Dacomitinib | Abbik

Dacomitinib, a new therapy for the treatment of non-small cell lung cancer
Christina Brzezniak, Corey A Carter & Giuseppe Giaccone†
†National Cancer Institute, Medical Oncology Branch, Bethesda, MD, USA

Introduction: Advanced or metastatic non-small cell lung cancer (NSCLC) is characterized by a poor prognosis and few second- or third-line treatments. First-generation reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI) has paved the way for targeted treatment in lung can- cer. These drugs result in excellent responses in patients with activating EGFR mutations. Unfortunately, resistance often develops. Second-generation irreversible inhibitors hope to prevent mutational progression to a resistant clone or delay the use of alternative non-targeted therapies.
Areas covered: This article focuses on the current published ongoing research using the second-generation irreversible TKI, dacomitinib. The use of dacomi- tinib, a pan inhibitor of the HER family of tyrosine kinases, will be reviewed along with its efficacy in the advanced or metastatic NSCLC population.
Expert opinion: Data available suggest dacomitinib is effective in NSCLC patients both in initial treatment and after failure of first-generation inhibitors. Furthermore, preclinical data suggest dacomitinib can achieve responses in tumors harboring the T790M, gatekeeper mutation, present in up to 50% of tumors that have acquired resistant to first-generation inhibitors. Its usefulness in potentially delaying development of resistant clones as well as in combination with other targeting strategies is under investigation.

Keywords: dacomitinib, EGFR tyrosine kinase, non-small cell lung cancer, pan-HER, PF-00299804, T790M

Expert Opin. Pharmacother. (2013) 14(2):247-253

1. Introduction

1.1 Overview of the market
The leading cause of cancer-related death for both men and women remains non- small cell lung cancer (NSCLC) both globally and in the United States. In 2012, lung cancer rates in the United States are estimated at 244,180 new cases with 164,770 deaths [1]. Lung cancer is categorized based on histology with non- small cell lung cancer (NSCLC) comprising 85% of all diagnoses. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [2]. Standard treatments for stage IV disease remains palliative with approximately 40% of all patients diagnosed at this advanced stage [3]. Systemic chemotherapy offers a survival advantage over best supportive care and involves platinum-based regimens [4]. How- ever, patients will inevitably have progressive disease following first-line therapy, and response rates to second- and third-line treatments are poor. The 5-year overall survival (OS) of metastatic disease is less than 4% [3].
Since discovery of the epidermal growth factor receptor (EGFR) family and rec- ognition of ErbB1 over-expression in NSCLC, the study of targeted therapies for this malignancy has advanced significantly [5]. The human epidermal growth factor receptors’ (HER) family of cell surface receptor tyrosine kinases consist of four receptors: EGFR (HER-1/ErbB1), HER-2 (HER2/neu, ErbB2), HER-3 (ErbB3),

and HER-4 (ErbB4) [6]. They regulate the activation of multi- ple signaling pathways related to cellular proliferation, angio- genesis, and survival [7]. Activation is achieved via ligand interactions resulting in homo- or heterodimerization [5]. Muta- tion, amplification or over-expression allow dysregulation and activation of the signaling pathways, outside of the normal inhibitory mechanisms, through auto-phosphorylation of the tyrosine kinase domain. Activated pathways include the RAS pathway with the extracellular signal-regulated kinase (ERK)/ mitogen-activated protein kinase (MAPK), the phosphati- dylinositol 3-kinase/Akt (PI3K/Akt) pathway and the signal transducer and activator of transcription (STAT) pathway [5]. Mutated EGFR cells become dependent on the dysfunc- tional signaling for continued survival termed ‘oncogenic addiction’ [7].
The two most common mutations in the EGFR tyrosine kinase domain involve the L858R point mutation on exon 21 and E746-A750 deletion on exon 19. These mutations are found in up to 30 — 50% of NSCLC tumor samples from Asian populations and approximately 10% in Caucasian populations. They also occur more frequently in female never or light smokers and patients with adenocarcinoma histo- logy [8]. Mutations of the EGFR tyrosine kinase domain con-
fer increased sensitivity to the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva®, Genentech, South San Francisco, CA, USA) and gefitinib (Iressa®, AstraZeneca, Wilmington, DE, USA). Tyrosine kinase inhibitors prevent auto-phosphorylation of the EGFR intracellular TK domain by adenosine triphosphate (ATP) competitive inhibition at the intracellular catalytic domain. EGFR TKIs fall into two broad classes: reversible inhibitors, such as gefitinib and erlo-
tinib, and irreversible inhibitors, such as dacomitinib (PF-00299804; Pfizer, Inc., New York, NY, USA) and afati- nib (Boehringer Ingelheim, Ingelheim, Germany). Irreversible inhibitors covalently bind specific cysteine residues in the ATP binding site of EGFR.
Use of gefitinib in the United States is restricted to patients who attained response from its initial release in 2003 and is no longer commercially available. Gefitinib is, however, available and utilized in Europe and Asia. Gefitinib along with erlotinib

