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A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours
European Journal of Cancer (2015) xxx, xxx– xxx
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A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours A. Suder a, J.E. Ang b, F. Kyle a, D. Harris c,1, S. Rudman a, R. Kristeleit c,2, F. Solca d, M. Uttenreuther-Fischer e, K. Pemberton f, K. Pelling g, D. Schnell h, J. de Bono b, J. Spicer i,⇑ a
Department of Medical Oncology, Guys and St Thomas’ NHS Foundation, Great Maze Pond, London SE1 9RT, UK Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK c The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK d Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A1120 Vienna, Austria e Therapeutic Area Oncology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss 88397, Germany f Medical Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK g Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK h Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss, 88397 Biberach an der Riss, Germany i King’s College London – Division of Cancer Studies, 3rd Floor, Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, UK b
Received 5 March 2015; received in revised form 8 July 2015; accepted 23 July 2015
KEYWORDS Afatinib Paclitaxel ErbB receptors Clinical trial phase I Neoplasms
Abstract Background: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. Methods: Oral afatinib was combined with intravenous paclitaxel (80 mg/m2; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of P3 patients. The primary objective was to determine the maximum tolerated dose
⇑ Corresponding author at: King’s College London – Division of Cancer Studies, 3rd Floor, Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. Tel.: +44 20 7188 4260. E-mail addresses: [email protected] (A. Suder), [email protected] (J.E. Ang), fi[email protected] (F. Kyle), dean.harris@cdhb. health.nz (D. Harris), [email protected] (S. Rudman), [email protected] (R. Kristeleit), fl[email protected] (F. Solca), martina.uttenreuther-fi[email protected] (M. Uttenreuther-Fischer), [email protected] (K. Pemberton), [email protected] (K. Pelling), [email protected] (D. Schnell), johann.de-Bono@ icr.ac.uk (J. de Bono), [email protected] (J. Spicer). 1 Present address: Department of Oncology, Christchurch Hospital, 2 Riccarton Avenue, Christchurch 4710, New Zealand. 2 Present address: Cancer Institute, University College London, 72 Huntley St, London WC1E 6BT, UK.
http://dx.doi.org/10.1016/j.ejca.2015.07.041 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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(MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. Results: Sixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m2, which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for P6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. Conclusions: The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m2 (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. Trial registration: ClinicalTrials.gov, NCT00809133. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Small-molecule tyrosine kinase inhibitors (TKIs) and specific monoclonal antibodies have validated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) as targets for the treatment of various cancers, including non-small cell lung cancer (NSCLC) and metastatic breast cancer [1,2]. Afatinib, an irreversible ErbB family blocker, covalently binds to and inhibits signalling of homo- and heterodimers formed by ErbB family members (EGFR, HER2, ErbB3 and ErbB4) [3,4]. Afatinib has demonstrated single-agent clinical activity in human cancers, particularly NSCLC and head and neck squamous cell carcinoma [5–9]. In randomised trials, afatinib prolonged progression-free survival (PFS) and improved quality of life as a first-line therapy or in later lines of treatment in patients with advanced NSCLC [5,6,9–12]. Based on the results of two phase III studies demonstrating superior PFS benefit of first-line afatinib versus platinum-based chemotherapy in patients with NSCLC harbouring distinct types of EGFR mutations [9,13], afatinib was approved for treatment of these patients in the US, EU and Japan [14–16]. An overall survival benefit with afatinib in NSCLC patients harbouring EGFR Del19 mutation in these studies was also recently reported [17]. Taxanes, including paclitaxel, are used widely in the treatment of solid tumours and exert their antitumour activity by disrupting microtubule polymerisation, which leads to mitotic arrest and cell death [18]. In preclinical studies, the combination of afatinib with paclitaxel was more effective than either agent alone in inhibiting the proliferation of SKOV-3 ovarian carcinoma cells (Fig. 1A) and HT29 colon cancer cells in soft agar assays (Fig. 1B); additive activity of afatinib with
docetaxel was demonstrated in vivo in a SKOV-3 xenograft model [19]. These preclinical observations suggest that the efficacy achieved through blockade of ErbB family signalling can be enhanced by combining with cytotoxic agents with non-overlapping mechanisms of action. The clinical feasibility of combining afatinib with docetaxel was studied in patients with advanced solid tumours [20–22], although antitumour activity was only observed in one study [22]. This phase I dose-escalation trial explored the efficacy and safety of afatinib in combination with paclitaxel. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with fixed-dose paclitaxel in pretreated patients with advanced solid tumours. Secondary objectives included evaluation of adverse events (AEs), pharmacokinetic assessments and antitumour activity. 2. Patients and methods 2.1. Patients Eligible patients had advanced non-resectable and/or metastatic solid malignancies likely to express EGFR and/or HER2, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Exclusion criteria included gastrointestinal dysfunction that could impair oral absorption; grade P2 (Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) neuropathy or neurotoxicity persisting after prior therapy; active brain metastases; use of full-dose anticoagulation medication; significant cardiovascular disease; known interstitial lung disease; active infectious disease; or treatment with radio-, chemo-, immuno- or hormone therapy, investigational agents, or EGFR- or HER2-targeted treatments within 4 weeks prior to the study start.
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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Fig. 1. Enhanced in vitro activity with the combination of afatinib and paclitaxel in SKOV-3 ovarian carcinoma cells (A) and HT29 colon cancer cells (B). For these anchorage-independent assays, cells were suspended in 0.3% SeaPlaquee agar in Iscove’s modification of Dulbecco’s medium supplemented with 10% foetal calf serum and layered over a 1% agar-medium base layer in 6-well plates. Colonies were assessed by Alamar blue in triplicate after 9 days of culture. Mean percent inhibition of cell proliferation is graphed (error bars represent standard deviation); results were normalised to control [19]. An afatinib plasma concentration of 2 nM at trough has been achieved with daily oral dosing of 10 mg in clinical studies [7].
