A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC)

Lung Cancer 79 (2013) 270–275

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A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC) Se Hyun Kim a , Hyo Sup Shim b , Jaeho Cho c , Jae Heon Jeong d , Sun Mi Kim e , Yun Kyoung Hong f , Ji Hee Sung f , Sang-Jun Ha g , Hye Ryun Kim a , Hyun Chang a , Joo Hang Kim a , Crombet Tania h , Byoung Chul Cho a,∗ a

Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea c Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea d Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, Republic of Korea e Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea f JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Republic of Korea g Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea h Center of Molecular Immunology, Havana 11600, Cuba b

a r t i c l e

i n f o

Article history: Received 26 March 2012 Received in revised form 7 August 2012 Accepted 20 November 2012 Keywords: NSCLC EGFR Gefitinib Nimotuzumab Phase I

a b s t r a c t Background: Nimotuzumab (TheraCIM® ) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Methods: Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100 mg or 200 mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We planned to enroll 10 additional patients at RPIID to ascertain the safety of treatment. EGFR mutations and KRAS mutations were analyzed from available tumor samples. Results: A total of 16 patients were enrolled (3 in 100 mg cohort, 13 in 200 mg cohort). Six patients (37.5%) were female, and 5 (31.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%). Treatment was well-tolerated without dose-limiting toxicity (DLT). Four patients (25.0%) experienced grade 2 skin toxicity (1 in 100 mg cohorts, 3 in 200 mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (25.0%) achieved partial response and 7 patients (43.8%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Conclusions: Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200 mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is the most common cancer and the leading cause of cancer-related mortality in the world. Despite introduction of new therapeutic agents, prognosis of lung cancer has remained poor and

∗ Corresponding author at: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50, YonseiRo, Seodaemungu, Seoul 120-752, Republic of Korea. Tel.: +82 2 2228 8126; fax: +82 2 393 3562. E-mail address: [email protected] (B.C. Cho). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.11.017

5-year survival rate is around 10–15% [1,2]. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung malignancies and 70% of patients are diagnosed with locally advanced or metastatic disease [3]. Although many patients are appropriate for systemic treatment, conventional platinum-based regimens have only modest activity for survival improvement and reached a therapeutic plateau [4]. The epidermal growth factor receptor (EGFR) is overexpressed in a variety of solid tumors, including NSCLC. EGFR expression has been correlated with poor prognosis in NSCLC [5,6]. A better understanding of dysregulated EGFR pathway in NSCLC has led to new drugs targeting this molecule. Currently available anti-EGFR drugs

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include monoclonal antibodies (mAbs) that bind to the extracellular domain of the receptor or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the kinase domain of the receptor. Gefitinib is an orally active reversible EGFR-TKI. In 2004, somatic mutations in EGFR gene, mainly deletions in exon 19 and single missense mutation in exon 21, were reported to correlate with clinical responsiveness to gefitinib [7–9]. These mutations lead to constitutive activation of EGFR pathway signaling and confer susceptibility to gefitinib. Recent large randomized phase III trial, known as IPASS trial, proved the concept that EGFR mutation in tumor is a strong predictor of a better outcome with gefitinib [10]. EGFR mutation positive patients experienced longer progression free survival (PFS) with gefitinib treatment compared to carboplatin/paclitaxel treatment. Consequently, gefitinib is now used as first-line therapy for patients with NSCLC with EGFR mutation. Gefitinib sensitive tumors harboring EGFR mutations eventually develop acquired resistance after 6–12 months of treatment [11]. Approximately half of those patients have a secondary EGFR mutation in exon 20 (T790M), which may cause resistance by steric interference with binding of TKIs or by increasing the affinity for ATP [12–14]. An alternative mechanism of resistance is MET amplification which occurs in about 20% of patients with acquired resistance [15]. Many preclinical data supported the combined EGFR targeting with EGFR-TKIs and anti-EGFR mAbs to overcome intrinsic and acquired resistance mechanisms [16–18]. Recent phase I/II trial of adding cetuximab to erlotinib, an EGFR-TKI, showed disease stabilizing effect in most patients (11 of 13) with acquired resistance. However, there was no radiographic partial response and one third (31%) of the patients discontinued combination therapy due to intolerable rash [19]. Nimotuzumab (TheraCIM® ) is a humanized IgG1 mAb targeting the EGFR. Nimotuzumab binds to the extracellular domain III of EGFR with a moderate affinity, blocking EGF binding and preventing the receptor dimerization by steric hindrance. Phase I and II trials with nimotuzumab demonstrated the lack of a severe dermatologic reaction, virtually absent in contrast to other anti-EGFR drugs, and other adverse reactions [20]. In previous trials, mainly with head and neck cancer or brain malignancies, nimotuzumab has shown an efficacy comparable to other anti-EGFR mAbs [21–25]. Two recent phase I trials in NSCLC patients confirmed the minimal toxicity of nimotuzumab in combination with radiation therapy and also documented favorable antitumor activities [26,27]. In a phase I trial of single agent nimotuzumab for patients with advanced solid tumors, dose was escalated to 800 mg per week and only a single DLT of grade 3 fatigue was observed at 100 mg per week. One partial response was observed at 200 mg per week and investigators of the trial found no correlations between nimotuzumab doses and response or toxicity [28]. Considering the excellent tolerability and efficacy to NSCLC patients, nimotuzumab is a prime candidate for combination therapy with gefitinib. This phase I trial was designed and conducted to determine the recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment.

