RESEARCH ARTICLE For reprint orders, please contact: [email protected]

A Phase I dose-escalation study of afatinib combined with nintedanib in patients with advanced solid tumors Michael S Gordon*,1, Gregory M Springett2, Yungpo Bernard Su3, Mahmoud Ould-Kaci4, Sven Wind5, Yihua Zhao6 & Patricia M LoRusso7,8

ABSTRACT Aims: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. Materials & methods: Patients received afatinib 10–20 mg daily plus nintedanib 150–200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. Results: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. Conclusion: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation. Targeting the multiple signaling pathways that contribute to the growth and development of solid tumors is a viable treatment option for patients with solid tumors [1] . However, single-agent strategies that are directed against targets such as the EGFR (ErbB1) or the VEGFRs appear to have only modest long-term effects on tumor growth [2] . Combining different targeted anticancer agents that inhibit multiple inter-linked signaling pathways may enhance antitumor activity, overcome resistance and, ultimately, improve therapeutic outcomes [2] . Afatinib and nintedanib are novel oral targeted anticancer agents. Afatinib is an ErbB family blocker that irreversibly blocks signaling via ErbB1, HER2 (ErbB2), ErbB4 and all relevant ErbB family dimers, as well as inhibiting transphosphorylation of ErbB3 [3,4] . Nintedanib is an oral triple angiokinase inhibitor that targets the three receptor classes – VEGFR1, 2 and 3, PDGFR-α and -β and FGFR1, 2 and 3, all of which are involved in angiogenesis [5] . Nintedanib is approved in the EU in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumor histology after first-line chemotherapy at a dose of 200 mg twice daily [6] , and in the USA for the treatment of idiopathic pulmonary fibrosis at a dose of 150 mg twice daily [7] . Afatinib monotherapy (40−50 mg once per day [q.d.]) has demonstrated promising antitumor activity in patients with non-small-cell lung cancer (NSCLC), with a manageable safety

KEYWORDS 

• afatinib • BIBF 1120 • BIBW 2992 • ErbB family blocker • nintedanib • pharmacokinetics • Phase I • triple angiokinase inhibitor

Pinnacle Oncology Hematology, 9055 E Del Camino, Suite 100, Scottsdale, AZ 85258, USA Experimental Therapeutics Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA 3 Nebraska Cancer Specialists, 8303 Dodge Street, Suite 250, Omaha, NE 68114, USA 4 Boehringer Ingelheim, 14 rue Jean Antoine de Baif, 75013 Paris, France 5 Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany 6 Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877, USA 7 Wayne State University/Karmanos Cancer Center, Detroit, MI 48201, USA 8 Yale Cancer Center, 333 Cedar Street, WWW211, PO Box 208028, New Haven, CT 06520-8028, USA *Author for correspondence: Tel.: +1 480 860 5000; Fax: +1 480 314 0033; [email protected] 1 2

10.2217/FON.15.50 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(10), 1479–1491

part of

ISSN 1479-6694

1479

Research Article  Gordon, Springett, Su et al. profile [8,9] . More recently, in two large Phase III randomized trials of previously untreated patients with advanced EGFR mutation-positive NSCLC (LUX-Lung 3 and LUX-Lung 6), afatinib (40 mg q.d.) significantly prolonged progression-free survival compared with chemotherapy, delayed the worsening of disease-related symptoms and improved quality of life, and demonstrated survival benefit in patients with lung adenocarcinoma harboring the EGFR Del19 mutation [10–14] . Afatinib is approved for treatment of patients with EGFR mutation-positive NSCLC in the USA [15] , the EU  [16] , Japan [17] and other countries and is in clinical development as a therapy for several other ErbB-driven cancers. Afatinib undergoes minimal metabolism, with negligible oxidative metabolism via CYP450, and its excretion is mainly via feces [18,19] . Typical side effects of afatinib treatment include gastrointestinal and skin-related adverse reactions [15,16] . For patients with advanced NSCLC progressing after first-line chemotherapy, treatment with nintedanib plus docetaxel significantly improved progression-free survival versus placebo plus docetaxel (primary end point) in the overall population of the Phase III LUME-Lung 1 trial, as well as in prespecified populations of patients with adenocarcinoma histology, and with adenocarcinoma histology and poor prognosis (defined as progression within 9 months of starting prior first-line therapy) [20] . Nintedanib metabolism is mainly via methyl ester cleavage and subsequent glucuronidation [21] , with minimal metabolism via CYP450; excretion of nintedanib and its metabolites is mainly via feces  [5] . Adverse events (AEs) observed with nintedanib plus docetaxel treatment include diarrhea, reversible increases in alanine aminotransferase and aspartate aminotransferase, nausea, decreased appetite and vomiting [20] . At the time this study was designed, the concept of attacking tumors from two different pathways was relatively new. The combination of afatinib and nintedanib potentially removes tumor proliferation signals and prevents new blood vessel formation and this combined approach was expected to have if not a synergistic effect, at least an additive effect on tumor control. Since then, preclinical data in colorectal xenografts have demonstrated synergistic growth inhibition with use of nintedanib and afatinib in combination, compared with either agent used alone [22] . The results of two

1480

Future Oncol. (2015) 11(10)

Phase II studies of sequential afatinib and nintedanib in patients with hormone-refractory prostate cancer [23] and advanced colorectal cancer  [24] showed that the combination of these agents was not associated with unexpected drug-related toxicities and, as expected, clinically manageable diarrhea, vomiting and nausea were prominent among the frequently occurring AEs; however, the regimen lacked antitumor activity  [23] . This Phase I, dose-escalation study was conducted to establish the safety and maximum tolerated dose (MTD) of afatinib given in combination with nintedanib in patients with advanced solid tumors. Secondary objectives included a preliminary evaluation of antitumor activity, and characterization of the p ­ harmacokinetic profile of the combination. Materials & methods ●●Study design

