Drug Evaluation
Afatinib in the treatment of head and neck squamous cell carcinoma
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Renata Ferrarotto & Kathryn A Gold† †
1.
Introduction
2.
Overview of the market
3.
Compound
4.
Pharmacodynamics
5.
Pharmacokinetics and metabolism
6.
Clinical efficacy
7.
Safety and tolerability
8.
Regulatory affairs
9.
Conclusion
10.
Expert opinion
The University of Texas MD Anderson Cancer Center, Department of Thoracic and Head and Neck Medical Oncology, Houston, TX, USA
Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death in the United States. Treatment of locally advanced disease is associated with significant acute side effects and can lead to chronic disabilities, while the prognosis of recurrent or metastatic disease is very poor. This highlights the need for better therapeutic options. Epidermal growth factor receptor is overexpressed in 90% of HNSCC patients and is an attractive therapeutic target in this patient population. Afatinib is a potent, irreversible pan-ErbB inhibitor. Preliminary studies in HNSCC show promising activity. Areas covered: This article reviews the current data evaluating small molecules inhibitors of the ErbB family in the treatment of HNSCC with a specific emphasis on afatinib, a second-generation, irreversible, pan-ErbB inhibitor. It also provides a description of afatinib’s drug characteristics, pharmacokinetics and toxicity profile as well as details of the published and ongoing clinical trials evaluating its efficacy in HNSCC patients. Expert opinion: Phase II trials in HNSCC show that daily oral treatment with afatinib is tolerable. Most common toxicities are skin rash and diarrhea. Afatinib has clinical activity as a single agent in a subset of refractory and/or metastatic HNSCC patients. It is thought that ongoing Phase III trials should better clarify the role of this compound in the treatment of HNSCC. Keywords: afatinib, epidermal growth factor receptor inhibitors, head and neck cancer Expert Opin. Investig. Drugs (2014) 23(1):135-143
1.
Introduction
It is estimated that 53,640 Americans will be diagnosed and 11,520 will die of head and neck cancer in 2013 [1]. Squamous cell carcinoma accounts for 90% of the head and neck tumors and the main risk factors include tobacco and alcohol use and human papillomavirus (HPV) infection [2,3]. Local treatment of head and neck squamous cell carcinoma (HNSCC) often incorporates multimodality therapy and can be associated with significant functional effects. Unfortunately, development of recurrent disease after therapy is common. Recurrent and/or metastatic disease is associated with poor outcomes and a median overall survival (OS) of 10 months, thus highlighting the current need for more efficacious and better tolerated therapy [4]. Epidermal growth factor receptor (EGFR, also known as ErbB1) overexpression is associated with decreased disease-free survival (DFS) and OS in HNSCC. Overexpression is found in ~ 90% of HNSCCs, though the activating EGFR mutations seen in lung cancer have not been found in HNSCC [5,6]. Deregulation of the ErbB receptor family is known to be oncogenic in epithelial cancers. The most commonly described oncogenic mechanisms include mutation and amplification of EGFR or HER2 (also known as ErbB2) [7,8]. ErbB-directed drugs include antibodies that prevent ligand-binding and/or receptor dimerization (e.g., cetuximab targeting EGFR and trastuzumab targeting HER2) and small molecule adenosine 10.1517/13543784.2014.858696 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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R. Ferrarotto & K. A. Gold
Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Afatinib III First-line treatment of EGFR-mutant NSCLC Pan-ErbB TKI Oral O
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O
N N
HN HN O F N H3C
Pivotal trial(s)
CH3
CI
LUX-Lung 3, Phase III [34] LUX-Head & Neck 1, Phase III (ongoing) (NCT01345682) LUX-Head & Neck 2, Phase III (ongoing) (NCT01345669)
triphosphate-competitive inhibitors of the intrinsic catalytic activity of ErbB receptors (e.g., erlotinib and gefitinib targeting EGFR and lapatinib targeting EGFR and HER2). To date, cetuximab is the only targeted therapy that has been approved for the treatment of HNSCC. Cetuximab is approved for use concurrently with radiotherapy for locoregional disease or in association with chemotherapy in the recurrent/metastatic setting [4,9]. In the United States, it is also approved as a single agent in the treatment of platinum-refractory HNSCC. First-generation small molecule EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib have shown minimal activity as monotherapy in HNSCC [10,11]. Afatinib (BIBW 2992, Gilotrif), in contrast to erlotinib and gefitinib, covalently binds to its targets and irreversibly inhibits the enzymatic activity of EGFR, HER2 and ErbB4 (Box 1). Owing to its irreversible activity and multi-receptor binding, afatinib is thought to be a more potent drug, potentially inhibiting the ErbB downstream signaling cascade activation by receptor heterodimerization or crosstalk [12,13]. This article will review the currently available clinical data and ongoing clinical trials evaluating afatinib in the treatment of HNSCC and critically discuss future directions regarding the use of this drug in the HNSCC patient population. 2.
Overview of the market
Most patients with head and neck cancer present with locally advanced disease either with involved lymph nodes or locally 136
invasive tumors. For these patients, multimodality treatment is the standard of care, either with surgery followed by postoperative radiation or chemoradiation or definitive chemoradiation [14-20]. Unfortunately, patients often develop disease recurrence, either locally or distantly. For patients with recurrent or metastatic HNSCC, outcomes are poor. Platinum-based combination chemotherapy represents the standard of care [4], but even for patients who initially respond to therapy, eventual progression is inevitable. Single agent cetuximab is a Food and Drug Administration (FDA)-approved option for platinum refractory disease [21], but responses are uncommon and survival is short. Because patients with recurrent/metastatic HNSCC are often older and have already experienced toxicities from treatment of localized disease, identifying well-tolerated treatment options is critical. TKIs with activity against EGFR have been extensively studied in this disease. Some of the clinical trials evaluating these agents in HNSCC are shown in Table 1. In the neoadjuvant setting for locally advanced HNSCC, preoperative treatment with erlotinib for a median of 20 days was associated with tumor shrinkage of at least 25% in 29% of treated patients [22]. More recently, a Phase II study randomized patients with advanced HNSCC to receive definitive standard cisplatin-based chemoradiation with or without erlotinib. The addition of the EGFR inhibitor to chemoradiotherapy did not improve complete response rate (RR) or progression-free survival (PFS) -- the primary study end points [23]. In the recurrent/metastatic setting, the RR with erlotinib as a single agent was only 4.3% in a Phase II trial [10]. In the adjuvant setting, a Phase II trial randomizing patients with intermediate and high risk postoperative HNSCC to receive cisplatin-based chemoradiation with or without gefitinib demonstrated a lack of benefit in DFS with the addition of the study drug [24]. Two Phase III trials have evaluated gefitinib in patients with recurrent/metastatic disease. In an ECOG study, 270 patients with previously treated head and neck cancer were randomized to receive docetaxel with or without gefitinib. This study was closed after an interim analysis due to lack of benefit and increased toxicity in the drug combination arm [25]. Another Phase III clinical trial enrolling 486 patients failed to show a survival benefit of gefitinib in either of two dosing schedules compared with methotrexate: median OS was 5.6 months for gefitinib 250 mg/day, 6 months for gefitinib 500 mg/day and 6.7 months for methotrexate [11]. These results suggest that, at least in an unselected patient population, the first-generation small molecules EGFR TKIs have minimal single agent activity in HNSCC. The absence of benefit with this class of drugs in contrast with the monoclonal antibody cetuximab may be explained by the distinct way the pathway is affected by the two different types of EGFR inhibitors. In addition to blocking EGFR ligand binding and receptor dimerization, cetuximab induces antibodydependent cellular cytotoxicity, which seems to play an important role in its efficacy in HNSCC [26]. Currently, there
Expert Opin. Investig. Drugs (2014) 23(1)
Afatinib
Table 1. Clinical trials of first-generation EGFR TKIs in HNSCC.