are used as second-line therapies in advanced unselected NSCLC. Although erlotinib is only FDA approved in the second- or third-line setting it is sometimes utilized for advanced EGFR mutation-selected NSCLC in the first- line setting and is currently under review for this indication [2]. Reliably, patients treated with these first-generation TKIs develop resistance to therapy [9]. The first identified and most common mutation conferring resistance, occurring in up to 50% of EGFR-mutated TKI-resistant patients, is the T790M mutation, referred to as the ‘gatekeeper mutation’ [10-12]. This mutation has also been found in EGFR-mutated tumors that have never been exposed to TKIs (de novo mutation) [12-14], suggesting this clone may be selected by first-generation TKI therapy. This mutation alters the TKI binding site leading to steric hindrance as well as causing an increased affinity for ATP, thus dramatically reducing the efficacy of reversible inhibitors to bind and induce their effects [11,15]. Manage- ment of EGFR-mutated NSCLC with resistance to the first-generation TKIs remains ill-defined. A need to find targeted therapy for patients harboring resistance mutations, specifically the T790M mutation, exists. This paper seeks to illustrate the supportive evidence and utility of dacomitinib, a second-generation TKI, in the treatment of the advanced NSCLC.
In a comprehensive review of current literature for dacomitinib (PF-00299804) (Box 1) on PubMed, a total of 32 articles were results. Clinical trials as well as reviews including human and animal studies and abstracts published to date were reviewed; no specified limits were placed on search results.

2. Introduction to the compound

Dacomitinib (PF-00299804; Pfizer, Inc., New York, NY, USA) is an irreversible pan-HER TKI that targets EGFR, ErbB2 and ErbB4 kinase domains of the EGFR signaling pathway. Unlike first-generation TKIs that inhibit signaling via competitive binding at the EGFR kinase domain only, pan-Erb inhibitors irreversibly bind the ATP domain of multiple EGFR family kinase domains [16,17].

Reversible EGFR inhibitors are typically used as second- line therapy in unselected advanced NSCLC after failure of upfront chemotherapy. Furthermore, erlotinib is sometimes used for treatment in the first-line setting of EGFR mutation selected advanced NSCLC patients in lieu of chemotherapy [2]. These therapies are oral preparations given daily until disease progression. Numerous studies evaluating the addition of TKIs to upfront chemotherapy have failed to demonstrate any survival advantage [18-21]. Once patients become resistant to this therapy they are often salvaged with second- or third-line chemotherapy, where response rates remain poor. Up to 50% of patients acquire resistance via the T790M mutation [12]. Simultaneous inhibition of multiple HER receptors (pan-HER inhibition) is one of the several strategies being evaluated to overcome acquired EGFR TKI resistance. Pre-clinical data suggest that dacomitinib has increased inhibition of the EGFR kinase domains as well as activity in cell lines harboring resistance mutations, specifically T790M [16,22,23]. Although KRAS and EGFR mutations are generally considered mutually exclusive, they rarely occur together. Tumors harboring KRAS mutations do not demonstrate in vitro activity to dacomitinib therapy and its clinical efficacy in this tumor population is under investiga- tion [16,17]. Dacomitinib’s pan-HER inhibition as well as activity in T790M patients makes it a compelling candidate for evaluation in the refractory or upfront setting of advanced NSCLC.

3. Chemistry

The chemical designation for dacomitinib is (2E)-N-16- 4-(piperidin-1-yl) but-2-enamide. The molecular formula is C24H25ClFN5O2 with a molecular weight of 469.94.