This was a Phase I, open-label, dose-escalation study conducted in four centers in the USA. Patients were assigned to cohorts to receive escalating doses of afatinib and nintedanib. Planned enrollment was three to six patients per cohort. This study was carried out in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice, US regulatory requirements and relevant local guidelines. Written informed consent was obtained prior to each patient’s participation. ●●Study population

Male or female patients, aged ≥18 years, with confirmed advanced nonresectable and/or metastatic solid tumors which had progressed on conventional therapies or who were not amenable to established treatments, were eligible. All patients were required to have an ECOG performance score of 0−2, life expectancy of ≥3 months and to have recovered from previous surgery or any drug-related AEs to Grade 0 or 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Patients recruited at the MTD were required to have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 [25] ; patients enrolled in the doseescalation phase were not required to have measurable disease. Additional eligibility criteria included cardiac left ventricular resting

future science group

Phase I study of afatinib plus nintedanib in advanced solid tumors  ejection fraction >50%, adequate bone marrow (absolute neutrophil count ≥1500 cells/mm 3 and platelet count ≥100,000 /mm 3 ), liver (bilirubin ≤1.5 mg/dl, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ≤2.5 × upper limit of normal) and kidney (serum creatinine ≤1.5 mg/dl) function. Higher ALT levels in patients with known liver metastases were not allowed as the trial combined two investigational agents, thereby meriting additional caution. Patients were excluded if they had: active infectious disease; gastrointestinal disorders that could have interfered with the absorption of the study drug, or chronic diarrhea; untreated or symptomatic brain metastases; previous chemo, immuno, radio or hormone therapy, or an EGFR/HER2-inhibiting drug within 4 weeks of study initiation (2 weeks for trastuzumab). ●●Dose selection, study treatment & dose

escalation

Previous dose-finding and toxicology studies of the combination conducted in rats showed in-life effects and clinical pathology changes at a dose of afatinib/nintedanib 5/32 mg/kg were mild in severity and included diarrhea, mild-to-moderate reductions of red blood cell counts, changes in the gastrointestinal tract and histopathological changes in the intestinal tract, hematopoietic system, thymus, spleen, axillary lymph node, Peyer’s patches, kidney, incisors, muzzle, knee, adrenal glands, ovaries, liver and pancreas (data on file). A daily dose of afatinib/nintedanib 10/100 mg/kg (reduced to 7.5/100 mg/kg on days 11–12) was associated with premature deaths and severe effects on the gastrointestinal tract (data on file). In the current study, patients were treated with oral afatinib q.d. plus oral nintedanib twice daily (b.i.d.) taken continuously. Both afatinib and nintedanib were taken together in the morning, 1 h before food. The second dose of nintedanib was taken in the evening, to ensure a dose interval of 12 h. The starting dose schedule was 10 mg q.d. afatinib and 150 mg b.i.d. nintedanib for 28 days in a 28-day treatment cycle (cohort 1); this was selected based on toxicity and incidence of DLT observed with each compound in Phase I trials [26,27] . Cohort 2 received afatinib 10 mg q.d., nintedanib 200 mg b.i.d., and cohort 3 received afatinib 20 mg q.d., nintedanib 200 mg b.i.d. with provision for dose

future science group

Research Article

escalation to a maximum of 40 mg q.d. afatinib plus 250 mg b.i.d. nintedanib. Study treatment was continued for as long as the combination was tolerated (absence of dose-limiting toxicity [DLT]) or until disease progression. Initially, three patients were treated per dose cohort; if one patient of the cohort had a DLT during the first 28-day treatment cycle, three additional patients were treated at that dose level, to provide a minimum of six evaluable patients. If no patients of three or one patient of six had a DLT during the first 28-day treatment cycle, the dose was escalated to the next level for the next cohort. If two or more of six patients had a DLT during the first 28-day treatment cycle, there was no further dose escalation. The MTD was defined as the highest dose at which no more than one of six patients had a DLT during the first 28-day treatment cycle. Once the MTD was established, a further six patients with measurable disease were treated at the MTD level. A DLT was defined as any of the following events occurring during the first 28-day cycle: grade 4 hematologic AE; grade 3 or 4 non­hematologic AE; grade ≥2 left ventricular cardiac function; grade ≥2 worsening of renal function; grade ≥2 diarrhea, or nausea or vomiting for ≥7 days despite supportive care or treatment; grade ≥3 hypertension despite supportive care or intervention; grade ≥2 AST and/or ALT in conjunction with increased plasma bilirubin; other AEs of grade ≥2 leading to interruption of treatment for 14 consecutive days or longer. During the first cycle of treatment, diarrhea, nausea and vomiting that reached DLT were to be treated as such. As diarrhea, nausea and vomiting were expected adverse events for both afatinib and nintedanib, recommendations were included in the study protocol for dose interruption and reduction to manage these events during subsequent cycles. In addition, treatment of diarrhea with loperamide was recommended. Loperamide was to be initiated as clinically indicated for all patients with diarrhea of grade ≥2; the recommended dose and schedule was 4 mg at first onset followed by 2 mg every 2–4 h until the patient was diarrhea-free for 12 h. For diarrhea of grade ≥2 that persisted for ≥7 consecutive days despite optimal antidiarrheal support, both trial medications (afatinib and nintedanib) were to be interrupted until recovery to grade ≤1. Vomiting was treated with 5-HT3 receptor antagonists and corticosteroids.

www.futuremedicine.com

1481

Research Article  Gordon, Springett, Su et al. ●●Study end points

Results

The primary end point was the safety of the afatinib and nintedanib combination, assessed by the occurrence of DLTs during the first 28-day treatment cycle. The safety profile was characterized by the incidence and intensity of all AEs. Secondary end points included pharmacokinetic parameters of afatinib and nintedanib and evaluation of antitumor activity.