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Trial
Phase
No.
Treatment
RR
Neoadjuvant for locally advanced HNSCC II 31 Erlotinib 29% Thomas et al. [22] II 31 Gefitinib 9.70% Tan et al. [47] Concurrent with chemoradiation for definitive treatment of locally advanced HNSCC II 204 CDDP vs CDDP + 40 vs 54% Martins et al. [23] Erlotinib (p = 0.08)* II 226 CDDP vs CDDP + 51.8 vs 60% Gregoire et al. [48] Gefitinib (p = 0.39) Recurrent and/or metastatic disease II 115 Erlotinib 4.3% Soulieres et al. [10] II 45 Lapatinib 0 de Souza et al. [49] III 486 Gefitinib vs 7.6 3.9% Stewart et al. [11] methotrexate (p = 0.17)
Median PFS
Median OS
NR 15 months
NR 28 months
46 vs 54% at 26 months (p = 0.71) 44.2 vs 38.6% at 2 years (p = 0.54)
NR (p = 0.88)
9.6 weeks 52 days NR
6 months 288 days 6 vs 6.7 months (p = 0.39)
57.1 vs 58.9% at 2 years (p = 0.45)
*Complete response rate. CDDP: Cisplatin; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; RR: Response rate.
are no validated biomarkers that predict for sensitive or resistance to ErbB inhibition in HNSCC. KRAS mutations, activating EGFR mutations, and HER2 amplification, which help to guide therapy in other malignancies, are not commonly found in HNSCC [6]. Afatinib, due to its distinct pharmacological and pharmacodynamic properties as well as broader spectrum of activity, might be more effective than the first-generation EGFR TKIs in the treatment of HNSCC. Another second-generation EGFR TKI under investigation is dacomitinib. Dacomitinib is a small molecule panErbB irreversible inhibitor with similar spectrum to afatinib and has shown some activity in HNSCC [27]. A Phase II trial evaluated the efficacy of oral dacomitinib 45 mg/day in the first-line treatment of recurrent/metastatic HNSCC. The observed RR in this trial was 12.7%, and 14% of patients had prolonged disease stabilization (‡ 24 weeks). Median PFS was 12.1 weeks and median OS was 34.6 weeks. Preliminary results of another Phase II study of single agent dacomitinib including patients with recurrent/metastatic disease showed a partial response (PR) in 11% of patients and disease stabilization for 6 or more months in another 11% of patients [28]. Dacomitinib is also being studied in a Phase I trial (NCT01737008) in combination with radiation therapy and with cisplatin-based chemoradiation. In head and neck cancer, the development of afatinib (with multiple Phase III trials ongoing) has moved further along than that of dacomitinib. 3.
Compound
Afatinib is available in film-coated tablets at dosage strengths of 20, 30 and 40 mg. It is described chemically as N-[4[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide. It is not available in intravenous form. Tablets should not be chewed or crushed, but they can be administered as a drinking suspension or via a feeding tube after dispersing the tablet.
4.
Pharmacodynamics
Afatinib is an oral, highly selective and irreversible secondgeneration ErbB family blocker that inhibits EGFR (IC50 = 0.5 nM), HER2 (IC50 = 14 nM) and ErbB4 (IC50 = 1 nM) [29]. Preclinical data have shown inhibitory activity of afatinib in non-small-cell lung cancer (NSCLC) cell lines with the T790M gatekeeper mutation in EGFR, which are resistant to erlotinib and gefitinib, and it has activity in HER2-amplified breast cancer cell lines that are resistant to trastuzumab and lapatinib [30]. Afatinib also inhibits the growth of cells harboring the EGFR truncation mutation variant III, which is often found in HNSCC and is associated with resistance to first-generation TKIs and cetuximab [31]. 5.
Pharmacokinetics and metabolism
Pharmacokinetic studies demonstrate that dose-dependent concentrations are achieved after oral administration. Maximum plasma concentrations are reached between 2 and 5 h after oral dosing and the mean terminal elimination half-life is ~ 37 h. Afatinib has a tissue distribution of around 4500 l and total body clearance mean of 1530 ml/min. Steady state is reached after 8 days of initiating continuous drug usage [32]. The interpatient variability in plasma concentrations is moderate to high and the exposure to afatinib correlated with the severity of the most common adverse events such as rash and diarrhea. Food intake before drug administration significantly decreases systemic exposure. The major route of elimination is via feces (85%). There was poor association between apparent total body clearance and weight or body surface area, justifying a fixed oral dose. Recommended dose for clinical use as single agent is 40 mg/day [33]. 6.
Clinical efficacy
Afatinib has been extensively studied in Phase III trials in NSCLC and in smaller studies in other malignancies (Table 2).
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Table 2. Selected clinical trials of afatinib in other malignancies. Trial
Phase
Disease
No.
Treatment
LUX-Lung 1 [32]
RR
Median PFS
IIb/III
NSCLC, s/p erlotinib or gefitinib
585
LUX-Lung 3 [34]
III
EGFR-mutant NSCLC
LUX-Lung 6 [35]
III
Lin et al. [36]
II
Janjigian et al. [37]
II
Median OS
Afatinib vs BSC
7 vs < 1% (p = 0.007)
3.3 vs 1.1 months (p < 0.001)
345
Afatinib vs cis/pem
EGFR-mutant NSCLC
364
Afatinib vs cis/gem
HER2-positive breast cancer HER2-positive gastric cancer
41
Afatinib
56 vs 23% (p = 0.001) 67 vs 23% (p = 0.001) 10%
11.1 vs 6.9 months (p = 0.001) 11 vs 5.6 months (p < 0.001) 15.1 weeks
61 weeks
9
Afatinib
14%
Not reported
Not reported
10.8 vs 12 months (p = 0.74) NR NR
BSC: Best supportive care; cis: Cisplatin; gem: Gemcitabine; NR: Not reached; OS: Overall survival; pem: Pemetrexed; PFS: Progression-free survival; RR: Response rate.