2. Materials and methods 2.1. Patient eligibility Patients with histologically confirmed unresectable NSCLC pretreated with a first-line platinum based doublet regimen were eligible for the study. Further inclusion criteria included age ≥18 years, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2, at least once unidimensionally measurable lesion, and completion of prior treatment at least 2 weeks prior to study entry. Patients with ≥3 prior chemotherapy, prior anti-EGFR

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therapy, uncontrolled or symptomatic central nervous system metastases, active pulmonary fibrosis, uncontrolled heart disease, and inadequate hematologic, hepatic, or renal function were excluded. All patients provided written informed consent before study registration. The study was approved by the institutional review boards of the Severance hospital and was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. 2.2. Trial design This was an open-label, uncontrolled, interventional, phase I, dose-escalation trial. Treatment consisted of nimotuzumab at two dose levels (100 mg or 200 mg) administered via i.v. infusion over 30 min once weekly and gefitinib at a fixed dose of 250 mg daily until disease progression or unacceptable toxicity. Each treatment cycle was defined as 28 days regardless of omitted doses. Dose modification for gefitinib was not allowed. Nimotuzumab dose was reduced in the event of severe toxicity, but no intra-patient dose escalation was allowed. The primary end point of the study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RPIID) of the combination treatment. The RPIID was to be defined by the MTD or the higher dose level of nimotuzumab (200 mg) if an MTD was not reached. The MTD was defined as the highest dose at which less than one third of the patients experienced a dose limiting toxicity (DLT) during the first cycle. If one of three patients experienced DLT during the first cycle, three more patients were to be enrolled at the same dose level. Additional 10 patients were to be enrolled and treated at the RPIID to confirm its safety. DLT was defined as any of the following adverse events during the first treatment cycle: grade 4 neutropenia lasting for ≥5 days; grade 3 or 4 neutropenia with fever >38.5 ◦ C and/or infection; grade 4 thrombocytopenia; any grade 4 infusion reaction; any grade 3 skin toxicity that requires treatment interruption for ≥2weeks; any other non-hematologic grade 3 or 4 toxicity. All adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. 2.3. Assessment plan At baseline all patients provided a medical history and underwent a physical examination. Laboratory evaluations and computed tomography (CT) scans of the chest and of other known metastatic regions were performed within 2 weeks of the first dose of study treatment. Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) version 1.1 [29] after 4 weeks of treatment (1cycle) and every 8 weeks (2 cycles) thereafter. EGFR mutation status, KRAS mutation status and EGFR expression by immunohistochemistry (IHC) of tumor were obtained in patients with sufficient pretreatment tumor samples. Exon 18 to exon 21 of EGFR gene and exon 2 of KRAS gene were analyzed using nested polymerase chain reaction amplification of the individual exons. DNA sequencing was performed as described previously [30–32]. EGFR expression by IHC was assessed with EGFR.25 (Novocastra, Newcastle upon Tyne, UK) at a dilution of 1:100 and scored on a continuous scale of 0 (negative) to 300 (strong expression) by one pathologist (Shim H.S.). EGFR IHC score was calculated with the formula as described in a previous study [33]: 1 × (percentage of cells staining weakly [1+]) + 2 × (percentage of cells staining moderately [2+]) + 3 × (percentage of cells staining strongly [3+]). All patients who received at least 1 complete dose of treatment were considered to be evaluable for safety and toxicity. Baseline