This study was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Tripartite Guideline for Good Clinical Practice and was approved after applicable regulatory and ethical review. All patients provided written informed consent prior to study participation. 2.2. Study design and treatment This phase I dose-escalation trial of afatinib combined with paclitaxel was conducted in two centres in the UK. The study followed a 3 + 3 dose-escalation design, with 3–6 patients entered into successive dose cohorts according to dose-limiting toxicities (DLTs) observed. In the event of a DLT, administration of study treatment was paused. Upon recovery of AEs to baseline or grade 61 within 14 days, treatment could be continued at a reduced dose. Treatment pauses of more than 14 days were allowed if an intercurrent illness or another event contributed to failure of an AE to resolve. The MTD for combination therapy was defined as the highest dose of afatinib combined with fixed-dose paclitaxel at which no more than one of six patients experienced DLTs during cycle 1 (first 28 days of treatment). To meet the minimum safety requirement for the determination of the MTD, patients must have completed the first 3 weeks of therapy or have experienced a DLT. Patients who did not meet either of these criteria were replaced. Afatinib was administered continuously at a starting oral dose of 20 mg/day, beginning on day 2 of cycle 1. Afatinib dose escalation was carried out in successive cohorts from 20 mg to 40 mg to 50 mg. An intermediate dose cohort of afatinib 30 mg was allowed if a DLT was experienced at the 40 mg dose. Weekly paclitaxel
80 mg/m2 was administered intravenously on days 1, 8 and 15 of a 4-week cycle. If two or more DLTs due to paclitaxel treatment were observed in the first cohort, a reduction in paclitaxel from 80 mg/m2 to 70 mg/m2 was permitted and the reduced dose was to be used for all other cohorts. Combination treatment was continued for up to 6 cycles. After completion of paclitaxel, patients benefiting from and tolerating treatment were eligible to continue treatment beyond this period with afatinib monotherapy until disease progression, occurrence of an AE, or withdrawal of consent. 2.3. Safety assessments AEs were assessed according to CTCAE version 3.0. DLTs were defined as: grade 4 uncomplicated neutropenia (fever < 38.3 °C) for >7 days, neutropenia with fever > 38.5 °C, platelets < 25 109/L or grade 3 thrombocytopenia associated with bleeding requiring transfusion, grade P2 decrease in left ventricular function, uncontrolled hypertension despite multiple therapies, grade P2 worsening of renal function, grade >2 diarrhoea despite anti-diarrhoeal medication, persistent grade >2 diarrhoea for P7 days despite supportive care, grade >2 nausea and/or vomiting despite antiemetic treatment and grade >1 vomiting for P7 days despite antiemetic treatment. All other drug-related non-haematological toxicities of grade P3, except incompletely treated nausea, vomiting or diarrhoea, were also considered to be DLTs. 2.4. Efficacy outcomes Tumour imaging using computerised tomography was performed at screening and every 8 weeks after
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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the start of afatinib treatment. Tumour response was assessed using Response Evaluation Criteria in Solid Tumours version 1.0, and patients were assigned to one of the following categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease, or not evaluable. Best overall response was defined as the best tumour response recorded at any time from the start of treatment to disease progression or recurrence. In patients with an objective response (CR or PR), this status was confirmed by a repeat assessment performed at least 4 weeks later. 2.5. Pharmacokinetic sampling and analysis Pharmacokinetic profiles were obtained in cycle 1 on days 1 and 15. Samples were taken pre- and post-paclitaxel infusion and/or afatinib administration (planned times pre-dose, 1, 2, 2.5, 3, 4, 6, 8 and 24 h) to allow comparison of paclitaxel in the absence and presence of afatinib, dosing of which began on day 2. Plasma concentrations of afatinib and paclitaxel were analysed using validated high-performance liquid chromatography tandem mass spectrometry assays. Pharmacokinetic evaluations were conducted using WinNonlinÒ version 5.2 and SASÒ version 9.2 (or higher) software. 2.6. Statistical analyses Safety and efficacy analyses were conducted in the treated set (all patients receiving at least one dose of afatinib). Statistical analyses, including determination of MTD, were descriptive. 3. Results 3.1. Patients and treatment Between June 2007 and April 2008, 16 patients received the combination of afatinib and paclitaxel. Baseline patient demographics and tumour characteristics are summarised in Table 1. Fifteen patients (94%) completed P1 cycle of combination treatment with afatinib and paclitaxel. Nine patients (56%) completed P6 cycles of treatment; of these, five patients continued treatment in the extension phase of the trial with afatinib monotherapy. Four patients (25%) received >12 cycles of therapy. Median time on treatment was 25 weeks (range, 3–165 weeks). Dose reductions of afatinib were implemented in four patients, including one patient treated with afatinib 40 mg plus paclitaxel 80 mg/m2 and three patients receiving afatinib 50 mg plus paclitaxel 80 mg/m2; in three of these patients, dose reduction occurred after the DLT-defining period.
Table 1 Baseline patient demographics and tumour characteristics. Characteristic Gender, n (%) Male Female Age, years Median (range) ECOG PS, n (%) 0 1 Time from initial diagnosis, years Median (range) Primary tumour, n (%) Non-small cell lung cancera Biliary treeb Oesophagealc Head and neckd Ovaryb Pancreasb Prostateb Stomachb Previous anticancer therapy, n (%) Surgery Chemotherapy Immunotherapy Hormone therapy Radiotherapy Other (including biological therapy)
N = 16 6 (38) 10 (63) 57 (38–72) 5 (31) 11 (69) 1.91 (0.7–9.3) 9 1 1 1 1 1 1 1
(56) (6) (6) (6) (6) (6) (6) (6)
9 (56) 13 (81) 2 (13) 1 (6) 6 (38) 1 (6)
ECOG PS, Eastern Cooperative Oncology Group performance status. a Histological subtypes included adenocarcinoma (n = 6) and not otherwise specified (n = 3). b Adenocarcinoma. c Histological subtype not specified. d Adenoid cystic carcinoma of the tongue.
3.2. Safety Fifteen patients were evaluable for determination of the MTD; one patient in the 40 mg cohort, who did not receive continuous treatment during the first 3 weeks of study participation, was excluded from analysis. No DLT was observed with 20 mg or 40 mg afatinib in combination with paclitaxel 80 mg/m2. DLTs were observed in two patients treated with afatinib 50 mg and paclitaxel 80 mg/m2 during cycle 1: grade 3 fatigue occurred in a 38-year-old female on day 4 of treatment but resolved with a 2-day afatinib dose interruption, and grade 3 mucositis was observed in a 63-year-old female on day 20 of treatment. This DLT required hospitalisation, but with supportive therapy (hydration and analgesia) resolved after a 9-day afatinib dose interruption. Both patients continued combination therapy when re-treated with afatinib at a reduced dose (40 mg) without recurrence of intolerable AEs. Following the occurrence of these DLTs, the next lower dose cohort of 40 mg afatinib with paclitaxel 80 mg/m2 was expanded to six patients, with no DLTs observed. The MTD of combination therapy was 40 mg afatinib and 80 mg/m2 paclitaxel.