The landmark Phase III study that led to FDA approval in NSCLC was LUX-Lung 3 [34]. In this trial, 345 patients with stage IIIB/IV lung adenocarcinoma harboring EGFRactivating mutations were randomly assigned in a two-to-one fashion to receive afatinib 40 mg/day or standard chemotherapy with cisplatin and pemetrexed. Median PFS, the primary study end point, was 11.1 months for afatinib as against 6.9 months for the chemotherapy arm (hazard ratio = 0.47, p = 0.001). RR was 56 and 23% for the afatinib and chemotherapy arms, respectively (p = 0.001). Patient-reported outcomes favored afatinib with better control of cough, dyspnea and pain. LUX-Lung 6 was performed in a similar population and showed improved PFS with afatinib over cisplatin/ gemcitabine [35]. For patients who have progressed on erlotinib or gefitinib, the utility of afatinib is less clear. The LUX-Lung 1 study randomized patients who had previously received benefit from erlotinib or gefitinib to either placebo or afatinib. Patients treated with afatinib had an improved RR (7 vs < 1%, p = 0.007) and PFS (3.3 vs 1.1 months, p < 0.001) but there were no differences in OS between the groups (10.8 vs 12 months, p = 0.74) [32]. Afatinib has also shown activity in HER2-amplified trastuzumab-resistant breast and esophagogastric tumors in Phase II studies [36,37]. Phase I clinical trials have shown tolerability of afatinib as a single agent or in combination with chemotherapy (cisplatin, paclitaxel, 5-fluorouracil and pemetrexed) or other targeted agents (volasertib and nintedanib) [38-41]. The largest study reported thus far in HNSCC is a Phase II trial that randomized patients with platinum-resistant recurrent or metastatic HNSCC to receive either afatinib or cetuximab. Patients could crossover to the other drug after progression or dose-limiting toxicity. In the first stage of the trial, 61 patients received afatinib and 60 patients received cetuximab. The primary end point of the study was RR. Both drugs showed comparable antitumor activity with a RR of 8.1 vs 9.7% and PFS of 13 vs 15 weeks (p = 0.71) for afatinib and cetuximab, respectively. Sixty-eight patients crossed over to the other arm following their initial treatment. Thirty-two (52.5%) of the patients 138
who were treated with afatinib went on to receive cetuximab, and 36 (60%) of the cetuximab-treated patients received afatinib. By independent review, one patient in each group had PR to crossover therapy by RECIST criteria. Disease stabilization was observed in 12 (33.3%) patients who crossed over to afatinib and in 6 (18.8%) patients who crossed over to cetuximab. More diarrhea, skin rash and mucositis were observed in the afatinib arm; however, those side effects were manageable and did not lead to an increased drug discontinuation [42]. This trial confirms single agent activity of afatinib, which is comparable with cetuximab, in platinum-refractory recurrent or metastatic HNSCC. In spite of not being powered to detect a difference in PFS, the overall results of the study demonstrate that sequential therapy with ErbB inhibitors is feasible and a subgroup of patients seem to benefit from this strategy [42]. Currently, various Phase II and Phase III studies evaluating afatinib in the neoadjuvant, adjuvant and recurrent or metastatic settings in HNSCC patients are ongoing. The pivotal trial LUX-Head & Neck 1 is a randomized Phase III trial evaluating oral afatinib 40 mg/day versus weekly intravenous methotrexate 40 mg/m2 in patients with recurrent/metastatic HNSCC who progressed after platinum-based chemotherapy. Patients must have a performance status ECOG 0 or 1 and no disease progression for 3 months following completion of curative intent treatment. Stratification will be according to performance status and prior use of EGFR-targeted antibody therapy in the recurrent/metastatic setting. The study primary end point is PFS. Secondary end points include OS, RR, quality of life and safety. The study is currently accruing and the target enrollment is 474 patients. The estimated final data collection for primary outcome measure is March 2014 [43]. Lux-Head & Neck 2 will evaluate oral afatinib 40 mg/day versus placebo given for 18 months following concurrent chemoradiation. Eligibility criteria include primary unresected stage III to IVb HNSCC who are disease-free following platinum-based chemoradiation, with or without neck dissection. Patients most likely to harbor HPV-associated cancer (base of tongue or tonsil primary and < 10 pack-year history of smoking) and patients
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Afatinib
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Table 3. Clinical trials evaluating afatinib in HNSCC available at Ref. [50]. Trial
Phase
No.
Study population
LUX-Head & Neck 1
III
474
LUX-Head & Neck 2
III
669
LUX-Head & Neck 3
III
300
GORTEC 2010-02
III
315
PREDICTOR
II
60
NCT01538381
II
30
NCT01824823
II
108
NCT01732640
I/II
71
NCT01783587
I
38
NCT01721525
I
22
Previously treated R/M HNSCC (second-line, platinum refractory) Stage III/IVa--b HNSCC postplatinum -based chemoradiation therapy Previously treated R/M HNSCC (second-line, platinum refractory) Resected HNSCC with high-risk features (post-chemoradiation therapy) Treatment-naı¨ve non-metastatic HNSCC (neoadjuvant) HNSCC selected for a primary surgical treatment (neoadjuvant) Stage III/IV HNSCC at high risk of recurrence (N+, postchemoradiation therapy) Stage III/IVa--b HNSCC HPVnegative (neoadjuvant) Resected HNSCC with intermediate or high risk features (concurrent with RT) Stage IVa--b HPV-positive oropharynx HNSCC (neoadjuvant)
Treatment
Estimated study completion
Primary end point
Afatinib vs MTX
03/2014
PFS
Afatinib vs placebo
05/2019
DFS
Afatinib vs MTX
04/2016
PFS
Afatinib vs placebo
09/2019
DFS
Afatinib
10/2013
Biomarkers
Afatinib
12/2013
RR/biomarkers
Afatinib vs placebo
02/2016
DFS
Afatinib, paclitaxel and platinum Afatinib (int. risk) vs Afatinib + docetaxel (high risk) Afatinib, ribavirin, weekly carboplatin and paclitaxel
01/2017
MTD/RR/toxicity
02/2015
MTD
11/2014
MTD/biomarkers
DFS: Disease-free survival; MTD: Maximum tolerated dose; MTX: Methotrexate; N+: Lymph node harboring tumor metastases; PFS: Progression-free survival; R/M: Recurrent and/or metastatic; RR: Response rate.
with nasopharyngeal, sinus and salivary gland primaries are excluded. Primary end point is DFS and secondary end points are DFS at 2 years, OS, quality of life and safety. The study is currently accruing and the total planned enrollment is 669 patients. The expected final data collection for primary outcome measure is August 2017. In both LUX-Head and Neck trials, archival tissues and serum samples will be collected in a voluntary basis. Investigation for biomarkers will be done in the available samples [44]. Table 3 enumerates studies currently registered in the United States. 7.
Safety and tolerability
Phase I clinical studies in advanced solid tumors have shown that afatinib has a manageable side effect profile, with most common adverse effects (any grade) being rash (68%), diarrhea (64%), mucositis (19%), nausea and vomiting (~ 10%) and fatigue (7.5%). Dose-limiting toxicities include rash, diarrhea and pneumonitis [45]. In a Phase III trial, enrolling patients with previously treated NSCLC, 390 patients were treated with afatinib 50 mg/day p.o.. Overall, 38% of patients required dose reduction due to adverse events: 21% because of diarrhea and 15% due to rash or acne. Drug-related serious side effects occurred
in 10% of patients, diarrhea being the most common (4%) and 7.7% of patients required treatment discontinuation. No cases of drug-induced pneumonitis were observed [32]. Quality of life assessment of the patients who received afatinib in this study reported a significant improvement in cancerrelated symptoms including cough, dyspnea, pain, fatigue, physical functioning and health-related quality of life [46]. Many side effects from afatinib, including skin rash and diarrhea, are thought to be secondary to inhibition of wildtype EGFR in normal tissue. These side effects are somewhat more severe with afatinib than with first-generation inhibitors erlotinib and gefitinib, thus suggesting increased potency of afatinib. Aggressive supportive management of rash and diarrhea can improve tolerance of therapy. 8.
Regulatory affairs
On 12 July 2013, the US FDA approved afatinib (Gilotrif) for the first-line treatment of patients with metastatic NSCLC harboring EGFR-activating mutations (exon 19 deletions and L858R mutations). In Europe, Boehringer Ingelheim Pharmaceuticals, Inc. submitted an application in September 2012 to the European Medicines Agency seeking approval of afatinib for the same indication.