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Table 1 Baseline characteristics (n = 16).

Table 3 Treatment efficacy (n = 16). n

Age, years Median Range Gender Male Female ECOG performance status 0 1 Smoking history Never Formera Current Histology Adenocarcinoma Squamoous cell carcinoma NSCLC (NOS) No. of Prior therapy regimens 1 chemotherapy 2 chemotherapy EGFR mutation Exon 19 deletion Exon 21 L858R Exon 20 mutation Wild-type Unknown Nimotuzumab dose level 100 mg 200 mg

(%) 69 45–78

10 6

62.5 37.5

9 7

56.3 43.8

5 5 6

31.3 31.3 37.5

13 2 1

81.3 12.5 6.3

14 2

87.5 12.5

CR PR SD PD

Nimo 100 mg (n = 3)

Nimo 200 mg (n = 13)

Total (n = 16)

n

%

n

%

n

%

0 2 1 0

0 66.7 33.3 0

0 2 6 5

0 15.4 46.1 38.5

0 4 7 5

0 25.0 43.8 31.2

Abbreviation: Nimo, nimotuzumab.

2 2 1b 7 5

3.2. Toxicity and safety assessment A total of 6 patients were treated at 100 mg/week and 200 mg/week dose levels of nimotuzumab in combination with gefitinib 250 mg/day. DLTs were not reported in both dose levels. Therefore, the recommended dose (RPIID) was defined as 200 mg nimotuzumab weekly and 250 mg gefitinib daily. Ten patients were additionally enrolled and treated at RPIID. All 16 patients were evaluable for toxicities. All treatment related toxicity profiles observed per patient are summarized in Table 2. Toxicities were generally mild and there were no grade 3 or 4 adverse events (AEs). The most frequent AEs were grade 1 or 2 skin rash and fatigue experienced by 6 patients (37.5%) each. Common AEs included grade 1 anorexia (25%), grade 1 diarrhea (25%), and mucositis (18.7%). There were no reported serious adverse events requiring hospitalization or treatment related death. None of 16 patients had treatment discontinuation or dose modification due to intolerable toxicities.

12.5 12.5 6.3 43.8 31.3

3 13

18.8 81.3

NOS: not otherwise specified. a Defined as quit >1 year before diagnosis. b The patient had both exon 20 2317–2319 CAC duplication mutationand exon 21 L858R mutation.

3.3. Efficacy assessment

characteristics, toxicity, efficacy, were analyzed with descriptive statistics.

Responses in 16 assessable patients included 4 PR, 7 SD, and 5 PD, producing disease control rate (DCR) of 68.8% (95% CI, 43.8–87.5%) and response rate (RR) of 25% (95% CI, 6.3–50.0%) by intent-to-treat analysis (Table 3). Individual best responses of target lesions are summarized in Fig. 1. Among 4 responders, EGFR mutation status was reported as following: 2 patients with exon 19 deletion mutation, 1 patient with wild type EGFR, while the remaining patient had no available tissue for EGFR mutation testing. One patient with tumor harboring both exon 20 duplication in 2317–2319 CAC mutation and exon 21 L858R mutation had progressive disease after 1 month of treatment. EGFR mutation, EGFR IHC score, drug response, and PFS of 11 patients with tumor samples available are summarized in Table 4. EGFR IHC was scored from 0 (no expression) to 220 (strong expression). When we select EGFR IHC score 100 (median value) as a cutoff point, there was no significant difference in response rate (Fisher‘s exact test, P = 0.545) and PFS rate at 3 months (Fisher‘s exact test, P = 0.567) between low and high expression groups.