4. Pharmacodynamics

Dacomitinib is an oral highly selective quinazalone-based irreversible small molecule inhibitor of human epidermal growth factor receptors HER-1, HER-2, and HER-4 tyrosine kinases. Dacomitinib achieves irreversible inhibition via cova- lent bonding of the cysteine residues in the catalytic domains of the HER receptors [24]. Although it is difficult to directly compare an irreversible inhibitor of the EGFR tyrosine kinase domain to a reversible inhibitor, the affinity of dacomitinib as compared to erlotinib has shown in vitro with an IC50 for EGFR 6.0 nmol/L vs 0.56, ERBB2 45.7 vs 512 nmol/L and ERBB4 73.7 vs 790 nmol/L. Additionally, using cellular assay to determine the activity, against EGFR wild type, dacomitinib has IC50 of 5.8 vs 19.3 nmol/L with erlotinib and ERBB2 activity of 41 vs 299 nmol/L with erlotinib [16]. Various EGFR mutant NSCLC cell lines have been used to assist in the characterization of dacomitinib to specifically evaluate T790M mutations. The NSCLC cell line H3255 GR and H1975 which has an L858R/T790M EGFR mutation have IC50 of 119 and 440 nmol/L respectively [16].

5. Pharmacokinetics and metabolism

Two Phase I studies have been conducted in the United States and South Korea. These studies accomplished both dose escalation and the safety of dacomitinib from doses (0.5 — 60 mg). Dose-limiting toxicities include stomatitis, rash, palmar-plantar erythrodysesthesia syndrome, dehydra- tion, paronychia, and diarrhea. The maximum tolerated dose (MTD) has been defined as the dose in which the dose-limiting toxicities (DLTs) did not exceed 33%, which is 45 mg [25]. The median time to maximum plasma concen- tration (Tmax) ranged from 6 to 24 h over a dose range from 15 to 45 mg. Mean apparent clearance ranged from 23.7 to 32 L/h across the dosing of 15 — 45 mg [26]. Dacomitinib has been shown to have linear kinetics after both single and multiple dose range studies. The pharmacokinetics does not appear to be affected by food intake or antacid although addi- tional studies are warranted, maximum plasma concentration (Cmax) was similar (22.5 vs 25.6 ng/ml) when compared to a fasting state [25]. The geometric mean of Cmax after a loading dose of 45 mg twice daily for 4 days is comparable to steady state level (104 vs 76.9 ng/mL) [25]. The mean half-life (t1/2) was 59 — 85 h with dosing ranging from 30 to 60 mg [25]. Dacomitinib is highly protein bound and is cleared through both glutathione mediated and P450 metabolism. In vitro studies with human liver microsomes and recombinant CYPs demonstrate that dacomitinib is a potent CYP2D6 inhibitor and caution should be taken in the use of drugs that are highly dependent on CYP2D6 metabolism. A recent clinical study verified these in vitro interactions, demonstrating a drug–drug interaction and further illustrat- ing the potential need for dose reduction or substitution when dacomitinib is co-administered with a drug that has potent CYP2D6 metabolism [27].

6. Clinical efficacy

In preclinical models, dacomitinib inhibited both wild type (WT) as well as the common activating mutations of the EGFR. Additionally, the activity against the EGFR T790M and mutations will confer de novo resistance to reversible TKIs [16,28]. Two Phase I dose-escalation studies, one in the United States and one in South Korea, utilizing dacomitinib in advanced NSCLC patients, both determined the maximum tolerated dose (MTD) to be 45 mg once daily [29,30]. In the Korean study, patients were selected for KRAS WT status and were refractory to platinum-based chemotherapy and erlotinib or gefitinib [29]; whereas the U.S. study selected an enriched population of patients with refractory NSCLC and HER1 mutation or KRAS WT [30]. Both studies demonstrated that dacomitinib was safe and well tolerated.
Studies evaluating dacomitinib as salvage therapy (third line or beyond) versus placebo in advanced NSCLC patients, who progressed following chemotherapy and erlotinib are ongoing. In a Phase II study by Campbell and colleagues of