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
A. Suder et al. / European Journal of Cancer xxx (2015) xxx–xxx
Treatment-related AEs were observed in all 16 patients (Table 2); the most common were diarrhoea (n = 15; 94%), fatigue (n = 13; 81%) and rash/acne (n = 13; 81%). The majority of treatment-related AEs were grade 1/2, with four patients (25%) experiencing grade 3 AEs. There were no grade P4 treatmentrelated AEs and none leading to death. Fatigue was the most frequently documented grade 3 treatment-related AE (n = 2 [13%]). Neutropenia, judged as unrelated to afatinib by the investigator, occurred in two patients (13%; grade 1); no febrile neutropenia was observed. One (6%) grade 4 AE was observed (pulmonary embolism unrelated to study treatment). 3.3. Pharmacokinetics Afatinib pharmacokinetic parameters were estimated for all dose levels in the presence of paclitaxel on day 15 (Table 3; Fig. S1A and S1B). Afatinib was rapidly absorbed and reached peak plasma concentration 2–6 h after administration. Afatinib exposure increased with increasing doses (Fig. S1C); there was no indication of saturation of elimination mechanisms at the doses studied. Paclitaxel pharmacokinetic parameters were estimated in the absence (day 1) and presence (day 15) of different afatinib doses (Table 3; Fig. S2A and S2B). There was no evidence that the Cmax and AUC0–24 of paclitaxel were affected by the presence or absence of concurrent afatinib administration or by different administered doses of afatinib (Fig. S2C). 3.4. Antitumour activity Thirteen treated patients were eligible for response assessment. Of these, seven patients (44%) achieved clinical benefit (PR or SD for P6 months). Best changes from baseline in tumour measurements are shown in Fig. 2A. Of five patients (31%) who experienced a confirmed PR (Fig. 2A), three had NSCLC and one patient each had cholangiocarcinoma and oesophageal cancer; two of these patients received previous treatment with docetaxel. Fig. 2B depicts the radiological PR in a patient with advanced oesophageal adenocarcinoma following two treatment cycles of afatinib 40 mg and paclitaxel 80 mg/m2. Fig. 2C illustrates radiological improvement in a female patient with wild-type EGFR lung adenocarcinoma, who experienced sustained clinical and radiological improvement in non-measurable disease persisting beyond 3 years. A PR was also observed in another patient with NSCLC harbouring a known activating EGFR mutation. 4. Discussion This phase I study defined the MTD of once-daily oral afatinib as 40 mg in combination with 80 mg/m2
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paclitaxel administered on days 1, 8 and 15 of a 4-week cycle. This combination had a manageable AE profile, with diarrhoea, rash and fatigue as the most common AEs, almost all of which were grade 1/2. Incidences of neutropenia were low, consistent with previously reported data for paclitaxel alone in patients with metastatic breast cancer [23] and NSCLC [24]; no febrile neutropenia or leucopaenia was observed. In a previous phase I study of afatinib (days 2–21) plus docetaxel 75 mg/m2 (day 1) in patients with advanced cancers, the MTD of afatinib was 20 mg/day [20]. Due to a higher incidence of grade 3/4 neutropenia and febrile neutropenia observed with the combination compared with docetaxel alone and the lack of antitumour activity, this dose was not suitable as a recommended phase II dose. Another phase I study of pulsatile administration of afatinib (days 2–4) in combination with docetaxel 75 mg/m2 (day 1) every 21 days demonstrated a manageable safety profile and clinical activity, and a recommended phase II dose of afatinib 90 mg/day was achieved [22]. The difference in tolerability between three-weekly docetaxel and weekly paclitaxel may account for the divergence of afatinib MTDs in combination with these various taxane regimens [25]. In the current study, almost all patients (94%) experienced combination treatment-related diarrhoea; this incidence is higher than that reported in phase I studies of afatinib monotherapy (64–77%) [7,26]. However, AEs relating to combination treatment at the MTD of afatinib (40 mg/day) were mild to moderate (grade 62) and manageable with supportive measures. Furthermore, a number of patients continued either combination treatment or afatinib monotherapy for a prolonged period. Pharmacokinetic assessments showed no relevant interactions between afatinib and paclitaxel, and parameters for afatinib at 40 mg/day in this study were similar to those previously reported for single-agent afatinib [7]. This is despite the fact that both agents are P-glycoprotein substrates [15,27], which may have implications for future studies elucidating mechanisms of resistance to this combination. Other clinical studies have indicated a lack of pharmacokinetic interactions between afatinib and other microtubule-targeting agents, including docetaxel [22] and vinorelbine [28]. The combination of afatinib and paclitaxel demonstrated antitumour activity, with 44% of evaluable patients achieving confirmed radiological PR or SD for P6 months. The mechanism by which afatinib and paclitaxel may exert synergistic effects has not yet been elucidated. In phase III studies in unselected patients with NSCLC, EGFR inhibition combined with chemotherapy did not improve efficacy over chemotherapy alone [29–31]. In contrast, recent phase II/III studies of erlotinib or lapatinib combined with paclitaxel-based regimens support the synergistic activity of such combinations in patients with NSCLC and breast cancer
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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Paclitaxel 80 mg/m2 plus afatinib 20 mg
Paclitaxel 80 mg/m2 plus afatinib 40 mg
n=3
n=7
Paclitaxel 80 mg/m2 plus afatinib 50 mg n=6
Paclitaxel 80 mg/m2 plus afatinib 20, 40, 50 mg N = 16
AEs, n (%)
All
Grade 3a
All AEs
Grade 3a
All AEs
Grade 3a
All AEs
Grade 3a
Any AE Diarrhoea Fatigue Rash/acneb Inflammation of mucosal membranesc Decreased appetite Dry skin Alopecia Nail disorderd Nausea Neuropathye Vomiting Dysgeusia Oropharyngeal pain Palmar-plantar erythrodysesthesia ALT increased Constipation Dry mouth Dyspepsia Dyspnoea Folliculitis Musculoskeletal and connective tissue disorders Pruritus Psychiatric disorders
3 2 2 1 1 2 2 3 1 1 1 1 1 1 1 0 1 0 1 1 0 1 0 1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7 7 6 7 5 5 4 2 4 4 2 2 2 2 0 2 1 2 1 1 1 1 1 1
2 0 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6 6 5 5 5 4 2 1 1 1 2 1 0 0 2 0 0 0 0 0 1 0 1 0
2 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
16 (100) 15 (94) 13 (81) 13 (81) 11 (69) 11 (69) 8 (50) 6 (38) 6 (38) 6 (38) 5 (31) 4 (25) 3 (19) 3 (19) 3 (19) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13)
4 0 2 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
(25) (0) (13) (6) (6) (0) (0) (0) (0) (6) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
AE, adverse event; ALT, alanine aminotransferase. a There were no grade 4 treatment-related AEs. b Pre-specified grouped term includes reported preferred terms of acne, blister, dermatitis acneiform, erythema, folliculitis, rash, rash maculo-papular, rash papular and skin disorder. c Pre-specified grouped term includes reported preferred terms of dry mouth, mucosal inflammation, mucosal ulceration, stomatitis and tongue ulceration. d Including preferred terms of nail disorder, nail infection, nail pitting, oncholysis and paronychia. e Including preferred terms of neuropathy peripheral and peripheral sensory neuropathy.