●●Patient characteristics

●●Safety & tolerability assessments

Patients were monitored for AEs during and after treatment. The NCI CTCAE version 3.0 was used to grade AEs. Laboratory examinations, 12-lead electrocardiogram and assessment of left ventricular cardiac function, by echocardiography or multigated acquisition scans, were performed at screening and repeated at various time points for the duration of the study. ●●Pharmacokinetic sampling & data analysis

For determination of the pharmacokinetic profiles of afatinib and nintedanib, 5 ml blood samples were taken before and at 1, 2, 3, 4, 6, 8 and 24 h after the start of study treatment, on Days 1 and 15. Blood samples were also collected on Days 8, 22 and 28, before afatinib and nintedanib administration, for assessment of trough plasma concentrations of both drugs. Afatinib and nintedanib plasma concentrations were determined by validated high-performance liquid chromatography tandem mass spectrometry at Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. Standard noncompartmental methods were applied to calculate pharmacokinetic parameters using WinNonlin (version 5.2, Pharsight) [28] .

Between January 2007 and August 2009, 47 patients were enrolled. Of these, 19 failed to meet the study screening criteria. A total of 28 patients received the combination of afatinib and nintedanib. In the three dose cohorts, dosing was as follows: cohort 1, afatinib 10 mg q.d. plus nintedanib 150 mg b.i.d. (n = 11); cohort 2, afatinib 10 mg q.d. plus nintedanib 200 mg b.i.d. (n = 13); and cohort 3, afatinib 20 mg q.d. plus nintedanib 200 mg b.i.d. (n = 4). The inclusion of 11 patients in Cohort 1 was the result of the discontinuation of five of the six patients initially enrolled (due to non-DLT AEs before the completion of cycle 1) and their subsequent replacement following discussion between the Sponsor and the Investigator as per protocol. Non-DLT AEs resulting in patients enrolled in cohort 1 discontinuing during cycle 1 were: reversible posterior leukoencephalopathy syndrome (one patient), severe fatigue (one patient), dysphagia, lymphadenopathy, nausea and vomiting (one patient), ALT/AST increased (one patient), and anorexia, nausea, vomiting, dehydration and fatigue (one patient). Patient baseline demographics and characteristics are shown in Table 1. The majority of participants were female (71.4%). The median age across all three dose cohorts was 56 years (range: 36–76). Most patients had an ECOG performance status score of ≤1 (92.9%). Overall, the most common cancer types were colorectal, breast and kidney/ureter (≥3 patients for each). A total of 75% of patients were heavily pretreated (≥3 lines of prior chemotherapy) and 50.0% had prior radiation therapy.

●●Efficacy assessments

Objective tumor response was assessed according to RECIST version 1.0 at every other treatment cycle after the start of afatinib and nintedanib treatment. Response was assessed in patients who had completed at least two 28-day cycles of treatment, and at the end of the study. Tumor assessments of target lesions by x-ray, computed tomography or MRI were performed at screening, and at subsequent tumor assessment time points. ●●Statistical analyses

All analyses in this study were descriptive and exploratory. All patients who received at least one dose of either afatinib or nintedanib were included in the safety analysis.

1482

Future Oncol. (2015) 11(10)

●●Treatment duration & patient disposition

Patients were treated for a median of 51 days (range: 1–537 days), with most receiving one or two cycles of afatinib and nintedanib combination therapy. The mean treatment duration was 62 days in cohort 1, 100 days in cohort 2 and 34 days in cohort 3. Durations of therapy for individual patients are shown in Figure 1. Overall, 13 patients (46.4%) discontinued combination treatment due to progressive disease. An additional four patients (14.3%) discontinued combination treatment due to DLTs, which are discussed in detail below. Eight patients (28.6%) discontinued due to other AEs, while the reasons for discontinuation of the

future science group

Phase I study of afatinib plus nintedanib in advanced solid tumors 

Research Article

Table 1. Patient demographics and disease characteristics of treated population at baseline.† Characteristic

Cohort 1: afatinib 10 mg q.d. + nintedanib 150 mg b.i.d. (n = 11)

Cohort 2: afatinib 10 mg q.d. + nintedanib 200 mg b.i.d. (n = 13)

Cohort 3: afatinib 20 mg q.d. + nintedanib 200 mg b.i.d. (n = 4)

All patients (n = 28)

Gender (%)‡: – Female/male Age, median (range); years ECOG performance status, n (%): –0 –1 –2 Cancer type, n (%): – Colorectal – Breast – Kidney/ureter – Ovary/fallopian tube – Other§ Prior anticancer therapy, n (%)¶: – Chemotherapy – Radiation therapy Number of prior chemotherapies, n (%): –0 – 1−2 – ≥3

  81.8/18.2 56 (40−76)

  61.5/38.5 55 (36−76)

  75.0/25.0 58 (43−67)

  71.4/28.6 56 (36−76)

4 (36.4) 5 (45.5) 2 (18.2)

4 (30.8) 9 (69.2) 0

1 (25.0) 3 (75.0) 0

9 (32.1) 17 (60.7) 2 (7.1)

1 (9.1) 3 (27.3) 2 (18.2) 0 5 (45.5)

4 (30.8) 1 (7.7) 1 (7.7) 2 (15.4) 5 (38.5)

0 0 0 0 (0) 4 (100.0)

5 (17.9) 4 (14.3) 3 (10.7) 2 (7.1) 14 (50.0)

9 (81.8) 6 (54.5)

13 (100) 7 (53.8)

4 (100) 1 (25.0)

26 (92.9) 14 (50.0)

2 (18.2) 1 (9.1) 8 (72.7)

0 2 (15.4) 11 (84.6)

0 2 (50.0) 2 (50.0)

2 (7.1) 5 (17.9) 21 (75.0)

Percentages may not total to 100% due to rounding. All patients were Caucasian, with the exception of one in cohort 2, who was Asian. § Includes one or two patients each with cancer of the cervix/vagina/vulva, lung (non-small-cell), pancreas, skin including melanoma, trachea, thyroid/parathyroid, gynecologic cancers or with primary site unknown. ¶ Patients could have received both chemotherapy and radiotherapy. b.i.d.: Twice daily; ECOG: Eastern Cooperative Oncology Group; q.d.: Once daily. † ‡

other three patients were: withdrawal of c­onsent; other reasons and noncompliance (Table 2) .l ●●DLTs & MTD