the 62 evaluable patients to date, 3 achieved a partial response with 35 demonstrated stable disease for greater than 6 weeks (ORR 5%) [31]. Here all patients were KRAS WT and the trial enrolled both adenocarcinoma and non- adenocarcinoma histology. A Phase I/II study in a Korean population, also refractory to chemotherapy and erlotinib or gefitinib, has shown preliminary activity for dacomitinib despite prior TKI failure [29]. A Phase III trial (JBR-26) is ongoing to further study dacomitinib as salvage therapy in patients who have failed both chemotherapy and first-generation TKIs (NCT01000025).
Dacomitinib has been studied in the second-line setting comparing it to erlotinib or as upfront (first-line) therapy in patients harboring EGFR mutation. A Phase II trial of 188 patients with advanced NSCLC who failed prior chemo- therapy regimens randomized patients to dacomitinib (45 mg daily) or erlotinib (150 mg daily). The primary endpoint of the trial was progression-free survival (PFS) demonstrating a statistical improvement for dacomitinib over erlotinib (median 2.8 vs 1.9 months, p = 0.012). No improvement in overall survival was demonstrated using dacomitinib (9.5 vs
7.4 months, p = 0.205). Baseline characteristics of the two arms were similar with the exception of performance status of 2 (19.1 vs 3.2%) and EGFR mutation (20.2 vs 11.7%) found with increased frequency in the dacomitinib arm [32]. Benefit from dacomitinib was seen across several subsets including wild-type EGFR with a PFS of 11.1 weeks vs 8 weeks compared to erlotinib [32]. A first-line, Phase II study of advanced lung adenocarcinoma with either EGFR muta- tion or less than a 10 pack-year smoking history evaluated dacomitinib (45 mg daily or 30 mg daily) in this chemother- apy na¨ıve population. Interim analysis of the overall popula- tion shows the primary endpoint of PFS at 4 months was 96% (95% CI: 84 — 99). Additionally, 34 of 46 evaluable patients with EGFR sensitizing mutation had objective responses with an ORR of 74% (95% CI: 59 — 86) [33].
Based on data from these two Phase II trials an ongoing Phase III trial (ARCHER 1009) in the second- or third- line setting is comparing the efficacy of dacomitinib to erloti- nib (NCT01360554). A review of dacomitinib presented in abstract evaluated dose-related tumor shrinkage rates from 200 patients across four clinical trials. Patients were treated with varying doses from 15 to 45 mg daily and at doses less than 45 mg daily demonstrated a lower tumor shrinkage rate. In addition, patients with activating EGFR mutations had an impressive tumor response rate of 83% [34]. A Phase II trial is ongoing to evaluate dacomitinib in selected populations (EGFR mutation, or non-smokers, or former light smokers or HER2 mutation or amplification) with PFS as the primary outcome (NCT00818441).

7. Safety and tolerability

Combined adverse events in the Phase I and Phase II data pub- lished to date illustrate side effects for dacomitinib similar to its

first-generation counterparts. However, the side effects occurred more frequently and often with greater intensity than seen with erlotinib or gefitinib. Most frequently encoun- tered adverse events across all data consisted of diarrhea (60 — 97%), acneiform rash/stomatitis (45 — 68%), and fatigue (40%) [29-33]. The Phase I/II study by Park and colleagues reported that no patients had dose-limiting toxicities [29]. How- ever, dose reductions secondary to drug-related toxicity were frequent: of the 42 patients enrolled 28.6% required dose reduction and 19% required dose delay [35]. In the first- line setting, dacomitinib often required dose reduction from the 45 mg daily dose to 30 mg daily. Initial results of the 46 evaluable patients reported that three patients discontinued treatment secondary to drug-limiting toxicities [33]. Further- more, up to 97% of this patient population experienced at least grade 1 diarrhea with an incidence of G3 diarrhea of 14% and G3 acneiform rash of 17% [33]. Although toxicities from daco- mitinib were more frequent and often of higher grade than the first-generation TKIs, as with to erlotinib or gefitinib toxicities were manageable with side effect-directed therapies and/ or dose reductions, discontinuation for adverse events was uncommon.

8. Conclusion

Both preclinical and clinical data have demonstrated the safety and response of dacomitinib to not only the advanced refractory NSCLC population but also the treatment na¨ıve. Dacomitinib may provide treatment following failure of first-generation TKI. This patient population often harbors resistant mutations that are difficult to target. While Phase III data have yet to be completed, Phase I/II studies are highly encouraging for continued targeted treatment on this refractory population. Further studies targeting the resistant EGFR (T790M) mutation are ongoing (NCT00769067). In a population with little effective treatment, dacomitinib remains a viable option.

9. Expert opinion

Irreversible, second-generation, TKIs potentially offer several advantages over their first-generation counterparts. They offer a toxicity profile that appears manageable. The more frequent and higher grade toxicity that occurs with dacomitinib requires further quality of life measures to quantify the limitations on patients. Although they are presumed to attain higher affinity to the EGFR receptor this remains controversial. Dacomitinib is a unique pan-Erb blocker that inhibits both EGFR and its dimerization partners, effectively offering a more complete sig- nal blockade of the entire HER family. Additionally, the irre- versible nature of the compound may result in a longer suppression of this activation pathway. Dacomitinib may provide benefit to EGFR-activating mutations beyond the first-line setting. Perhaps the most intriguing benefit of daco- mitinib is its potential to suppress EGFR T790M mutation,