3. Results 3.1. Patient characteristics Sixteen patients with metastatic or recurrent NSCLC were recruited from June 2011 to October 2011. The baseline characteristics of all 16 patients are summarized in Table 1. The median age was 69 years (range, 45–78 years). Ten patients (62.5%) were men. Major histologic type was adenocarcinoma (81.3%). Patients who had never smoked made up 31.3%. Fourteen patients (87.5%) had received one prior-chemotherapy with platinum based regimen, with the remaining two receiving two prior regimens. Among 11 patients with paraffin-embedded tumor samples available, EGFR mutations were detected in 4 patients (25%) and one patient had both exon 20 2317–2319 CAC duplication mutation and exon 21 L858R mutation. None of 11 patients harbored KRAS mutations. Table 2 Adverse events (all cycles). Adverse events

Nimo100 mg (n = 3) Grade 1

Skin rash Gastrointestinal toxicity Anorexia Diarrhea Mucositis Fatigue Infusion reaction Abbreviation: Nimo, nimotuzumab.

Nimo200 mg (n = 13) Grade 2

Total (n = 16)

Grade 1

Grade 2

Any grade

(%)

0

1

2

3

6

37.5

0 2 1 0 0

0 0 0 0 0

4 2 2 6 0

0 0 0 0 0

4 4 3 6 0

25.0 25.0 18.7 37.5 0.0

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Fig. 1. Best % change from baseline in target tumor lesions. A patient (a ) with coexisting exon 20 and exon 21 mutant tumor had progressive disease due to the appearance of new lesions.

4. Discussion This is the first prospective study of combination therapy with nimotuzumab (TheraCIM® ) plus gefitinib in patients with advanced NSCLC. This study demonstrated the feasibility of combining nimotuzumab with gefitinib. The safety profile for the combination was consistent with the individual safety profile of each drug and no unexpected toxicities occurred. The RPIID was determined to be the highest dose evaluated nimotuzumab 200 mg weekly and gefitinib 250 mg daily. The safety findings of this study were more favorable than another phase I/II study in which escalating doses of cetuximab and fixed dose of erlotinib were used. Although there was no DLTs according to protocol, relatively high incidence of AEs were reported and one third of the patients (6 of 19) discontinued study treatment due to intolerable rash [19]. In the current trial, we utilized nimotuzumab instead of cetuximab to maximize inhibition of EGFR signaling pathway and minimize the skin toxicity. Consequently, skin toxicities were generally mild and treatment discontinuation due to toxicity was not reported. This finding is similar to those of previous studies that reported the dermatologic AEs of nimotuzumab treatment. The skin toxicities were mainly limited to grade 1 or 2 and grade 3 or 4 skin toxicity was absent [20–23,26,27]. The benign toxicity

profile of nimotuzumab also includes the absence of severe hypomagnesemia and a lack of grade 3 or 4 gastrointestinal toxicities [34]. Efficacy measurements were secondary endpoints in this study due to small number of study population. Four patients (25%) achieved partial response with combination treatment, among them one patient had tumor with wild-type EGFR and relatively strong EGFR expression (IHC score of 180). Recent preclinical studies and clinical trials showed that dual agent targeting against EGFR in NSCLC is promising [16–18,35]. In a phase I trial of combining afatinib (BIBW2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib, 8 of 22 patients (36%) achieved confirmed partial response and 76% of patients had tumor size reduction [35]. The dermatologic toxicity, however, was grade 1/2 in 81% of patients and grade 3 in 11.5% of patients. An interesting observation in this study is the inherent resistance to anti-EGFR therapy in patient with dual EGFR mutation, rare exon 20 mutations and exon 21 L858R mutations. This finding is compatible with previous studies that only a small portion of patients whose tumors harbor EGFR exon 20 mutation had clinical response to EGFR-TKIs [36,37]. In a previous study, Wu and colleagues documented lower response rate to gefitinib treatment in patients with an exon 20 mutation. Patients with coexisting mutations had better response rate to gefitinib than those with a single exon 20 mutation. However, the response rate of 44% in

Table 4 EGFR status and treatment outcome of 11 patients with available tissue. Patient no.