Four patients had DLTs during the first 28-day treatment cycle that resulted in treatment being permanently discontinued (Table 2 & Figure 1) . DLTs (highest CTC grade), were: cohort 1, one patient with increased ALT (grade 3; 862 U/l) starting on day 8 and lasting 42 days and associated with a grade 2 increase of total bilirubin (2.40 mg/dl; normal range: 0.2–1.3 mg/gl) but no increase in prothrombin time, baseline ALT and total bilirubin values were 32 U/L and 0.60 mg/dl, respectively; cohort 2, one patient with diarrhea (grade 3); cohort 3, one patient with dehydration (grade 3), resulting from grade 2 diarrhea lasting from day 6 to 15, the patient was treated with intravenous fluids and antidiarrheic agents to control the cause of the dehydration; and one patient with diarrhea (grade 3) with grade 3 elevated ALT (408 U/l) and AST (388 U/l) lasting 2 days, without an associated increase in total bilirubin level or prothrombin

future science group

time. All patients with DLTs recovered fully following appropriate supportive care. As two patients in cohort 3 had DLTs, the combination of afatinib 10 mg q.d. plus nintedanib 200 mg b.i.d. (cohort 2) was expanded and seven additional patients were recruited. No further DLTs occurred and afatinib 10 mg q.d. plus nintedanib 200 mg b.i.d. was determined to be the MTD. ●●Safety & tolerability

All patients reported AEs. Altogether, 50% of AEs were ≥grade 3, including DLTs and events not meeting DLT criteria. There were no grade 4 events. In total, 25 patients (89.3%) had treatmentrelated AEs. Treatment-related AEs were more frequent in cohort 3 (100%) and cohort 2 (92.3%) than cohort 1 (81.8%). Table 3 summarizes the incidence of the most commonly occurring treatment-related AEs by treatment group. Diarrhea (78.6%), nausea (71.4%), anorexia (50.0%), vomiting (42.9%) and fatigue (42.9%) were the most frequently reported AEs. Fourteen

www.futuremedicine.com

1483

Research Article  Gordon, Springett, Su et al.

Afatinib

Nintedanib

Days

Tumor

0

100

200

300

400

500

600

Lung (NSCLC) Breast

DLT

Skin including melanoma Breast Endometrial 10 mg q.d.

150 mg b.i.d.

Breast Colorectal Kidney and ureter Skin including melanoma Kidney and ureter Thyroid Pancreas Colorectal Colorectal Thyroid Ovary PR

Kidney and ureter 10 mg q.d.

200 mg b.i.d.

Cervix DLT

Colorectal Ovary CUP Tracheal Colorectal Breast Ovarian 20 mg q.d.

200 mg b.i.d.

Pancreas Pancreas Lung (NSCLC)

DLT DLT

Figure 1. Duration of therapy for all patients. Data are duration of treatment for each individual patient. DLTs occurred during the patient’s first 28-day treatment cycle. b.i.d.: Twice daily; CUP: Cancer of unknown primary; DLT: Dose-limiting toxicity; NSCLC: Non-small-cell lung cancer; PR: Partial response; q.d.: Once daily.

patients had treatment-related grade ≥3 (8/14), or grade ≥2 diarrhea lasting at least 7 days (6/14); five had treatment-related grade ≥3 (0/5), or grade ≥2 nausea lasting at least 7 days

1484

Future Oncol. (2015) 11(10)

(5/5); and four patients had treatment-related grade ≥3 (1/4), or grade ≥2 vomiting lasting at least 7 days (3/4). Treatment discontinuation due to AEs (any causality) was less frequent in

future science group

Phase I study of afatinib plus nintedanib in advanced solid tumors 

Research Article

Table 2. Patient disposition, dose-limiting toxicity and treatment discontinuation. Treatment

Cohort 1: afatinib 10 mg q.d. + nintedanib 150 mg b.i.d.

Cohort 2: afatinib 10 mg q.d.+ nintedanib 200 mg b.i.d.

Cohort 3: afatinib 20 mg q.d. + nintedanib 200 mg b.i.d.

All patients

Patients treated (n) Patients who completed at least one cycle, n (%) DLTs occurring during the first treatment cycle§, n (%):

11† 5 (45.5)

13‡ 12 (92.3)

4 2 (50.0)

28 19 (67.9)

1 (9.1) Grade 3 elevated ALT

1 (7.7) Grade 3 diarrhea

4 (14.3)

Discontinued overall due to, n (%): – AEs, overall:   • DLT   • Other AEs – Disease progression – Consent withdrawn – Other (unspecified) – Noncompliance

 

 

2 (50.0) Grade 3 dehydration (n = 1) Grade 3 diarrhea and ALT/AST elevation (n = 1)  

7 (63.6) 1 (9.1) 6 (54.5) 3 (27.3) 0 0 1 (9.1)

3 (23.1) 1 (7.7) 2 (15.4) 8 (61.5) 1 (7.7) 1 (7.7) 0

2 (50.0) 2 (50.0) 0 2 (50.0) 0 0 0

12 (42.9) 4 (14.3) 8 (28.6) 13 (46.4) 1 (3.6) 1 (3.6) 1 (3.6)

 