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9.
Conclusion
Patients with recurrent or metastatic HNSCC have a poor prognosis and new treatment strategies are urgently needed. Thus far, cetuximab is the only targeted therapy approved for the treatment of HNSCC. Considering the importance of the EGFR pathway in the tumorigenesis of HNSCC, there is a strong rationale for the use of afatinib, a pan-ErbB irreversible inhibitor that has an acceptable toxicity profile. Preliminary results from Phase II clinical trials have shown activity of afatinib in a subset of HNSCC patients, justifying further investigation of this drug in this population. Ongoing Phase III trials should elucidate the role of afatinib in the treatment of this deadly malignancy. Validated biomarkers and elucidation of resistance mechanisms are urgently needed to better predict treatment benefit and understand mechanisms of treatment failure. 10.
Expert opinion
EGFR is expressed at high levels in HNSCC, making it an attractive therapeutic target. Initial studies of EGFR inhibition have had some success, with the benefits of anti-EGFR monoclonal antibody cetuximab demonstrated in several large trials. Clinical trials utilizing small molecule inhibitors of EGFR, such as erlotinib and gefitinib, have had disappointing results thus far. Afatinib is a second-generation small molecule TKI of the ErbB family, including EGFR, HER2 and HER4. It is potent and irreversible. In HNSCC, the largest trial to date has enrolled patients with platinum-refractory disease, who were randomized to receive cetuximab or afatinib. This study suggested that afatinib and cetuximab have similar efficacy in patients with previously treated disease. Crossover data from this trial suggested that afatinib may have some activity in patients with disease refractory to cetuximab. Afatinib was associated with more severe skin rash, diarrhea and mucositis than cetuximab. The role of afatinib in the treatment of HNSCC will in large part be decided by the results of two currently accruing Phase III trials. LUX Head & Neck 1 trial (NCT01345682) is enrolling patients with platinum-refractory HNSCC to be randomized between afatinib and methotrexate. The primary end point of this trial is PFS, though the trial is also powered to detect differences in OS. If this trial is able to demonstrate an improvement in survival outcomes with afatinib over methotrexate, it would present a potential road to regulatory
140
approval. The only drug currently approved in this setting in the United States is cetuximab, while methotrexate is often used in Europe. The major potential competitor for afatinib in this space in the United States is cetuximab, which is approved in combination with platinum-based chemotherapy for frontline treatment of recurrent and metastatic disease [4] as well as in the platinum-refractory setting as a single agent [21]. If cetuximab is used as frontline treatment, afatinib may be a good option in the second-line setting, as there seems to be some activity in patients whose disease progressed on cetuximab [42]. LUXHead & Neck 1 trial allows prior cetuximab, and analysis of the subgroup of patients who have received cetuximab will be of interest. The randomized Phase II trial comparing afatinib to cetuximab did not show significant differences in outcome between the groups [42]. Afatinib was associated with more severe toxicity, but some patients prefer oral administration of drugs and may find afatinib more convenient. LUX-Head & Neck 2 (NCT01345669) is another randomized Phase III trial. Eligible patients will have completed platinum-based concurrent chemoradiation for locally advanced HNSCC. Following completion of definitive therapy, patients will be randomized to receive either placebo or afatinib as adjuvant therapy for up to 18 months. Currently, the standard of care for patients with no evidence of disease after chemoradiation for HNSCC is observation. If afatinib is able to reduce recurrence and prolong survival after definitive treatment, it could fill a niche for these patients who have a high risk of recurrent disease. Treatment, however, is difficult to administer in this setting. Many patients are debilitated after completion of definitive treatment. Afatinib, though it is a targeted oral therapy, has side effects which can be difficult to manage. Only a portion of patients seem to benefit from therapy with afatinib. Unfortunately, no biomarkers predicting benefit from EGFR-targeted therapies in HNSCC have been identified. This continues to be an area of active investigation, and the ongoing clinical trials will be collecting patient tissues for correlative studies.
Declaration of interest The authors have been supported by the P Calabresi (K12) National Institutes of Health Award. K Gold also declares that she serves on the advisory boards for both Pfizer and Bristol-Myers Squibb.
Expert Opin. Investig. Drugs (2014) 23(1)
Afatinib
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Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. J Clin Oncol 2013;31(11):1415-21
24.
Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas. 2011 ASCO Annual Meeting Proceedings. J Clin Oncol 2011;29(15s):5500
25.
Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebocontrolled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol 2013;31(11):1405-14
26.
Martinelli E, De Palma R, Orditura M, et al. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol 2009;158(1):1-9
27.
Abdul Razak AR, Soulieres D, Laurie SA, et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann Oncol 2013;24(3):761-9
15.
Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999;91(24):2081-6
16.
Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three metaanalyses of updated individual data. MACH-NC Collaborative Group. MetaAnalysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355(9208):949-55
17.
Fletcher GH, Evers WT. Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck. Radiology 1970;95(1):185-8
18.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350(19):1945-52
19.
20.
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for highrisk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19):1937-44 Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced
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28.
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29.
30.
31.
32.
33.
34.
..
35.
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Siu LL, Hotte SJ, Laurie SA, et al. Phase II trial of the irreversible oral panhuman EGF receptor inhibitor PF00299804 as first-line treatment in recurrent and/or metastatic squamous cell carcinoma of the head and neck. 2011 ASCO Annual Meeting Proceedings. J Clin Oncol 2011;29(15s):5561 Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/ HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27(34):4702-11 Canonici A, Pederson K, Browne B, et al. Effect of afatinib alone or in combination with trastuzumab in HER2positive breast cancer cell lines. 2013 ASCO Annual Meeting Proceedings. J Clin Oncol 2013;31(15s):632 Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 2006;12(17):5064-73 Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012;13(5):528-38 Stopfer P, Marzin K, Narjes H, et al. Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother Pharmacol 2012;69(4):1051-61 Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31(27):3327-34 Trial leading to the FDA approval of afatinib for EGFR-mutant NSCLC. Wu Y, Zhou C, Hu CP, et al. LUX-Lung 6: a randomized, open-label, phase III study of afatinib versus gemcitabine/cisplatin as first-line treatment for Asian patients with EGFR mutation-positive advanced adenocarcinoma of the lung. 2013 ASCO Annual Meeting
.
36.
Proceedings. J Clin Oncol 2013;31(15s):8016 Another pivotal trial of afatinib in EGFR-mutant NSCLC. Lin NU, Winer EP, Wheatley D, et al. A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 2012;133(3):1057-65
37.
Janjigian YY, Capanu M, Gromisch CM, et al. A phase II study of afatinib in patients with metastatic HER2-positive trastuzumab-refractory esophagogastric cancer. 2013 ASCO Annual Meeting Proceedings. J Clin Oncol 2013;31(15s):e15017
38.
Vermorken JB, Rottey S, Ehrnrooth E, et al. A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors. Ann Oncol 2013;24(5):1392-400
39.
40.
41.
42.
..
43.
..
44.
..
Machiels JP, Licitra L, Haddad RI, et al. LUX-H&N 1: A phase III, randomized trial of afatinib versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy. 2012 ASCO Annual Meeting Proceedings. J Clin Oncol 2012;30(15s):TPS5598 Description of ongoing Phase III trial, LUX-Head & Neck 1. Burtness B, Bourhis J, Vermorken JB, et al. LUX head and neck 2: a randomized, double-blind, placebocontrolled, phase III study of afatinib as adjuvant therapy after chemoradiation in primarily unresected, clinically high-risk, head and neck cancer patients. 2012 ASCO Annual Meeting Proceedings. J Clin Oncol 2012;31(15s):TPS5599 Description of ongoing Phase III trial, LUX-Head & Neck 2.