A. Suder et al. / European Journal of Cancer xxx (2015) xxx–xxx
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
Table 2 Treatment-related AEs in P10% of patients during treatment with combined afatinib and paclitaxel.
Paclitaxel 80 mg/m2 plus afatinib 20 mg Day 1 gMean
Day 15 gCV, %
gMean
Paclitaxel 80 mg/m2 plus afatinib 40 mg Day 1
gCV, %
gMean
Day 15 gCV, %
gMean
Paclitaxel 80 mg/m2 plus afatinib 50 mg Day 1
gCV, %
gMean
Day 15 gCV, %
gMean
Paclitaxel 80 mg/m2 plus afatinib 20, 40, 50 mga Day 1
gCV, %
gMean
Day 15 gCV, %
gMean
gCV, %
b
Paclitaxel AUC0–24, ngh/ml Cmax, ng/ml Afatinibc AUCs,ss, ngh/ml Cmax,ss, ng/ml
n=3 1970 n=2 428
52.2 387 – –
n=3 3560 n=3 1880 n=3 250 n=3 12.3
12.6 42.2
n=6 3730 n=6 2090
28.5 37.7 –
9.63 – 15.5
n=5 3170 n=6 1590 n=6 813 n=6 46.0
67.7 82.2
58.4 – 61.9
n=4 3260 n=5 1480
30.1 63.1
n=4 3950 n=5 2120 n=4 939 n=5 63.5
51.8 68.2
n = 15 3130 n = 15 1510
39.2 94.0
n = 12 3510 n = 14 1830
49.0 65.7
– 60.0 – 74.6
AUC0–24, area under the concentration–time curve of the analyte in plasma over 0 to 24 h; AUCs,ss, area under the concentration–time curve of the analyte in plasma at steady state; Cmax, maximum measured concentration of the analyte in plasma; Cmax,ss, Cmax at steady state; gCV, geometric coefficient of variation; gMean, geometric mean. a Pooled data from all dose cohorts, including two patients who received paclitaxel 80 mg/m2 without afatinib. b Paclitaxel pharmacokinetic parameters were determined in the absence (day 1) and presence (day 15) of different afatinib doses. c Afatinib steady state pharmacokinetic parameters were determined after administration of different doses of afatinib in the presence of paclitaxel (day 15 only).
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Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
Table 3 Summary of pharmacokinetic parameters of paclitaxel before (day 1) and after (day 15) administrations of afatinib.
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Fig. 2. Antitumour activity. (A) Waterfall plot for patients with measurable disease displaying best change in tumour measurement from baseline (%)a. (B) Computed tomography images of a male patient with oesophageal adenocarcinoma demonstrating a partial response to afatinib 40 mg and paclitaxel 80 mg/m2 after two 28-day treatment cycles. (C) A female patient with non-small cell lung cancer (NSCLC) who showed sustained radiological and clinical benefit for >3 years, continuing to receive single-agent afatinib following completion of combination treatment. EGFR, epidermal growth factor receptor; GI, gastrointestinal. aBest change from baseline is the difference between the sum of the longest diameters of target lesions at baseline and at best response. bNSCLC patient with stable disease. cNSCLC patient with activating EGFR mutation. dPancreas (n = 1), head and neck squamous cell carcinoma (n = 1), prostate (n = 1), biliary tree (n = 1).
selected for biomarker expression [32,33]. Although patients included in this dose-escalation trial were not selected for EGFR/HER2 overexpression or amplification, one patient with NSCLC harbouring a known activating EGFR mutation achieved radiological PR; this finding is consistent with documented activity of afatinib in EGFR-mutated lung cancer [6,7]. The encouraging tolerability findings and antitumour activity of the combination reported herein provided the basis for further clinical studies in patients with HER2-positive breast cancer [34] and EGFR TKI-refractory NSCLC [35]. In the recently completed LUX-Lung 5 phase III trial, afatinib 40 mg plus weekly
paclitaxel significantly improved PFS (median 5.6 versus 2.8 months; hazard ratio 0.60 [95% CI 0.43–0.85; p = 0.003]) and response rate (32.1% versus 13.2%; p = 0.005) versus investigator’s choice of single-agent chemotherapy, with a manageable safety profile, in patients with EGFR TKI-refractory NSCLC following progression on afatinib monotherapy [35]. These results suggest that afatinib combined with weekly paclitaxel is an effective therapeutic option for advanced cancers driven by ErbB family signalling, even after prior treatment with reversible EGFR TKIs. In conclusion, the MTD of oral afatinib was defined as 40 mg/day in combination with paclitaxel 80 mg/m2
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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administered on days 1, 8 and 15 every four weeks, with a manageable AE profile. No pharmacokinetic interactions between the two agents were observed. The combination was clinically active, with a response rate of 31%, and 50% of patients remained on treatment for at least 6 months. Funding This study was supported financially by Boehringer Ingelheim, as well as by the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility), and to The Institute of Cancer Research and Royal Marsden Hospital NHS Foundation Trust. King’s College London and the Royal Marsden hold Experimental Cancer Medicine Centre grants. RK is supported by the NIHR/Wellcome University College London (UCL) Hospitals Clinical Research Facility, the UCL Hospitals Biomedical Research Centre and the UCL Experimental Cancer Medicine Centre. Conflict of interest statement M. Uttenreuther-Fischer, K. Pemberton, K. Pelling and D. Schnell are employees of Boehringer Ingelheim. J. de Bono has reported consultancy roles for Boehringer Ingelheim (unpaid) and AstraZeneca. J. Spicer has reported consultancy roles for Boehringer Ingelheim. All remaining authors have declared no conflicts of interest. Acknowledgements Boehringer Ingelheim provided financial support for this study and managed the clinical trial database. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Aurora O’Brate of Ogilvy Healthworld, and Katie McClendon, of GeoMed, an Ashfield company, part of UDG Healthcare plc. The study investigators and the Boehringer Ingelheim study team were responsible for the study design and the collection, analysis and interpretation of the data. All authors had full access to the study data, contributed to the development of the manuscript, were fully responsible for all content and editorial decisions, and made the final decision to submit the manuscript for publication. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.07.041.