Five of the initial six patients enrolled discontinued treatment due to other AEs before completing cycle 1 and, as these were not DLTs, these five patients were replaced and cohort 1 was expanded to include 11 patients. ‡ After two patients experienced DLT in cohort 3, seven additional patients were recruited to cohort 2 (rather than six) because two patients entered and provided written informed consent at approximately the same time. Therefore, the number of patients in cohort 2 was expanded to include 13 patients. § All DLTs listed were NCI CTCAE Grade 3. AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; b.i.d.: Twice daily; DLT: Dose-limiting toxicity; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; q.d.: Once daily. †

cohort 2 (23.1%) than cohort 1 (63.6%) and cohort 3 (50%) (Table 2) . A total of four patients (14.3%) had AEs that led to dose reductions. Three patients in cohort 2 had their nintedanib dose reduced from 200 to 150 mg due to treatment-related AEs. One patient had a further dose reduction from nintedanib 150 to 100 mg, not due to an AE. One patient in cohort 3 had their afatinib dose reduced from 20 to 10 mg due to treatment-related grade 3 diarrhea. There were three deaths during the study, but none were considered to be related to study treatment. Two deaths were due to disease progression (one patient each in Cohort 1 and Cohort 2). One patient in Cohort 3 died from bacterial peritonitis 17 days after the last drug administration. This patient had a history of pancreatic cancer and discontinued due to progressive disease before the event in question. No further data are available as the bacterial peritonitis event was fatal. Increases in liver enzymes (ALT or AST) that were considered related to study treatment occurred in five patients; five patients (17.9%) had elevated ALT, four of these (14.3%) also had elevated AST. Three patients (10.7%) had grade ≥3 ALT and AST elevations, or had grade ≥2 elevations with total bilirubin >1.5-times the

future science group

upper limit of normal, considered related to study treatment. No patients had grade ≥2 left ventricular cardiac function or renal function AEs during the study. ●●Pharmacokinetics

Geometric means of afatinib and nintedanib pharmacokinetic parameters for the MTD group (afatinib 10 mg q.d./nintedanib 200 mg b.i.d.) after single dosing and multiple administrations are summarized in Table 4. There was considerable variability in pharmacokinetic parameters for both agents, as indicated by the geometric coefficient of variation (between 72.2 and 118% for afatinib and between 104 and 144% for nintedanib). Steady-state exposure (AUC and Cmax) of afatinib and nintedanib was similar to that previously reported (Figures 2A & B) [26–27,29–32] . ●●Antitumor activity

A total of 26 of the 28 treated patients were evaluable for response according to RECIST. One patient with kidney cancer treated at the MTD had a confirmed partial response (PR; 1/28; 3.6% overall, or 7.7% of those treated at the MTD [1/13]). This patient had metastatic lesions in the bone, adrenal gland, left renal fossa, and para aortic lymph nodes and had previously

www.futuremedicine.com

1485

Research Article  Gordon, Springett, Su et al. Table 3. Treatment-related adverse events occurring in >10% of patients overall, by treatment and preferred term; adverse events reported as any National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) grades.

Patients with any treatment-related AE (all grades), n (%) Diarrhea, n (%) Nausea, n (%) Anorexia, n (%) Vomiting, n (%) Fatigue, n (%) Dehydration, n (%) Rash, n (%) Dysgeusia, n (%) Abdominal distension, n (%) ALT increase, n (%) GGT increase, n (%) AST increase, n (%) Headache, n (%) Dry mouth, n (%) Abdominal pain, n (%) Chills, n (%) Dry skin, n (%) Dry eye, n (%) Hypokalemia, n (%) Weight decreased, n (%)

Cohort 1: afatinib 10 mg q.d./nintedanib 150 mg b.i.d. (n = 11)

Cohort 2: afatinib 10 mg q.d./nintedanib 200 mg b.i.d. (n = 13)

Cohort 3: afatinib 20 mg q.d./nintedanib 200 mg b.i.d. (n = 4)

All patients (n = 28)

9 (81.8)

12 (92.3)

4 (100)

25 (89.3)

7 (63.6) 8 (72.7) 5 (45.5) 8 (72.7) 6 (54.5) 3 (27.3) 2 (18.2) 4 (36.4) 2 (18.2) 1 (9.1) 2 (18.2) 1 (9.1) 1 (9.1) 1 (9.1) 2 (18.2) 3 (27.3) 2 (18.2) 1 (9.1) 2 (18.2) 3 (27.3)

11 (84.6) 9 (69.2) 7 (53.8) 3 (23.1) 6 (46.2) 2 (15.4) 3 (23.1) 2 (15.4) 3 (23.1) 3 (23.1) 3 (23.1) 2 (15.4) 3 (23.1) 3 (23.1) 2 (15.4) 1 (7.7) 1 (7.7) 2 (15.4) 0 0

4 (100) 3 (75.0) 2 (50.0) 1 (25.0) 0 2 (50.0) 1 (25.0) 0 0 1 (25.0) 0 1 (25.0) 0 0 0 0 0 0 1 (25.0) 0

22 (78.6) 20 (71.4) 14 (50.0) 12 (42.9) 12 (42.9) 7 (25.0) 6 (21.4) 6 (21.4) 5 (17.9) 5 (17.9) 5 (17.9) 4 (14.3) 4 (14.3) 4 (14.3) 4 (14.3) 4 (14.3) 3 (10.7) 3 (10.7) 3 (10.7) 3 (10.7)

AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; b.i.d.: Twice daily; GGT: Gamma-glutamyltransferase; q.d.: Once daily.

received four lines of therapy, with a best response of disease progression on their most recent treatment regimen before study entry. Nine patients (cohort 1, n = 4; cohort 2, n = 5) with various tumor types achieved stable disease (SD; 9/28; 32.1% overall); 5/13 patients treated at the MTD had SD [38.5%]). Among the patients with stable disease, only one patient, with heavily pretreated ovarian carcinoma, had evaluable and stable tumor markers (CA125 values decreased by 9% [from 763 U/ml to 703 U/ml] and stable over 5 months). The remaining patients had no evaluable tumor markers. Almost all patients were heavily pretreated and had progressive disease as best response on their most recent treatment regimen before study entry. Discussion This Phase I, dose-escalation study was designed to determine the MTD of afatinib when combined with nintedanib. The MTD was determined to be afatinib 10 mg q.d. plus nintedanib 200 mg b.i.d. administered concomitantly and continuously. As such, the MTD of afatinib in combination with nintedanib is lower than