45.
Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 2010;28(25):3965-72
46.
Chu QS, Sangha RS, Hotte SJ, et al. A phase I, dose-escalation trial of continuous and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors: final analysis. 2013 ASCO Annual Meeting Proceedings. J Clin Oncol 2013;31(15s):2523
Hirsh V, Cadranel J, Cong XJ, et al. Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUXLung 1). J Thorac Oncol 2013;8(2):229-37
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Bouche O, Maindrault-Goebel F, Ducreux M, et al. Phase II trial of weekly alternating sequential BIBF 1120 and afatinib for advanced colorectal cancer. Anticancer Res 2011;31(6):2271-81
Tan EH, Goh C, Lim WT, et al. Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers. Ann Oncol 2012;23(4):1010-16
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Gregoire V, Hamoir M, Chen C, et al. Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: a phase II, randomized, double-blind, placebocontrolled study. Radiother Oncol 2011;100(1):62-9
49.
de Souza JA, Davis DW, Zhang Y, et al. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2012;18(8):2336-43
50.
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Peeters M, Machiels JP, Pilz K, et al. Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumros. 2013 ASCO Annual Meeting Proceedings. J Clin Oncol 2013;31(15s):2521
Cupissol D, Seiwert TY, Fayette J, et al. A randomized, open-label, phase II study of afatinib versus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: analysis of stage 2 following crossover. 2013 ASCO Annual Meeting Proceedings. J Clin Oncol 2013;31(15s):6001 Largest reported experience thus far of afatinib in HNSCC; it led to Phase III trial of afatinib in platinum-refractory HNSCC which is currently ongoing.
Expert Opin. Investig. Drugs (2014) 23(1)
Afatinib
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Affiliation Renata Ferrarotto1 MD & Kathryn A Gold†2 MD † Author for correspondence 1 Clinical Fellow, The University of Texas MD Anderson Cancer Center, Department of Thoracic and Head and Neck Medical Oncology, 1515 Holcombe Blvd, Unit 0432, Houston, TX 77030, USA 2 Assistant Professor, The University of Texas MD Anderson Cancer Center, Department of Thoracic and Head and Neck Medical Oncology, 1515 Holcombe Blvd, Unit 0432, Houston, TX 77030, USA Tel: +1 713 792 6363; Fax: +1 713 792 1220; E-mail: [email protected]
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Afatinib in the treatment of head and neck squamous cell carcinoma
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Renata Ferrarotto & Kathryn A Gold† †
1.
Introduction
2.
Overview of the market
3.
Compound
4.
Pharmacodynamics
5.
Pharmacokinetics and metabolism
6.
Clinical efficacy
7.
Safety and tolerability
8.
Regulatory affairs
9.
Conclusion
10.
Expert opinion
The University of Texas MD Anderson Cancer Center, Department of Thoracic and Head and Neck Medical Oncology, Houston, TX, USA
Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death in the United States. Treatment of locally advanced disease is associated with significant acute side effects and can lead to chronic disabilities, while the prognosis of recurrent or metastatic disease is very poor. This highlights the need for better therapeutic options. Epidermal growth factor receptor is overexpressed in 90% of HNSCC patients and is an attractive therapeutic target in this patient population. Afatinib is a potent, irreversible pan-ErbB inhibitor. Preliminary studies in HNSCC show promising activity. Areas covered: This article reviews the current data evaluating small molecules inhibitors of the ErbB family in the treatment of HNSCC with a specific emphasis on afatinib, a second-generation, irreversible, pan-ErbB inhibitor. It also provides a description of afatinib’s drug characteristics, pharmacokinetics and toxicity profile as well as details of the published and ongoing clinical trials evaluating its efficacy in HNSCC patients. Expert opinion: Phase II trials in HNSCC show that daily oral treatment with afatinib is tolerable. Most common toxicities are skin rash and diarrhea. Afatinib has clinical activity as a single agent in a subset of refractory and/or metastatic HNSCC patients. It is thought that ongoing Phase III trials should better clarify the role of this compound in the treatment of HNSCC. Keywords: afatinib, epidermal growth factor receptor inhibitors, head and neck cancer Expert Opin. Investig. Drugs (2014) 23(1):135-143
1.
Introduction
It is estimated that 53,640 Americans will be diagnosed and 11,520 will die of head and neck cancer in 2013 [1]. Squamous cell carcinoma accounts for 90% of the head and neck tumors and the main risk factors include tobacco and alcohol use and human papillomavirus (HPV) infection [2,3]. Local treatment of head and neck squamous cell carcinoma (HNSCC) often incorporates multimodality therapy and can be associated with significant functional effects. Unfortunately, development of recurrent disease after therapy is common. Recurrent and/or metastatic disease is associated with poor outcomes and a median overall survival (OS) of 10 months, thus highlighting the current need for more efficacious and better tolerated therapy [4]. Epidermal growth factor receptor (EGFR, also known as ErbB1) overexpression is associated with decreased disease-free survival (DFS) and OS in HNSCC. Overexpression is found in ~ 90% of HNSCCs, though the activating EGFR mutations seen in lung cancer have not been found in HNSCC [5,6]. Deregulation of the ErbB receptor family is known to be oncogenic in epithelial cancers. The most commonly described oncogenic mechanisms include mutation and amplification of EGFR or HER2 (also known as ErbB2) [7,8]. ErbB-directed drugs include antibodies that prevent ligand-binding and/or receptor dimerization (e.g., cetuximab targeting EGFR and trastuzumab targeting HER2) and small molecule adenosine 10.1517/13543784.2014.858696 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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R. Ferrarotto & K. A. Gold
Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Afatinib III First-line treatment of EGFR-mutant NSCLC Pan-ErbB TKI Oral O
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O
N N
HN HN O F N H3C
Pivotal trial(s)
CH3
CI
LUX-Lung 3, Phase III [34] LUX-Head & Neck 1, Phase III (ongoing) (NCT01345682) LUX-Head & Neck 2, Phase III (ongoing) (NCT01345669)
triphosphate-competitive inhibitors of the intrinsic catalytic activity of ErbB receptors (e.g., erlotinib and gefitinib targeting EGFR and lapatinib targeting EGFR and HER2). To date, cetuximab is the only targeted therapy that has been approved for the treatment of HNSCC. Cetuximab is approved for use concurrently with radiotherapy for locoregional disease or in association with chemotherapy in the recurrent/metastatic setting [4,9]. In the United States, it is also approved as a single agent in the treatment of platinum-refractory HNSCC. First-generation small molecule EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib have shown minimal activity as monotherapy in HNSCC [10,11]. Afatinib (BIBW 2992, Gilotrif), in contrast to erlotinib and gefitinib, covalently binds to its targets and irreversibly inhibits the enzymatic activity of EGFR, HER2 and ErbB4 (Box 1). Owing to its irreversible activity and multi-receptor binding, afatinib is thought to be a more potent drug, potentially inhibiting the ErbB downstream signaling cascade activation by receptor heterodimerization or crosstalk [12,13]. This article will review the currently available clinical data and ongoing clinical trials evaluating afatinib in the treatment of HNSCC and critically discuss future directions regarding the use of this drug in the HNSCC patient population. 2.