for which first-generation TKIs are ineffective. Data demonstrat- ing rare de novo development of the T790M mutation suggest that treatment with dacomitinib may prolong response in the upfront setting and potentially suppress this clone rather than selecting for it as in the case of using erlotinib or gefitinib. The potential to target resistance in the upfront setting may change the paradigm on treatment of EGFR-mutated NSCLC.
Tumors expressing an ‘oncogenic addiction’ to the EGFR mutations require the aberrant signaling from the constitu- tively activated EGFR to both grow and proliferate. The idea of continued inhibition of the ‘oncogenic addiction’ pathway via irreversible inhibition is promising, further investigation will better characterize the effects of irreversible inhibition. The addition of chemotherapy to irreversible inhibition may also prove promising. Although the addition of first- generation TKIs to first-line chemotherapy has not proven as efficacious as hoped, review of the Phase II study using erloti- nib in combination with cisplatin/paclitaxel did demonstrate a trend toward improved OS (39 vs 31.3 months) [36]. Contin- ued suppression of the mutated EGFR TK following gefitinib failure with the addition of gefitinib to second-line paclitaxel showed a benefit of the combination in a select group [37]. This intriguing observation is being further evaluated with another second-generation irreversible TKI (afatinib) in the LUX-Lung 5 trial (NCT01085136). Given dacomitinib’s demonstrated effectiveness in patients following first- generation TKI failure, the study of it in combination with chemotherapy is needed.
The T790M mutation represents a unique opportunity for dacomitinib. Tumors harboring this mutation are resistant to first-generation reversible TKIs and preclinical data suggest dacomitinib has activity in this population. In a NSCLC xenograft model, tumors with the T790M mutation showed tumor response when combining afatinib with cetuximab but not gefitinib [38]. This supports the notion of second- generation TKI activity in the T790M mutant population; however, this success must be approached with caution. Emergence of alternative resistance mechanisms with these treatment strategies appears unavoidable and data suggest that amplification of the T790M clones eventually to provide resistance to second-generation irreversible TKIs.

Although resistance to first-generation TKIs is primarily achieved via a second-driver mutation, such as the gatekeeper T790M, there is a significant portion of the resistant tumors for which no mutation can be found. Amplification of MET has been shown as an alternative mechanism for achieving resistance has been discovered. Studies to block these signaling pathways as a means to overcome resistance include combina- tion with monoclonal antibodies (mAbs) or c-MET/ALK inhibitors with dacomitinib. Additionally, using the mono-
clonal antibody cetuximab (Erbitux®; ImClone systems,
Inc., Branchburg, New Jersey, U.S.A., licensed to Merck & Co., Darmstadt, Germany) (extracellular domain) in combi- nation with dacomitinib may provide enhanced EGFR inhibi- tion. There is currently a Phase Ib study of an alternative irreversible TKI (afatinib), in combination with cetuximab underway [39]. A Phase I trial (NCT01121575) is currently enrolling to study dacomitinib in combination with an oral c-MET/ALK inhibitor (PF-02341066). The development of dacomitinib in combination with other targeted agents will further help with the understanding of TKI-resistant patients. Further investigation into acquired resistance and mechanisms to delay or inhibit these resistant clones is essential in overcoming the treatment complexities for the TKI-resistant patients.
Given resistance to first-generation TKIs remains inevi- table, the expectations for irreversible pan HER family inhi- bitors are high. Continued evaluation of dacomitinib in the first-line setting with the potential to avoid the most common resistant mutation (T790M) is important and will likely result in an overall delaying of progression. The initial data and early development of dacomitinib are promising. It is impor- tant to note that until data from ongoing trial returns we do not have definitive evidence suggesting advantage to the irreversible TKIs over their first-generation counterparts. However, ongoing studies suggest dacomitinib is poised to play a major role in NSCLC future treatments.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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Papers of special note have been highlighted as either of interest (●) or of considerable interest (●●) to readers.
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Affiliation
Christina Brzezniak1, Corey A Carter1 & Giuseppe Giaccone†2
†Author for correspondence
1Walter Reed National Military Medical Center, 8901 Wisconsin Ave,
Bethesda, MD 20889, USA
2National Cancer Institute, Medical Oncology Branch, 9000 Rockville Pike,
Bldg. 10, Room 12N226, Bethesda, MD 20892, USA Tel: +1 301 496 4916;
Fax: +1 301 402 0172;
E-mail: [email protected]