1486

Future Oncol. (2015) 11(10)

the recommended effective dose when given as monotherapy (i.e., 40–50 mg continuous q.d.). A later study, conducted by Soria et al., that explored higher doses of afatinib with lower doses of nintedanib identified MTDs for afatinib plus nintedanib of afatinib 40 mg q.d. every other week plus nintedanib 150 mg b.i.d. and afatinib 30 mg q.d. continuously plus n­intedanib 150 mg b.i.d. [33] . In the current study, excessive dose-limiting diarrhea may have restricted dose escalation of afatinib to 20 mg when in combination with nintedanib. However, as diarrhea was manageable, this suggests that proactive and/or more aggressive management of this AE might improve tolerability and allow further dose escalation. This is supported by observations from afatinib monotherapy studies [9,34] . Interestingly, Soria et al. administered afatinib 20 mg q.d. continuously plus nintedanib 200 mg b.i.d. without observing any DLT, which may reflect the more robust diarrhea management employed by this study  [33] . In the Soria study the duration of Grade 2 diarrhea triggering drug interruption was reduced from the ≥7-day period employed

future science group

Phase I study of afatinib plus nintedanib in advanced solid tumors  in the current study to ≥2 days (48 h). In addition, a second antidiarrheal agent, racecadotril (Tiorfan®), with an antisecretory effect was commonly used by Soria and his team to control severe diarrhea episodes (data on file/personal communication). The safety profile observed with the afatinib 10 mg q.d. plus nintedanib 200 mg b.i.d. MTD combination is consistent with known safety observations for each agent [26–27,35] ; no new safety concerns were identified. Diarrhea, nausea and vomiting were among the most frequently reported treatment-related AEs, whereas liver enzyme elevations and diarrhea were the most common DLTs in this study. These findings are consistent with observations of reversible liver enzyme elevations with nintedanib monotherapy [26] and reports from combination studies of sequential afatinib and nintedanib [23,24] . The pharmacokinetic parameters calculated in this study were highly variable. Nevertheless, both AUC and Cmax values of afatinib and nintedanib were comparable to those reported previously for each agent when administered as monotherapy or in combination [26–27,29–32,35–37] . These findings suggest that there were no pharmacokinetic interactions between afatinib and nintedanib in the applied dosing schedule. The observed high inter-patient variability of pharmacokinetic parameters may be attributable to the nature of the patient population. Participating patients had various advanced solid tumors, were likely to be on polypharmacy and generally had received several types of anticancer therapies before enrolment in the study. The variability in pharmacokinetic parameters might also

Research Article

be explained by administration of food, which was not strictly controlled; afatinib is preferably administered under fasting conditions, as food intake is associated with reduced bioavailability of oral doses of afatinib [15,16] , while nintedanib shows slightly increased bioavailability when taken with food. Furthermore, previously identified covariates affecting afatinib pharmacokinetics (gender, weight, CRCL, ECOG performance score, lactate dehydrogenase levels, alkaline phosphatase levels and total plasma protein levels [38]) varied in the current patient population. For nintedanib, a further important factor may be its low absolute bioavailability [7] . Comedication with potent P-glycoprotein inhibitors or inducers may also have introduced variability, as both afatinib and nintedanib are substrates of the P-glycoprotein transporter [7,15– 16,19] . While these factors may have influenced the pharmacokinetics of afatinib and nintedanib, it should also be noted that moderate to high variability has also been reported for other orally administered tyrosine kinase inhibitors [39–43] . As a result of the variability of the PK data generated and the low patient numbers in this Phase I study, retrospective exploratory analyses of the relationship between PK parameters and AEs were not conducted. Although antitumor activity was not the primary objective of this study, some signs of clinical activity were observed in this treatment-refractory patient population. In the MTD cohort, one patient (7.7%) with kidney cancer had a confirmed PR and five patients (38.5%) had SD. Similarly, a preliminary report from a Phase I combination trial conducted

Table 4. Comparison of pharmacokinetic parameters of afatinib and nintedanib for the 10 mg once daily/200 mg twice daily maximum tolerated dose group after single dose and at steady state for treatment cycle one. Parameter

Unit

 

 

Single dose (day 1)

Steady state (day 15)

n

gMean

gCV (%)

n

gMean

gCV (%)

12 12 12

73.1 5.95 3.58

72.2 85.5 2.00−6.00

10 11 11

183 9.58 2.60

97.1 118 0.983−8.02

184 39.2 2.47

121 114 1.00−8.00

10 11 11

240 34.9 1.83

104 144 0.983−3.00

Afatinib pharmacokinetics AUC0–24(τ,ss) Cmax(ss) tmax(ss)†

ng•h/ml ng/ml h

Nintedanib pharmacokinetics AUC0–12(τ,ss) Cmax(ss) tmax(ss)†

ng•h/ml ng/ml h

13 13 13

Median and range. AUC: Area under the concentration–time curve; Cmax: Maximum plasma concentration; gMean: Geometric mean; gCV: Geometric co-efficient of variation; tmax: Time to maximum plasma concentration; τ: Dosing interval; ss: Steady state. †

future science group

www.futuremedicine.com

1487

Research Article  Gordon, Springett, Su et al.

A

1800 1600 1400

AUCT,ss (ng.h/ml)

1200 1000 800 600 400 200 0 Present study (n = 10) B

Studies 1200.1–1200.419–22 (n = 12) Afatinib 10 mg q.d.

Present study (n = 12)

Studies 1199.1–1199.2623–24 (n = 64) Nintedanib 200 mg b.i.d.

Studies 1200.1–1200.419–22 (n = 12) Afatinib 10 mg q.d.

Present study (n = 13)

270 240 210

Cmax,ss (ng.h/ml)

180 150 120 90 60 30 0 Present study (n = 11)

Studies 1199.1–1199.2623–24 (n = 67) Nintedanib 200 mg b.i.d.

Figure 2. Comparison of individual pharmacokinetic parameters of afatinib and nintedanib for the 10 mg/200 mg maximum tolerated dose group versus previous data. (A) Comparison of individual AUC values of afatinib and nintedanib for the 10 mg/200 mg MTD group versus previous data. (B) Comparison of individual Cmax values of afatinib and nintedanib for the 10 mg/200 mg MTD group versus previous data.