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Available at www.sciencedirect.com
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A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours A. Suder a, J.E. Ang b, F. Kyle a, D. Harris c,1, S. Rudman a, R. Kristeleit c,2, F. Solca d, M. Uttenreuther-Fischer e, K. Pemberton f, K. Pelling g, D. Schnell h, J. de Bono b, J. Spicer i,⇑ a
Department of Medical Oncology, Guys and St Thomas’ NHS Foundation, Great Maze Pond, London SE1 9RT, UK Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK c The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK d Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A1120 Vienna, Austria e Therapeutic Area Oncology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss 88397, Germany f Medical Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK g Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK h Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss, 88397 Biberach an der Riss, Germany i King’s College London – Division of Cancer Studies, 3rd Floor, Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, UK b
Received 5 March 2015; received in revised form 8 July 2015; accepted 23 July 2015
KEYWORDS Afatinib Paclitaxel ErbB receptors Clinical trial phase I Neoplasms
Abstract Background: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. Methods: Oral afatinib was combined with intravenous paclitaxel (80 mg/m2; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of P3 patients. The primary objective was to determine the maximum tolerated dose
⇑ Corresponding author at: King’s College London – Division of Cancer Studies, 3rd Floor, Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. Tel.: +44 20 7188 4260. E-mail addresses: [email protected] (A. Suder), [email protected] (J.E. Ang), fi[email protected] (F. Kyle), dean.harris@cdhb. health.nz (D. Harris), [email protected] (S. Rudman), [email protected] (R. Kristeleit), fl[email protected] (F. Solca), martina.uttenreuther-fi[email protected] (M. Uttenreuther-Fischer), [email protected] (K. Pemberton), [email protected] (K. Pelling), [email protected] (D. Schnell), johann.de-Bono@ icr.ac.uk (J. de Bono), [email protected] (J. Spicer). 1 Present address: Department of Oncology, Christchurch Hospital, 2 Riccarton Avenue, Christchurch 4710, New Zealand. 2 Present address: Cancer Institute, University College London, 72 Huntley St, London WC1E 6BT, UK.
http://dx.doi.org/10.1016/j.ejca.2015.07.041 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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(MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. Results: Sixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m2, which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for P6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. Conclusions: The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m2 (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. Trial registration: ClinicalTrials.gov, NCT00809133. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Small-molecule tyrosine kinase inhibitors (TKIs) and specific monoclonal antibodies have validated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) as targets for the treatment of various cancers, including non-small cell lung cancer (NSCLC) and metastatic breast cancer [1,2]. Afatinib, an irreversible ErbB family blocker, covalently binds to and inhibits signalling of homo- and heterodimers formed by ErbB family members (EGFR, HER2, ErbB3 and ErbB4) [3,4]. Afatinib has demonstrated single-agent clinical activity in human cancers, particularly NSCLC and head and neck squamous cell carcinoma [5–9]. In randomised trials, afatinib prolonged progression-free survival (PFS) and improved quality of life as a first-line therapy or in later lines of treatment in patients with advanced NSCLC [5,6,9–12]. Based on the results of two phase III studies demonstrating superior PFS benefit of first-line afatinib versus platinum-based chemotherapy in patients with NSCLC harbouring distinct types of EGFR mutations [9,13], afatinib was approved for treatment of these patients in the US, EU and Japan [14–16]. An overall survival benefit with afatinib in NSCLC patients harbouring EGFR Del19 mutation in these studies was also recently reported [17]. Taxanes, including paclitaxel, are used widely in the treatment of solid tumours and exert their antitumour activity by disrupting microtubule polymerisation, which leads to mitotic arrest and cell death [18]. In preclinical studies, the combination of afatinib with paclitaxel was more effective than either agent alone in inhibiting the proliferation of SKOV-3 ovarian carcinoma cells (Fig. 1A) and HT29 colon cancer cells in soft agar assays (Fig. 1B); additive activity of afatinib with
docetaxel was demonstrated in vivo in a SKOV-3 xenograft model [19]. These preclinical observations suggest that the efficacy achieved through blockade of ErbB family signalling can be enhanced by combining with cytotoxic agents with non-overlapping mechanisms of action. The clinical feasibility of combining afatinib with docetaxel was studied in patients with advanced solid tumours [20–22], although antitumour activity was only observed in one study [22]. This phase I dose-escalation trial explored the efficacy and safety of afatinib in combination with paclitaxel. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with fixed-dose paclitaxel in pretreated patients with advanced solid tumours. Secondary objectives included evaluation of adverse events (AEs), pharmacokinetic assessments and antitumour activity. 2. Patients and methods 2.1. Patients Eligible patients had advanced non-resectable and/or metastatic solid malignancies likely to express EGFR and/or HER2, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Exclusion criteria included gastrointestinal dysfunction that could impair oral absorption; grade P2 (Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) neuropathy or neurotoxicity persisting after prior therapy; active brain metastases; use of full-dose anticoagulation medication; significant cardiovascular disease; known interstitial lung disease; active infectious disease; or treatment with radio-, chemo-, immuno- or hormone therapy, investigational agents, or EGFR- or HER2-targeted treatments within 4 weeks prior to the study start.
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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Fig. 1. Enhanced in vitro activity with the combination of afatinib and paclitaxel in SKOV-3 ovarian carcinoma cells (A) and HT29 colon cancer cells (B). For these anchorage-independent assays, cells were suspended in 0.3% SeaPlaquee agar in Iscove’s modification of Dulbecco’s medium supplemented with 10% foetal calf serum and layered over a 1% agar-medium base layer in 6-well plates. Colonies were assessed by Alamar blue in triplicate after 9 days of culture. Mean percent inhibition of cell proliferation is graphed (error bars represent standard deviation); results were normalised to control [19]. An afatinib plasma concentration of 2 nM at trough has been achieved with daily oral dosing of 10 mg in clinical studies [7].