Gender/Age

Smoking

Histology

EGFR IHCa

EGFR mutation

Response

PFS (m)

1 2 3 4 5 6 7 8 9 10 11

M/47 M/71 M77 M/70 F/54 F/69 F/45 F/58 M/69 M/68 F/72

Current Former Current Former Never Never Never Never Former Current Never

ADC ADC ADC ADC ADC ADC ADC ADC ADC ADC ADC

0 50 70 80 100 100 180 190 190 210 220

WT WT WT Exon 21 Exon 19 Exon 20b , exon 21 WT Exon 19 WT WT WT

PD PD SD SD PR PD PR PR SD SD PD

1 1 5 3+ 6+ 1 5+ 6+ 2 3+ 1

Abbreviation: ADC, adenocarcinoma; EGFR IHC, EGFR immunohistochemistry score; WT, wild type; exon 19, exon 19 deletion; exon 21, exon 21 L858R; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression-free survival. a EGFR IHC score range: 0–300 (300: strong expression). b Exon 20 2317–2319 CAC duplication mutation.

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patients with dual EGFR mutations is much lower than that of about 70% in patients with a single EGFR mutation in exon 19 or 21 [10,36]. Much to our disappointment, adding nimotuzumab to gefitinib failed to overcome the drug resistance of tumor with coexisting mutation. This might be possibly explained by relatively low EGFR expression in tumor of the patient. The previous study that examined the role of EGFR density and EGFR binding property of anti-EGFR mAbs documented that nimotuzumab has selective binding property depending on EGFR expression density of the target tissue [38,39]. As a result, nimotuzumab binds with low affinity monovalent bond to tumors with low EGFR expression. In contrast, when EGFR expression is moderate to high, nimotuzumab binds with high affinity bivalent bond. This distinct property of nimotuzumab may result in low toxicity profile sparing healthy tissues and superior targeting of tumors with strong EGFR expression. In addition, response rate or response related endpoints as PFS are not the best to assess the benefit of targeted therapy. Correlations with survival benefit will be established after following the patients for a prolonged time. We designed this trial considering previous results that nimotuzumab 200 mg weekly would be the optimal biological dose and result in EGFR signaling pathway inhibition. First, phase I dose escalation studies found no dose-dependent activity of nimotuzumab [26,28]. Bebb et al. also documented that nimotuzumab 100 or 200 mg weekly had systemic efficacy in 3 NSCLC patients [26]. Currently, there is no clear clinical data that 400 mg weekly or more dosing of nimotuzumab is more effective than 200 mg weekly in patients with NSCLC. Second, pharmacodynamic study of nimotuzumab in patients with advanced head and neck cancer documented similar antitumor effect, inhibition of p-EGFR, between 200 and 400 mg weekly [24]. Third, pharmacokinetic parameters, such as elimination half-life, AUC and Cmax, are comparable at both 200 and 400 mg weekly [40]. In conclusion, this study demonstrated that dual agent molecular targeting of EGFR with nimotuzumab and gefitinib is well-tolerated in patients with advanced NSCLC, and determined the RPIID of combination treatment. Based upon this phase I trial, we are planning to conduct a multicenter randomized phase II trial in patients with advanced NSCLC in Korea (clinicaltrials.gov NCT01498562). Correlative studies will include immunohistochemical assessment of EGFR expression as well as sequencing of EGFR and KRAS. The larger number of patients and correlative studies of the following trial will provide efficacy information of the combination treatment with nimotuzumab and gefitinib. Conflict of interest statement None declared. Acknowledgement This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2012R1A2A2A01046927). References [1] Youlden DR, Cramb SM, Baade PD. The international epidemiology of lung cancer: geographical distribution and secular trends. J Thorac Oncol 2008;3:819–31. [2] Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24:2137–50. [3] Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584–94.

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