1488

Future Oncol. (2015) 11(10)

future science group

Phase I study of afatinib plus nintedanib in advanced solid tumors 

Research Article

Figure 2. Comparison of individual pharmacokinetic parameters of afatinib and nintedanib for the 10 mg/200 mg maximum tolerated dose group versus previous data (cont). AUC: Area under the concentration-time curve; b.i.d.: Twice daily; Cmax: Maximum plasma concentration; MTD: Maximum tolerated dose; q.d.: Once daily; ss: Steady state; τ: Dosing interval. Data taken from [26–27,29–32].

by Soria et al. noted that four of six patients treated with afatinib 30 mg q.d. plus nintedanib 150 mg b.i.d., had SD [33] . In addition, PRs were observed in two patients; one with triplenegative breast cancer and one with head and neck carcinoma receiving afatinib 40 mg q.d. every other week plus continuous nintedanib 200 mg b.i.d. [33] . This is in contrast to the lack of antitumor activity reported in Phase II studies of alternating sequential afatinib with nintedanib in hormone-refractory prostate cancer and advanced colorectal cancer, which may have resulted from a suboptimal (alternating) dosing regimen, in addition to the heavily-pretreated patient population enrolled in the colorectal cancer trial [23,24] . Conclusion The MTD of afatinib was found to be 10 mg q.d. when given in combination with nintedanib 200 mg b.i.d. on a continuous daily schedule.

This treatment regimen demonstrated a manageable safety profile, and pharmacokinetic data suggest that there were no drug–drug interactions. However, although signs of antitumor activity were observed, the afatinib dose was considered to be subtherapeutic in this combination, possibly as a result of ineffective management of diarrhea, which may have limited further afatinib dose escalation. Consequently, a recommended Phase II dose for the combination was not established in this study. Future perspective The rapid development of targeted therapies directed against specific or multiple signaling pathways has dramatically changed the landscape of cancer treatment. However, trials of targeted therapies that inhibit a single signaling molecule have been disappointing, partly due to the rapid development of resistance via upregulation of alternative signaling pathways [33,44] .

EXECUTIVE SUMMARY Introduction ●●

Combining different targeted anticancer agents that inhibit multiple inter-linked signaling pathways may improve therapeutic outcomes.

●●

Afatinib is an irreversible ErbB family blocker that covalently binds to and blocks signaling from all the cancer-relevant homo- and hetero-dimers of the ErbB Family members.

●●

Nintedanib is a triple angiokinase inhibitor that targets the three receptor classes involved in the formation of blood

●●

Sequential use of nintedanib and afatinib showed synergistic antitumor activity when compared with either single

vessels: VEGFR (1, 2 and 3), PDFGR (α and β) and FGFR (1, 2 and 3). agent alone in colorectal cancer xenografts and cells.

Aim ●●

This Phase I, open-label, dose-escalation study was designed to determine the maximum tolerated dose (MTD)

of afatinib in combination with nintedanib in patients with advanced cancer who had progressed following prior standard therapies. Results ●●

The MTD of afatinib was determined to be 10 mg/day once daily when given in combination with nintedanib 200 mg twice daily in a 28-day treatment cycle.

●●

Of 13 patients treated at the MTD, one (7.7%) had a partial response and five (38.5%) had stable disease.

●●

There was no evidence of pharmacokinetic interactions between afatinib and nintedanib in the applied dosing schedule.

future science group

www.futuremedicine.com

1489

Research Article  Gordon, Springett, Su et al. Therefore, combining targeted agents to inhibit several parts of a signaling network may enhance clinical activity and delay the emergence of resistance. However, a number of questions remain unanswered, including how targeted inhibitors can be combined to optimize efficacy without comprising tolerability. This practical issue needs to be considered when performing early clinical trials. Disclosure The authors were fully responsible for all content and editorial decisions. They were involved at all stages of manuscript development and have approved the final version.

with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing assistance, supported financially by Boehringer Ingelheim Pharma GmbH & Co. KG, was provided by Kay Roche of Ogilvy Healthworld and Christine Arris of GeoMed, an Ashfield business, part of UDG Healthcare plc, during the preparation of this article.

Ethical conduct of research The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Financial & competing interests disclosure M Ould-Kaci, S Wind and Y Zhao are employees of Boehringer Ingelheim. This study was supported by Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict

References Papers of special note have been highlighted as: •• of considerable interest 1

Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285(21), 1182–1186 (1971).

2

Dent P, Curiel DT, Fisher PB et al. Synergistic combinations of signaling pathway inhibitors: mechanisms for improved cancer therapy. Drug Resist. Updat. 12(3), 65–73 (2009).

Open access This work is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/ licenses/by-nc-nd/3.0/

(initial authorisation). www.ema.europa.eu 7

Food and Drug Administration. OFEV prescribing information. www.accessdata.fda.gov

8

Yang JC, Shih JY, Su WC et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a Phase 2 trial. Lancet Oncol. 13(5), 539–548 (2012).

3

Li D, Ambrogio L, Shimamura T et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34), 4702–4711 (2008).

•• Large Phase II study of afatinib monotherapy in patients with EGFR mutation-positive non-small-cell lung cancer that shows the promising antitumor activity for afatinib with a manageable safety profile.

4

Solca F, Dahl G, Zoephel A et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J. Pharmacol. Exp. Ther. 343(2), 342–350 (2012).

9

5

Hilberg F, Roth GJ, Krssak M et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68(12), 4774–4782 (2008).

•• Preclinical report that details the activity of nintedanib in three cell types – endothelial cells, pericytes and smooth muscle cells – known to contribute to tumor angiogenesis, encouraging the clinical testing of nintedanib in patients with cancer. 6

European Medicines Agency. Nintedanib Committee for Medicinal Products for Human Use (CHMP) summary of opinion

1490

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. 13(5), 528–538 (2012).

•• Phase IIb/III study of afatinib plus best supportive care in non-small-cell lung cancer patients who had progressed after prior chemotherapy and erlotinib/gefitinib that shows the encouraging antitumor activity of this afatinib combination. 10 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. 31(Suppl. 27), Abstract 3327 (2013).