Overview of the market
Most patients with head and neck cancer present with locally advanced disease either with involved lymph nodes or locally 136
invasive tumors. For these patients, multimodality treatment is the standard of care, either with surgery followed by postoperative radiation or chemoradiation or definitive chemoradiation [14-20]. Unfortunately, patients often develop disease recurrence, either locally or distantly. For patients with recurrent or metastatic HNSCC, outcomes are poor. Platinum-based combination chemotherapy represents the standard of care [4], but even for patients who initially respond to therapy, eventual progression is inevitable. Single agent cetuximab is a Food and Drug Administration (FDA)-approved option for platinum refractory disease [21], but responses are uncommon and survival is short. Because patients with recurrent/metastatic HNSCC are often older and have already experienced toxicities from treatment of localized disease, identifying well-tolerated treatment options is critical. TKIs with activity against EGFR have been extensively studied in this disease. Some of the clinical trials evaluating these agents in HNSCC are shown in Table 1. In the neoadjuvant setting for locally advanced HNSCC, preoperative treatment with erlotinib for a median of 20 days was associated with tumor shrinkage of at least 25% in 29% of treated patients [22]. More recently, a Phase II study randomized patients with advanced HNSCC to receive definitive standard cisplatin-based chemoradiation with or without erlotinib. The addition of the EGFR inhibitor to chemoradiotherapy did not improve complete response rate (RR) or progression-free survival (PFS) -- the primary study end points [23]. In the recurrent/metastatic setting, the RR with erlotinib as a single agent was only 4.3% in a Phase II trial [10]. In the adjuvant setting, a Phase II trial randomizing patients with intermediate and high risk postoperative HNSCC to receive cisplatin-based chemoradiation with or without gefitinib demonstrated a lack of benefit in DFS with the addition of the study drug [24]. Two Phase III trials have evaluated gefitinib in patients with recurrent/metastatic disease. In an ECOG study, 270 patients with previously treated head and neck cancer were randomized to receive docetaxel with or without gefitinib. This study was closed after an interim analysis due to lack of benefit and increased toxicity in the drug combination arm [25]. Another Phase III clinical trial enrolling 486 patients failed to show a survival benefit of gefitinib in either of two dosing schedules compared with methotrexate: median OS was 5.6 months for gefitinib 250 mg/day, 6 months for gefitinib 500 mg/day and 6.7 months for methotrexate [11]. These results suggest that, at least in an unselected patient population, the first-generation small molecules EGFR TKIs have minimal single agent activity in HNSCC. The absence of benefit with this class of drugs in contrast with the monoclonal antibody cetuximab may be explained by the distinct way the pathway is affected by the two different types of EGFR inhibitors. In addition to blocking EGFR ligand binding and receptor dimerization, cetuximab induces antibodydependent cellular cytotoxicity, which seems to play an important role in its efficacy in HNSCC [26]. Currently, there
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Afatinib
Table 1. Clinical trials of first-generation EGFR TKIs in HNSCC.
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Trial
Phase
No.
Treatment
RR
Neoadjuvant for locally advanced HNSCC II 31 Erlotinib 29% Thomas et al. [22] II 31 Gefitinib 9.70% Tan et al. [47] Concurrent with chemoradiation for definitive treatment of locally advanced HNSCC II 204 CDDP vs CDDP + 40 vs 54% Martins et al. [23] Erlotinib (p = 0.08)* II 226 CDDP vs CDDP + 51.8 vs 60% Gregoire et al. [48] Gefitinib (p = 0.39) Recurrent and/or metastatic disease II 115 Erlotinib 4.3% Soulieres et al. [10] II 45 Lapatinib 0 de Souza et al. [49] III 486 Gefitinib vs 7.6 3.9% Stewart et al. [11] methotrexate (p = 0.17)
Median PFS
Median OS
NR 15 months
NR 28 months
46 vs 54% at 26 months (p = 0.71) 44.2 vs 38.6% at 2 years (p = 0.54)
NR (p = 0.88)
9.6 weeks 52 days NR
6 months 288 days 6 vs 6.7 months (p = 0.39)
57.1 vs 58.9% at 2 years (p = 0.45)
*Complete response rate. CDDP: Cisplatin; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; RR: Response rate.
are no validated biomarkers that predict for sensitive or resistance to ErbB inhibition in HNSCC. KRAS mutations, activating EGFR mutations, and HER2 amplification, which help to guide therapy in other malignancies, are not commonly found in HNSCC [6]. Afatinib, due to its distinct pharmacological and pharmacodynamic properties as well as broader spectrum of activity, might be more effective than the first-generation EGFR TKIs in the treatment of HNSCC. Another second-generation EGFR TKI under investigation is dacomitinib. Dacomitinib is a small molecule panErbB irreversible inhibitor with similar spectrum to afatinib and has shown some activity in HNSCC [27]. A Phase II trial evaluated the efficacy of oral dacomitinib 45 mg/day in the first-line treatment of recurrent/metastatic HNSCC. The observed RR in this trial was 12.7%, and 14% of patients had prolonged disease stabilization (‡ 24 weeks). Median PFS was 12.1 weeks and median OS was 34.6 weeks. Preliminary results of another Phase II study of single agent dacomitinib including patients with recurrent/metastatic disease showed a partial response (PR) in 11% of patients and disease stabilization for 6 or more months in another 11% of patients [28]. Dacomitinib is also being studied in a Phase I trial (NCT01737008) in combination with radiation therapy and with cisplatin-based chemoradiation. In head and neck cancer, the development of afatinib (with multiple Phase III trials ongoing) has moved further along than that of dacomitinib. 3.
Compound
Afatinib is available in film-coated tablets at dosage strengths of 20, 30 and 40 mg. It is described chemically as N-[4[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide. It is not available in intravenous form. Tablets should not be chewed or crushed, but they can be administered as a drinking suspension or via a feeding tube after dispersing the tablet.
4.
Pharmacodynamics
Afatinib is an oral, highly selective and irreversible secondgeneration ErbB family blocker that inhibits EGFR (IC50 = 0.5 nM), HER2 (IC50 = 14 nM) and ErbB4 (IC50 = 1 nM) [29]. Preclinical data have shown inhibitory activity of afatinib in non-small-cell lung cancer (NSCLC) cell lines with the T790M gatekeeper mutation in EGFR, which are resistant to erlotinib and gefitinib, and it has activity in HER2-amplified breast cancer cell lines that are resistant to trastuzumab and lapatinib [30]. Afatinib also inhibits the growth of cells harboring the EGFR truncation mutation variant III, which is often found in HNSCC and is associated with resistance to first-generation TKIs and cetuximab [31]. 5.
Pharmacokinetics and metabolism
Pharmacokinetic studies demonstrate that dose-dependent concentrations are achieved after oral administration. Maximum plasma concentrations are reached between 2 and 5 h after oral dosing and the mean terminal elimination half-life is ~ 37 h. Afatinib has a tissue distribution of around 4500 l and total body clearance mean of 1530 ml/min. Steady state is reached after 8 days of initiating continuous drug usage [32]. The interpatient variability in plasma concentrations is moderate to high and the exposure to afatinib correlated with the severity of the most common adverse events such as rash and diarrhea. Food intake before drug administration significantly decreases systemic exposure. The major route of elimination is via feces (85%). There was poor association between apparent total body clearance and weight or body surface area, justifying a fixed oral dose. Recommended dose for clinical use as single agent is 40 mg/day [33]. 6.