This study was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Tripartite Guideline for Good Clinical Practice and was approved after applicable regulatory and ethical review. All patients provided written informed consent prior to study participation. 2.2. Study design and treatment This phase I dose-escalation trial of afatinib combined with paclitaxel was conducted in two centres in the UK. The study followed a 3 + 3 dose-escalation design, with 3–6 patients entered into successive dose cohorts according to dose-limiting toxicities (DLTs) observed. In the event of a DLT, administration of study treatment was paused. Upon recovery of AEs to baseline or grade 61 within 14 days, treatment could be continued at a reduced dose. Treatment pauses of more than 14 days were allowed if an intercurrent illness or another event contributed to failure of an AE to resolve. The MTD for combination therapy was defined as the highest dose of afatinib combined with fixed-dose paclitaxel at which no more than one of six patients experienced DLTs during cycle 1 (first 28 days of treatment). To meet the minimum safety requirement for the determination of the MTD, patients must have completed the first 3 weeks of therapy or have experienced a DLT. Patients who did not meet either of these criteria were replaced. Afatinib was administered continuously at a starting oral dose of 20 mg/day, beginning on day 2 of cycle 1. Afatinib dose escalation was carried out in successive cohorts from 20 mg to 40 mg to 50 mg. An intermediate dose cohort of afatinib 30 mg was allowed if a DLT was experienced at the 40 mg dose. Weekly paclitaxel
80 mg/m2 was administered intravenously on days 1, 8 and 15 of a 4-week cycle. If two or more DLTs due to paclitaxel treatment were observed in the first cohort, a reduction in paclitaxel from 80 mg/m2 to 70 mg/m2 was permitted and the reduced dose was to be used for all other cohorts. Combination treatment was continued for up to 6 cycles. After completion of paclitaxel, patients benefiting from and tolerating treatment were eligible to continue treatment beyond this period with afatinib monotherapy until disease progression, occurrence of an AE, or withdrawal of consent. 2.3. Safety assessments AEs were assessed according to CTCAE version 3.0. DLTs were defined as: grade 4 uncomplicated neutropenia (fever < 38.3 °C) for >7 days, neutropenia with fever > 38.5 °C, platelets < 25 109/L or grade 3 thrombocytopenia associated with bleeding requiring transfusion, grade P2 decrease in left ventricular function, uncontrolled hypertension despite multiple therapies, grade P2 worsening of renal function, grade >2 diarrhoea despite anti-diarrhoeal medication, persistent grade >2 diarrhoea for P7 days despite supportive care, grade >2 nausea and/or vomiting despite antiemetic treatment and grade >1 vomiting for P7 days despite antiemetic treatment. All other drug-related non-haematological toxicities of grade P3, except incompletely treated nausea, vomiting or diarrhoea, were also considered to be DLTs. 2.4. Efficacy outcomes Tumour imaging using computerised tomography was performed at screening and every 8 weeks after
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
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the start of afatinib treatment. Tumour response was assessed using Response Evaluation Criteria in Solid Tumours version 1.0, and patients were assigned to one of the following categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease, or not evaluable. Best overall response was defined as the best tumour response recorded at any time from the start of treatment to disease progression or recurrence. In patients with an objective response (CR or PR), this status was confirmed by a repeat assessment performed at least 4 weeks later. 2.5. Pharmacokinetic sampling and analysis Pharmacokinetic profiles were obtained in cycle 1 on days 1 and 15. Samples were taken pre- and post-paclitaxel infusion and/or afatinib administration (planned times pre-dose, 1, 2, 2.5, 3, 4, 6, 8 and 24 h) to allow comparison of paclitaxel in the absence and presence of afatinib, dosing of which began on day 2. Plasma concentrations of afatinib and paclitaxel were analysed using validated high-performance liquid chromatography tandem mass spectrometry assays. Pharmacokinetic evaluations were conducted using WinNonlinÒ version 5.2 and SASÒ version 9.2 (or higher) software. 2.6. Statistical analyses Safety and efficacy analyses were conducted in the treated set (all patients receiving at least one dose of afatinib). Statistical analyses, including determination of MTD, were descriptive. 3. Results 3.1. Patients and treatment Between June 2007 and April 2008, 16 patients received the combination of afatinib and paclitaxel. Baseline patient demographics and tumour characteristics are summarised in Table 1. Fifteen patients (94%) completed P1 cycle of combination treatment with afatinib and paclitaxel. Nine patients (56%) completed P6 cycles of treatment; of these, five patients continued treatment in the extension phase of the trial with afatinib monotherapy. Four patients (25%) received >12 cycles of therapy. Median time on treatment was 25 weeks (range, 3–165 weeks). Dose reductions of afatinib were implemented in four patients, including one patient treated with afatinib 40 mg plus paclitaxel 80 mg/m2 and three patients receiving afatinib 50 mg plus paclitaxel 80 mg/m2; in three of these patients, dose reduction occurred after the DLT-defining period.
Table 1 Baseline patient demographics and tumour characteristics. Characteristic Gender, n (%) Male Female Age, years Median (range) ECOG PS, n (%) 0 1 Time from initial diagnosis, years Median (range) Primary tumour, n (%) Non-small cell lung cancera Biliary treeb Oesophagealc Head and neckd Ovaryb Pancreasb Prostateb Stomachb Previous anticancer therapy, n (%) Surgery Chemotherapy Immunotherapy Hormone therapy Radiotherapy Other (including biological therapy)
N = 16 6 (38) 10 (63) 57 (38–72) 5 (31) 11 (69) 1.91 (0.7–9.3) 9 1 1 1 1 1 1 1
(56) (6) (6) (6) (6) (6) (6) (6)
9 (56) 13 (81) 2 (13) 1 (6) 6 (38) 1 (6)
ECOG PS, Eastern Cooperative Oncology Group performance status. a Histological subtypes included adenocarcinoma (n = 6) and not otherwise specified (n = 3). b Adenocarcinoma. c Histological subtype not specified. d Adenoid cystic carcinoma of the tongue.
3.2. Safety Fifteen patients were evaluable for determination of the MTD; one patient in the 40 mg cohort, who did not receive continuous treatment during the first 3 weeks of study participation, was excluded from analysis. No DLT was observed with 20 mg or 40 mg afatinib in combination with paclitaxel 80 mg/m2. DLTs were observed in two patients treated with afatinib 50 mg and paclitaxel 80 mg/m2 during cycle 1: grade 3 fatigue occurred in a 38-year-old female on day 4 of treatment but resolved with a 2-day afatinib dose interruption, and grade 3 mucositis was observed in a 63-year-old female on day 20 of treatment. This DLT required hospitalisation, but with supportive therapy (hydration and analgesia) resolved after a 9-day afatinib dose interruption. Both patients continued combination therapy when re-treated with afatinib at a reduced dose (40 mg) without recurrence of intolerable AEs. Following the occurrence of these DLTs, the next lower dose cohort of 40 mg afatinib with paclitaxel 80 mg/m2 was expanded to six patients, with no DLTs observed. The MTD of combination therapy was 40 mg afatinib and 80 mg/m2 paclitaxel.