Future Oncol. (2015) 11(10)

•• First Phase III study in patients with advanced lung adenocarcinoma and EGFR mutations (LUX-Lung 3) showing that afatinib is associated with prolongation of PFS, improved quality of life and a manageable safety profile when compared with standard first-line cisplatin/pemetrexed chemotherapy. 11 Yang JC, Hirsh V, Schuler M et al. Symptom

control and quality of life in LUX-Lung 3: a Phase III study of afatinib or cisplatin/ pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31(27), 3342–3350 (2013). •• This paper details the benefits associated with the significant prolongation of progression-free survival in the quality of life of afatinib-treated patients from the LUX-Lung 3 Phase III study. 12 Wu YL, Zhou C, Hu CP et al. LUX-Lung 6:

a randomized, open-label, Phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung. J. Clin. Oncol. 31(15s), Abstract 8016 (2013). 13 Geater SL, Zhou C, Hu CP et al. LUX-Lung

6: Patient-reported outcomes (PROs) from a randomized open-label, Phase III study in first-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations. ASCO Meeting Abstracts 31(15 Suppl.), 8061 (2013).

future science group

Phase I study of afatinib plus nintedanib in advanced solid tumors  14 Yang JCH, Wu Y-L, Schuler M et al. Effect of

afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma: outcomes of the two randomised Phase III trials LUX-Lung 3 and LUX-Lung 6. Lancet Oncol. (2014) (In Press). 15 Food and Drug Administration. Gilotrif

prescribing information. www.accessdata.fda.gov 16 European Medicines Agency. Giotrif -

European Public Assessment Report (product information). www.ema.europa.eu 17 Pharmaceuticals and Medical Devices Agency

J. New drugs approved in FY 2013. www.pmda.go.jp 18 Stopfer P, Marzin K, Narjes H et al. Afatinib

pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother. Pharmacol. 69(4), 1051–1061 (2012). 19 Wind S, Giessmann T, Jungnik A et al.

Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir. Clin. Drug Investig. 34(3), 173–182 (2014). 20 Reck M, Kaiser R, Mellemgaard A et al.

Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUMELung 1): a Phase 3, double-blind, randomised controlled trial. Lancet Oncol. 15(2), 143–155 (2014). 21 Stopfer P, Rathgen K, Bischoff D et al.

Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 41(4), 297–311 (2011). 22 Poindessous V, Ouaret D, El OK et al.

EGFR- and VEGF(R)-targeted small molecules show synergistic activity in colorectal cancer models refractory to combinations of monoclonal antibodies. Clin. Cancer Res. 17(20), 6522–6530 (2011). 23 Molife LR, Omlin A, Jones RJ et al.

Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer. Future Oncol. 10(2), 219–231 (2014). 24 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. 31(6), 2271–2281 (2011). 25 Therasse P, Arbuck SG, Eisenhauer EA et al.

New guidelines to evaluate the response to treatment in solid tumors. European

future science group

Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92(3), 205–216 (2000). 26 Mross K, Stefanic M, Gmehling D et al.

Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin. Cancer Res. 16(1), 311–319 (2010). 27 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. 28(25), 3965–3972 (2010). 28 Gabrielsson J, Weiner D. Pharmacokinetic

And Pharmacodynamic Data Analysis: Concepts And Applications. Swedish Pharmaceutical Press, Section 2.8, Sweden (2007). 29 Eskens FA, Mom CH, Planting AS et al. A

Phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br. J. Cancer 98(1), 80–85 (2008). 30 Marshall J, Hwang J, Eskens FA et al. A

Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors. Invest. New Drugs 31(2), 399–408 (2013). 31 Gordon MS, Mendelson DS, Gross M et al. A

Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors. Invest. New Drugs. 31(2), 409–416 (2013). 32 Eisen T, Shparyk Y, Macleod N et al. Effect of

small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, Phase II study. Invest. New Drugs 31(5), 1283–1293 (2013). 33 Soria JC, Hollebecque A, Massard C et al.

Phase I study of afatinib (BIBW 2992), an ErbB Family Blocker plus nintedanib (BIBF 1120), a triple angiokinase inhibitor, in patients with advanced solid tumours. Ann. Oncol. 23(9 Suppl.), 979- (2012). 34 Yang JC, Reguart N, Barinoff J et al. Diarrhea

associated with afatinib: an oral ErbB family blocker. Expert Rev. Anticancer Ther. 13(6), 729–736 (2013). 35 Doebele RC, Conkling P, Traynor AM et al.

A Phase I, open-label dose-escalation study of

Research Article

continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann. Oncol. 23(8), 2094–2102 (2012). 36 Bousquet G, Alexandre J, Le TC et al. Phase I

study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients. Br. J. Cancer 105(11), 1640–1645 (2011). 37 Marshall J, Shapiro GI, Uttenreuther-Fischer

M et al. Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer. Future Oncol. 9(2), 271–281 (2013). 38 Freiwald M, Schmid U, Fleury A et al.

Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors. Cancer Chemother. Pharmacol. 73(4), 759–770 (2014). 39 Baselga J, Rischin D, Ranson M et al. Phase I

safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J. Clin. Oncol. 20(21), 4292–4302 (2002). 40 Ranson M, Hammond LA, Ferry D et al.

ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a Phase I trial. J. Clin. Oncol. 20(9), 2240–2250 (2002). 41 Hidalgo M and Bloedow D.

Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of erlotinib (Tarceva). Semin. Oncol. 30(3 Suppl. 7), 25–33 (2003). 42 Burris HA III, Hurwitz HI, Dees EC et al.

Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J. Clin. Oncol. 23(23), 5305–5313 (2005). 43 van Erp NP, Gelderblom H, Guchelaar HJ.

Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat. Rev. 35(8), 692–706 (2009). 44 Engelman JA, Zejnullahu K, Mitsudomi T

et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827), 1039–1043 (2007).

www.futuremedicine.com

1491