Clinical efficacy
Afatinib has been extensively studied in Phase III trials in NSCLC and in smaller studies in other malignancies (Table 2).
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Table 2. Selected clinical trials of afatinib in other malignancies. Trial
Phase
Disease
No.
Treatment
LUX-Lung 1 [32]
RR
Median PFS
IIb/III
NSCLC, s/p erlotinib or gefitinib
585
LUX-Lung 3 [34]
III
EGFR-mutant NSCLC
LUX-Lung 6 [35]
III
Lin et al. [36]
II
Janjigian et al. [37]
II
Median OS
Afatinib vs BSC
7 vs < 1% (p = 0.007)
3.3 vs 1.1 months (p < 0.001)
345
Afatinib vs cis/pem
EGFR-mutant NSCLC
364
Afatinib vs cis/gem
HER2-positive breast cancer HER2-positive gastric cancer
41
Afatinib
56 vs 23% (p = 0.001) 67 vs 23% (p = 0.001) 10%
11.1 vs 6.9 months (p = 0.001) 11 vs 5.6 months (p < 0.001) 15.1 weeks
61 weeks
9
Afatinib
14%
Not reported
Not reported
10.8 vs 12 months (p = 0.74) NR NR
BSC: Best supportive care; cis: Cisplatin; gem: Gemcitabine; NR: Not reached; OS: Overall survival; pem: Pemetrexed; PFS: Progression-free survival; RR: Response rate.
The landmark Phase III study that led to FDA approval in NSCLC was LUX-Lung 3 [34]. In this trial, 345 patients with stage IIIB/IV lung adenocarcinoma harboring EGFRactivating mutations were randomly assigned in a two-to-one fashion to receive afatinib 40 mg/day or standard chemotherapy with cisplatin and pemetrexed. Median PFS, the primary study end point, was 11.1 months for afatinib as against 6.9 months for the chemotherapy arm (hazard ratio = 0.47, p = 0.001). RR was 56 and 23% for the afatinib and chemotherapy arms, respectively (p = 0.001). Patient-reported outcomes favored afatinib with better control of cough, dyspnea and pain. LUX-Lung 6 was performed in a similar population and showed improved PFS with afatinib over cisplatin/ gemcitabine [35]. For patients who have progressed on erlotinib or gefitinib, the utility of afatinib is less clear. The LUX-Lung 1 study randomized patients who had previously received benefit from erlotinib or gefitinib to either placebo or afatinib. Patients treated with afatinib had an improved RR (7 vs < 1%, p = 0.007) and PFS (3.3 vs 1.1 months, p < 0.001) but there were no differences in OS between the groups (10.8 vs 12 months, p = 0.74) [32]. Afatinib has also shown activity in HER2-amplified trastuzumab-resistant breast and esophagogastric tumors in Phase II studies [36,37]. Phase I clinical trials have shown tolerability of afatinib as a single agent or in combination with chemotherapy (cisplatin, paclitaxel, 5-fluorouracil and pemetrexed) or other targeted agents (volasertib and nintedanib) [38-41]. The largest study reported thus far in HNSCC is a Phase II trial that randomized patients with platinum-resistant recurrent or metastatic HNSCC to receive either afatinib or cetuximab. Patients could crossover to the other drug after progression or dose-limiting toxicity. In the first stage of the trial, 61 patients received afatinib and 60 patients received cetuximab. The primary end point of the study was RR. Both drugs showed comparable antitumor activity with a RR of 8.1 vs 9.7% and PFS of 13 vs 15 weeks (p = 0.71) for afatinib and cetuximab, respectively. Sixty-eight patients crossed over to the other arm following their initial treatment. Thirty-two (52.5%) of the patients 138
who were treated with afatinib went on to receive cetuximab, and 36 (60%) of the cetuximab-treated patients received afatinib. By independent review, one patient in each group had PR to crossover therapy by RECIST criteria. Disease stabilization was observed in 12 (33.3%) patients who crossed over to afatinib and in 6 (18.8%) patients who crossed over to cetuximab. More diarrhea, skin rash and mucositis were observed in the afatinib arm; however, those side effects were manageable and did not lead to an increased drug discontinuation [42]. This trial confirms single agent activity of afatinib, which is comparable with cetuximab, in platinum-refractory recurrent or metastatic HNSCC. In spite of not being powered to detect a difference in PFS, the overall results of the study demonstrate that sequential therapy with ErbB inhibitors is feasible and a subgroup of patients seem to benefit from this strategy [42]. Currently, various Phase II and Phase III studies evaluating afatinib in the neoadjuvant, adjuvant and recurrent or metastatic settings in HNSCC patients are ongoing. The pivotal trial LUX-Head & Neck 1 is a randomized Phase III trial evaluating oral afatinib 40 mg/day versus weekly intravenous methotrexate 40 mg/m2 in patients with recurrent/metastatic HNSCC who progressed after platinum-based chemotherapy. Patients must have a performance status ECOG 0 or 1 and no disease progression for 3 months following completion of curative intent treatment. Stratification will be according to performance status and prior use of EGFR-targeted antibody therapy in the recurrent/metastatic setting. The study primary end point is PFS. Secondary end points include OS, RR, quality of life and safety. The study is currently accruing and the target enrollment is 474 patients. The estimated final data collection for primary outcome measure is March 2014 [43]. Lux-Head & Neck 2 will evaluate oral afatinib 40 mg/day versus placebo given for 18 months following concurrent chemoradiation. Eligibility criteria include primary unresected stage III to IVb HNSCC who are disease-free following platinum-based chemoradiation, with or without neck dissection. Patients most likely to harbor HPV-associated cancer (base of tongue or tonsil primary and < 10 pack-year history of smoking) and patients
Expert Opin. Investig. Drugs (2014) 23(1)
Afatinib
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Table 3. Clinical trials evaluating afatinib in HNSCC available at Ref. [50]. Trial
Phase
No.
Study population
LUX-Head & Neck 1
III
474
LUX-Head & Neck 2
III
669
LUX-Head & Neck 3
III
300
GORTEC 2010-02
III
315
PREDICTOR
II
60
NCT01538381
II
30
NCT01824823
II
108
NCT01732640
I/II
71
NCT01783587
I
38
NCT01721525
I
22
Previously treated R/M HNSCC (second-line, platinum refractory) Stage III/IVa--b HNSCC postplatinum -based chemoradiation therapy Previously treated R/M HNSCC (second-line, platinum refractory) Resected HNSCC with high-risk features (post-chemoradiation therapy) Treatment-naı¨ve non-metastatic HNSCC (neoadjuvant) HNSCC selected for a primary surgical treatment (neoadjuvant) Stage III/IV HNSCC at high risk of recurrence (N+, postchemoradiation therapy) Stage III/IVa--b HNSCC HPVnegative (neoadjuvant) Resected HNSCC with intermediate or high risk features (concurrent with RT) Stage IVa--b HPV-positive oropharynx HNSCC (neoadjuvant)
Treatment
Estimated study completion
Primary end point
Afatinib vs MTX
03/2014
PFS
Afatinib vs placebo
05/2019
DFS
Afatinib vs MTX
04/2016
PFS
Afatinib vs placebo
09/2019
DFS
Afatinib
10/2013
Biomarkers
Afatinib
12/2013
RR/biomarkers
Afatinib vs placebo
02/2016
DFS
Afatinib, paclitaxel and platinum Afatinib (int. risk) vs Afatinib + docetaxel (high risk) Afatinib, ribavirin, weekly carboplatin and paclitaxel
01/2017
MTD/RR/toxicity
02/2015
MTD
11/2014
MTD/biomarkers
DFS: Disease-free survival; MTD: Maximum tolerated dose; MTX: Methotrexate; N+: Lymph node harboring tumor metastases; PFS: Progression-free survival; R/M: Recurrent and/or metastatic; RR: Response rate.
with nasopharyngeal, sinus and salivary gland primaries are excluded. Primary end point is DFS and secondary end points are DFS at 2 years, OS, quality of life and safety. The study is currently accruing and the total planned enrollment is 669 patients. The expected final data collection for primary outcome measure is August 2017. In both LUX-Head and Neck trials, archival tissues and serum samples will be collected in a voluntary basis. Investigation for biomarkers will be done in the available samples [44]. Table 3 enumerates studies currently registered in the United States. 7.
