation EGFR TKI, had the best outcome, with a long median OS (36.7 months). These data raise some questions about the optimal sequencing of EGFR TKIs, which is still to be defined. Indeed, similar long survival outcomes have been reached with afatinib in first-line followed by osimertinib. Moreover, combinatorial approaches, including first- generation EGFR TKI and anti-angiogenic drugs or chemotherapy, have also shown promising efficacy data in the first-line setting. However, beyond efficacy, toxicity data need to be carefully evaluated when testing EGFR TKIs with other targeted agents or chemotherapy. Indeed, compared with gefitinib, dacomitinib as a single agent has been associated with significantly higher grade 3 and 4 adverse events, with most patients requiring dose reductions during the study. As for other EGFR TKIs, as well as dacomitinib, the emergence of intrinsic, adaptive and acquired resistance mechanisms can finally limit initial responses and long-term efficacy. As suggested by recent reports, EGFR-mutant NSCLC is a heterogeneous disease and concomitant molecular alterations can affect response to specific targeted agents. Molecular profiling of EGFR-mutant tumors in tissue- and/or liquid-biopsies is necessary and can suggest novel, potential effective therapeutic strategies to be used upfront or at time of resistance development.


This paper was not funded.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

A reviewer on this manuscript has disclosed a consultancy role and speaker's fee for Pfizer, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Pfizer provided a scientific accuracy review at the request of the journal editor.

Key publications:
Wu YL, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation- positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
Lancet Oncol. 2017 Nov;18(11):1454-1466.
Mok TS, et al. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR- Activating Mutations. J Clin Oncol. 2018 Aug 1;36(22):2244-2250.

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** In this study, first-line therapy with dacomitinib showed superior efficacy compared to a first- generation TKI, gefitinib, in advanced NSCLC patients with EGFR mutations.
⦁ Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018; 36: 2244–50.
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Table 1. Phase I trials of dacomitinib

Treatment n DLT RP2D ORR PFS OS Ref.
Dacomitinib 122 5 45 mg od 3.6% - - [37]
Dacomitinib 13 0 45 mg od 7.7% - - [38]
Dacomitinib 12 ph I
43 ph II - 45 mg od 17.1% 15.4
weeks 46.3
weeks [39]
Dacomitinib + Crizotinib 33
escal 37 exp 3 30 mg od
+ 200 mg crizotinib td 1% 2.1
months - [41]
Dacomitinib + Figitumumab 74 3 10-15 mg od + figitumumab 20 mg/kg,
every three weeks 4.9% - - [42]

Table 2. Ongoing trials of dacomitinib

Clinicaltrials.gov Treatment (line and
drug) Phase Centres Population Sample size Primary endpoint Sponsor
NCT03755102 II;
Dacomitinib I Single- center EGFR
mutated NSCLC,
pretreated with
osimertinib 24 ORR MSK
NCT03810807 I;
Osimertinib I Single- center Untreated, EGFR
mutated NSCLC 34 MTD; ORR MSK

NCT02039336 Dacomitinib
+ PD- 0325901 I/II Multicentre KRAS
mutated NSCLC 35 incidence rates of

NCI =Netherlands Cancer Institute

Table 3. Phase II trials of dacomitinib

Study Patient population Study drugs N. of patients PFS OS Ref

ITT n Population ECOG Primary endpoint ORR Median PFS Median OS Ref
(89 EGFR-mutated advanced NSCLC 0-2 4 months PFS rate 53.9
% 11.5 months 29.5 months [43]
30 HER-2-mutated advanced NSCLC 0-2 no predefined primary
endpoint 12% 3 months 9 months [44]
66 KRAS wild-type or EGFR mutated
advanced NSCLC 0-2 BOR 4.8
% 12 weeks 37 weeks [45]
188 Advanced NSCLC 0-2 PFS 17% 2.86 months 9.53 months [46]
ITT=intention to treat;

NCIC CTG Advanced or Dacomitinib 720 2.66 6.83 [47]
BR.26 metastatic NSCLC versus placebo (182
EGFR- (dacomitinib) vs. 1.38 (dacomitinib) vs.
6.31 months
patients, pretreated mutant) (placebo) months. (placebo): NS; EGFR-mutant:
with p<0.0001; 7.23
chemotherapy EGFR- (dacomitinib) vs.
and 1st- mutant: 3.52 7.52 (placebo):
generation EGFR TKI (dacomitinib) vs. 0.95 NS
(erlotinib or months
gefitinib) (placebo):
ARCHER 1009 Advanced NSCLC Dacomitinib versus 878
(519 2.6 months (for both Overall population: 7.9 [48]
patients, pretreated Erlotinib KRAS
wild- dacomitinib and (dacomitinib) vs.
8.4 months
with type, 91 erlotinib); (erlotinib): NS;
chemotherapy EGFR-
mutant) KRAS
wildtype: 2.6 KRAS wild-type: 8.1
months (for (dacomitinib) vs.
both 8.5 months
dacomitinib (erlotinib): NS;
and EFGR mutant:
erlotinib) 26.6
(dacomitinib) vs.
NR (gefitinib)
ARCHER 1050 Locally- avanced or Dacomitinib versus 452 14.7
(dacomitinib) 34.1
(dacomitinib) vs. [49,50]
metastatic, Gefitinib vs. 9.2 26.8 months
EGFR- months (gefitinib).
mutation- (gefitinib). p=0.044
positive NSCLC p<0.0001
patients (first-
line therapy)
Table 4. Phase III trials of dacomitinib.

NS= Non-significant