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Treatment-related AEs were observed in all 16 patients (Table 2); the most common were diarrhoea (n = 15; 94%), fatigue (n = 13; 81%) and rash/acne (n = 13; 81%). The majority of treatment-related AEs were grade 1/2, with four patients (25%) experiencing grade 3 AEs. There were no grade P4 treatmentrelated AEs and none leading to death. Fatigue was the most frequently documented grade 3 treatment-related AE (n = 2 [13%]). Neutropenia, judged as unrelated to afatinib by the investigator, occurred in two patients (13%; grade 1); no febrile neutropenia was observed. One (6%) grade 4 AE was observed (pulmonary embolism unrelated to study treatment). 3.3. Pharmacokinetics Afatinib pharmacokinetic parameters were estimated for all dose levels in the presence of paclitaxel on day 15 (Table 3; Fig. S1A and S1B). Afatinib was rapidly absorbed and reached peak plasma concentration 2–6 h after administration. Afatinib exposure increased with increasing doses (Fig. S1C); there was no indication of saturation of elimination mechanisms at the doses studied. Paclitaxel pharmacokinetic parameters were estimated in the absence (day 1) and presence (day 15) of different afatinib doses (Table 3; Fig. S2A and S2B). There was no evidence that the Cmax and AUC0–24 of paclitaxel were affected by the presence or absence of concurrent afatinib administration or by different administered doses of afatinib (Fig. S2C). 3.4. Antitumour activity Thirteen treated patients were eligible for response assessment. Of these, seven patients (44%) achieved clinical benefit (PR or SD for P6 months). Best changes from baseline in tumour measurements are shown in Fig. 2A. Of five patients (31%) who experienced a confirmed PR (Fig. 2A), three had NSCLC and one patient each had cholangiocarcinoma and oesophageal cancer; two of these patients received previous treatment with docetaxel. Fig. 2B depicts the radiological PR in a patient with advanced oesophageal adenocarcinoma following two treatment cycles of afatinib 40 mg and paclitaxel 80 mg/m2. Fig. 2C illustrates radiological improvement in a female patient with wild-type EGFR lung adenocarcinoma, who experienced sustained clinical and radiological improvement in non-measurable disease persisting beyond 3 years. A PR was also observed in another patient with NSCLC harbouring a known activating EGFR mutation. 4. Discussion This phase I study defined the MTD of once-daily oral afatinib as 40 mg in combination with 80 mg/m2
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paclitaxel administered on days 1, 8 and 15 of a 4-week cycle. This combination had a manageable AE profile, with diarrhoea, rash and fatigue as the most common AEs, almost all of which were grade 1/2. Incidences of neutropenia were low, consistent with previously reported data for paclitaxel alone in patients with metastatic breast cancer [23] and NSCLC [24]; no febrile neutropenia or leucopaenia was observed. In a previous phase I study of afatinib (days 2–21) plus docetaxel 75 mg/m2 (day 1) in patients with advanced cancers, the MTD of afatinib was 20 mg/day [20]. Due to a higher incidence of grade 3/4 neutropenia and febrile neutropenia observed with the combination compared with docetaxel alone and the lack of antitumour activity, this dose was not suitable as a recommended phase II dose. Another phase I study of pulsatile administration of afatinib (days 2–4) in combination with docetaxel 75 mg/m2 (day 1) every 21 days demonstrated a manageable safety profile and clinical activity, and a recommended phase II dose of afatinib 90 mg/day was achieved [22]. The difference in tolerability between three-weekly docetaxel and weekly paclitaxel may account for the divergence of afatinib MTDs in combination with these various taxane regimens [25]. In the current study, almost all patients (94%) experienced combination treatment-related diarrhoea; this incidence is higher than that reported in phase I studies of afatinib monotherapy (64–77%) [7,26]. However, AEs relating to combination treatment at the MTD of afatinib (40 mg/day) were mild to moderate (grade 62) and manageable with supportive measures. Furthermore, a number of patients continued either combination treatment or afatinib monotherapy for a prolonged period. Pharmacokinetic assessments showed no relevant interactions between afatinib and paclitaxel, and parameters for afatinib at 40 mg/day in this study were similar to those previously reported for single-agent afatinib [7]. This is despite the fact that both agents are P-glycoprotein substrates [15,27], which may have implications for future studies elucidating mechanisms of resistance to this combination. Other clinical studies have indicated a lack of pharmacokinetic interactions between afatinib and other microtubule-targeting agents, including docetaxel [22] and vinorelbine [28]. The combination of afatinib and paclitaxel demonstrated antitumour activity, with 44% of evaluable patients achieving confirmed radiological PR or SD for P6 months. The mechanism by which afatinib and paclitaxel may exert synergistic effects has not yet been elucidated. In phase III studies in unselected patients with NSCLC, EGFR inhibition combined with chemotherapy did not improve efficacy over chemotherapy alone [29–31]. In contrast, recent phase II/III studies of erlotinib or lapatinib combined with paclitaxel-based regimens support the synergistic activity of such combinations in patients with NSCLC and breast cancer
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
6
Paclitaxel 80 mg/m2 plus afatinib 20 mg
Paclitaxel 80 mg/m2 plus afatinib 40 mg
n=3
n=7
Paclitaxel 80 mg/m2 plus afatinib 50 mg n=6
Paclitaxel 80 mg/m2 plus afatinib 20, 40, 50 mg N = 16
AEs, n (%)
All
Grade 3a
All AEs
Grade 3a
All AEs
Grade 3a
All AEs
Grade 3a
Any AE Diarrhoea Fatigue Rash/acneb Inflammation of mucosal membranesc Decreased appetite Dry skin Alopecia Nail disorderd Nausea Neuropathye Vomiting Dysgeusia Oropharyngeal pain Palmar-plantar erythrodysesthesia ALT increased Constipation Dry mouth Dyspepsia Dyspnoea Folliculitis Musculoskeletal and connective tissue disorders Pruritus Psychiatric disorders
3 2 2 1 1 2 2 3 1 1 1 1 1 1 1 0 1 0 1 1 0 1 0 1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
7 7 6 7 5 5 4 2 4 4 2 2 2 2 0 2 1 2 1 1 1 1 1 1
2 0 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
6 6 5 5 5 4 2 1 1 1 2 1 0 0 2 0 0 0 0 0 1 0 1 0
2 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
16 (100) 15 (94) 13 (81) 13 (81) 11 (69) 11 (69) 8 (50) 6 (38) 6 (38) 6 (38) 5 (31) 4 (25) 3 (19) 3 (19) 3 (19) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13) 2 (13)
4 0 2 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
(25) (0) (13) (6) (6) (0) (0) (0) (0) (6) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)
AE, adverse event; ALT, alanine aminotransferase. a There were no grade 4 treatment-related AEs. b Pre-specified grouped term includes reported preferred terms of acne, blister, dermatitis acneiform, erythema, folliculitis, rash, rash maculo-papular, rash papular and skin disorder. c Pre-specified grouped term includes reported preferred terms of dry mouth, mucosal inflammation, mucosal ulceration, stomatitis and tongue ulceration. d Including preferred terms of nail disorder, nail infection, nail pitting, oncholysis and paronychia. e Including preferred terms of neuropathy peripheral and peripheral sensory neuropathy.