Safety and tolerability
Phase I clinical studies in advanced solid tumors have shown that afatinib has a manageable side effect profile, with most common adverse effects (any grade) being rash (68%), diarrhea (64%), mucositis (19%), nausea and vomiting (~ 10%) and fatigue (7.5%). Dose-limiting toxicities include rash, diarrhea and pneumonitis [45]. In a Phase III trial, enrolling patients with previously treated NSCLC, 390 patients were treated with afatinib 50 mg/day p.o.. Overall, 38% of patients required dose reduction due to adverse events: 21% because of diarrhea and 15% due to rash or acne. Drug-related serious side effects occurred
in 10% of patients, diarrhea being the most common (4%) and 7.7% of patients required treatment discontinuation. No cases of drug-induced pneumonitis were observed [32]. Quality of life assessment of the patients who received afatinib in this study reported a significant improvement in cancerrelated symptoms including cough, dyspnea, pain, fatigue, physical functioning and health-related quality of life [46]. Many side effects from afatinib, including skin rash and diarrhea, are thought to be secondary to inhibition of wildtype EGFR in normal tissue. These side effects are somewhat more severe with afatinib than with first-generation inhibitors erlotinib and gefitinib, thus suggesting increased potency of afatinib. Aggressive supportive management of rash and diarrhea can improve tolerance of therapy. 8.
Regulatory affairs
On 12 July 2013, the US FDA approved afatinib (Gilotrif) for the first-line treatment of patients with metastatic NSCLC harboring EGFR-activating mutations (exon 19 deletions and L858R mutations). In Europe, Boehringer Ingelheim Pharmaceuticals, Inc. submitted an application in September 2012 to the European Medicines Agency seeking approval of afatinib for the same indication.
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9.
Conclusion
Patients with recurrent or metastatic HNSCC have a poor prognosis and new treatment strategies are urgently needed. Thus far, cetuximab is the only targeted therapy approved for the treatment of HNSCC. Considering the importance of the EGFR pathway in the tumorigenesis of HNSCC, there is a strong rationale for the use of afatinib, a pan-ErbB irreversible inhibitor that has an acceptable toxicity profile. Preliminary results from Phase II clinical trials have shown activity of afatinib in a subset of HNSCC patients, justifying further investigation of this drug in this population. Ongoing Phase III trials should elucidate the role of afatinib in the treatment of this deadly malignancy. Validated biomarkers and elucidation of resistance mechanisms are urgently needed to better predict treatment benefit and understand mechanisms of treatment failure. 10.
Expert opinion
EGFR is expressed at high levels in HNSCC, making it an attractive therapeutic target. Initial studies of EGFR inhibition have had some success, with the benefits of anti-EGFR monoclonal antibody cetuximab demonstrated in several large trials. Clinical trials utilizing small molecule inhibitors of EGFR, such as erlotinib and gefitinib, have had disappointing results thus far. Afatinib is a second-generation small molecule TKI of the ErbB family, including EGFR, HER2 and HER4. It is potent and irreversible. In HNSCC, the largest trial to date has enrolled patients with platinum-refractory disease, who were randomized to receive cetuximab or afatinib. This study suggested that afatinib and cetuximab have similar efficacy in patients with previously treated disease. Crossover data from this trial suggested that afatinib may have some activity in patients with disease refractory to cetuximab. Afatinib was associated with more severe skin rash, diarrhea and mucositis than cetuximab. The role of afatinib in the treatment of HNSCC will in large part be decided by the results of two currently accruing Phase III trials. LUX Head & Neck 1 trial (NCT01345682) is enrolling patients with platinum-refractory HNSCC to be randomized between afatinib and methotrexate. The primary end point of this trial is PFS, though the trial is also powered to detect differences in OS. If this trial is able to demonstrate an improvement in survival outcomes with afatinib over methotrexate, it would present a potential road to regulatory
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approval. The only drug currently approved in this setting in the United States is cetuximab, while methotrexate is often used in Europe. The major potential competitor for afatinib in this space in the United States is cetuximab, which is approved in combination with platinum-based chemotherapy for frontline treatment of recurrent and metastatic disease [4] as well as in the platinum-refractory setting as a single agent [21]. If cetuximab is used as frontline treatment, afatinib may be a good option in the second-line setting, as there seems to be some activity in patients whose disease progressed on cetuximab [42]. LUXHead & Neck 1 trial allows prior cetuximab, and analysis of the subgroup of patients who have received cetuximab will be of interest. The randomized Phase II trial comparing afatinib to cetuximab did not show significant differences in outcome between the groups [42]. Afatinib was associated with more severe toxicity, but some patients prefer oral administration of drugs and may find afatinib more convenient. LUX-Head & Neck 2 (NCT01345669) is another randomized Phase III trial. Eligible patients will have completed platinum-based concurrent chemoradiation for locally advanced HNSCC. Following completion of definitive therapy, patients will be randomized to receive either placebo or afatinib as adjuvant therapy for up to 18 months. Currently, the standard of care for patients with no evidence of disease after chemoradiation for HNSCC is observation. If afatinib is able to reduce recurrence and prolong survival after definitive treatment, it could fill a niche for these patients who have a high risk of recurrent disease. Treatment, however, is difficult to administer in this setting. Many patients are debilitated after completion of definitive treatment. Afatinib, though it is a targeted oral therapy, has side effects which can be difficult to manage. Only a portion of patients seem to benefit from therapy with afatinib. Unfortunately, no biomarkers predicting benefit from EGFR-targeted therapies in HNSCC have been identified. This continues to be an area of active investigation, and the ongoing clinical trials will be collecting patient tissues for correlative studies.
Declaration of interest The authors have been supported by the P Calabresi (K12) National Institutes of Health Award. K Gold also declares that she serves on the advisory boards for both Pfizer and Bristol-Myers Squibb.
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Affiliation Renata Ferrarotto1 MD & Kathryn A Gold†2 MD † Author for correspondence 1 Clinical Fellow, The University of Texas MD Anderson Cancer Center, Department of Thoracic and Head and Neck Medical Oncology, 1515 Holcombe Blvd, Unit 0432, Houston, TX 77030, USA 2 Assistant Professor, The University of Texas MD Anderson Cancer Center, Department of Thoracic and Head and Neck Medical Oncology, 1515 Holcombe Blvd, Unit 0432, Houston, TX 77030, USA Tel: +1 713 792 6363; Fax: +1 713 792 1220; E-mail: [email protected]
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