A. Suder et al. / European Journal of Cancer xxx (2015) xxx–xxx
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
Table 2 Treatment-related AEs in P10% of patients during treatment with combined afatinib and paclitaxel.
Paclitaxel 80 mg/m2 plus afatinib 20 mg Day 1 gMean
Day 15 gCV, %
gMean
Paclitaxel 80 mg/m2 plus afatinib 40 mg Day 1
gCV, %
gMean
Day 15 gCV, %
gMean
Paclitaxel 80 mg/m2 plus afatinib 50 mg Day 1
gCV, %
gMean
Day 15 gCV, %
gMean
Paclitaxel 80 mg/m2 plus afatinib 20, 40, 50 mga Day 1
gCV, %
gMean
Day 15 gCV, %
gMean
gCV, %
b
Paclitaxel AUC0–24, ngh/ml Cmax, ng/ml Afatinibc AUCs,ss, ngh/ml Cmax,ss, ng/ml
n=3 1970 n=2 428
52.2 387 – –
n=3 3560 n=3 1880 n=3 250 n=3 12.3
12.6 42.2
n=6 3730 n=6 2090
28.5 37.7 –
9.63 – 15.5
n=5 3170 n=6 1590 n=6 813 n=6 46.0
67.7 82.2
58.4 – 61.9
n=4 3260 n=5 1480
30.1 63.1
n=4 3950 n=5 2120 n=4 939 n=5 63.5
51.8 68.2
n = 15 3130 n = 15 1510
39.2 94.0
n = 12 3510 n = 14 1830
49.0 65.7
– 60.0 – 74.6
AUC0–24, area under the concentration–time curve of the analyte in plasma over 0 to 24 h; AUCs,ss, area under the concentration–time curve of the analyte in plasma at steady state; Cmax, maximum measured concentration of the analyte in plasma; Cmax,ss, Cmax at steady state; gCV, geometric coefficient of variation; gMean, geometric mean. a Pooled data from all dose cohorts, including two patients who received paclitaxel 80 mg/m2 without afatinib. b Paclitaxel pharmacokinetic parameters were determined in the absence (day 1) and presence (day 15) of different afatinib doses. c Afatinib steady state pharmacokinetic parameters were determined after administration of different doses of afatinib in the presence of paclitaxel (day 15 only).
A. Suder et al. / European Journal of Cancer xxx (2015) xxx–xxx 7
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
Table 3 Summary of pharmacokinetic parameters of paclitaxel before (day 1) and after (day 15) administrations of afatinib.
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A. Suder et al. / European Journal of Cancer xxx (2015) xxx–xxx
Fig. 2. Antitumour activity. (A) Waterfall plot for patients with measurable disease displaying best change in tumour measurement from baseline (%)a. (B) Computed tomography images of a male patient with oesophageal adenocarcinoma demonstrating a partial response to afatinib 40 mg and paclitaxel 80 mg/m2 after two 28-day treatment cycles. (C) A female patient with non-small cell lung cancer (NSCLC) who showed sustained radiological and clinical benefit for >3 years, continuing to receive single-agent afatinib following completion of combination treatment. EGFR, epidermal growth factor receptor; GI, gastrointestinal. aBest change from baseline is the difference between the sum of the longest diameters of target lesions at baseline and at best response. bNSCLC patient with stable disease. cNSCLC patient with activating EGFR mutation. dPancreas (n = 1), head and neck squamous cell carcinoma (n = 1), prostate (n = 1), biliary tree (n = 1).
selected for biomarker expression [32,33]. Although patients included in this dose-escalation trial were not selected for EGFR/HER2 overexpression or amplification, one patient with NSCLC harbouring a known activating EGFR mutation achieved radiological PR; this finding is consistent with documented activity of afatinib in EGFR-mutated lung cancer [6,7]. The encouraging tolerability findings and antitumour activity of the combination reported herein provided the basis for further clinical studies in patients with HER2-positive breast cancer [34] and EGFR TKI-refractory NSCLC [35]. In the recently completed LUX-Lung 5 phase III trial, afatinib 40 mg plus weekly
paclitaxel significantly improved PFS (median 5.6 versus 2.8 months; hazard ratio 0.60 [95% CI 0.43–0.85; p = 0.003]) and response rate (32.1% versus 13.2%; p = 0.005) versus investigator’s choice of single-agent chemotherapy, with a manageable safety profile, in patients with EGFR TKI-refractory NSCLC following progression on afatinib monotherapy [35]. These results suggest that afatinib combined with weekly paclitaxel is an effective therapeutic option for advanced cancers driven by ErbB family signalling, even after prior treatment with reversible EGFR TKIs. In conclusion, the MTD of oral afatinib was defined as 40 mg/day in combination with paclitaxel 80 mg/m2
Please cite this article in press as: Suder A. et al., A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.07.041
A. Suder et al. / European Journal of Cancer xxx (2015) xxx–xxx
administered on days 1, 8 and 15 every four weeks, with a manageable AE profile. No pharmacokinetic interactions between the two agents were observed. The combination was clinically active, with a response rate of 31%, and 50% of patients remained on treatment for at least 6 months. Funding This study was supported financially by Boehringer Ingelheim, as well as by the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility), and to The Institute of Cancer Research and Royal Marsden Hospital NHS Foundation Trust. King’s College London and the Royal Marsden hold Experimental Cancer Medicine Centre grants. RK is supported by the NIHR/Wellcome University College London (UCL) Hospitals Clinical Research Facility, the UCL Hospitals Biomedical Research Centre and the UCL Experimental Cancer Medicine Centre. Conflict of interest statement M. Uttenreuther-Fischer, K. Pemberton, K. Pelling and D. Schnell are employees of Boehringer Ingelheim. J. de Bono has reported consultancy roles for Boehringer Ingelheim (unpaid) and AstraZeneca. J. Spicer has reported consultancy roles for Boehringer Ingelheim. All remaining authors have declared no conflicts of interest. Acknowledgements Boehringer Ingelheim provided financial support for this study and managed the clinical trial database. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Aurora O’Brate of Ogilvy Healthworld, and Katie McClendon, of GeoMed, an Ashfield company, part of UDG Healthcare plc. The study investigators and the Boehringer Ingelheim study team were responsible for the study design and the collection, analysis and interpretation of the data. All authors had full access to the study data, contributed to the development of the manuscript, were fully responsible for all content and editorial decisions, and made the final decision to submit the manuscript for publication. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.07.041.
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