Cancer Chemother Pharmacol DOI 10.1007/s00280-015-2784-x
ORIGINAL ARTICLE
Phase II study of erlotinib in elderly patients with non‑small cell lung cancer harboring epidermal growth factor receptor mutations Yusuke Inoue1 · Naoki Inui1,2 · Kazuhiro Asada3 · Masato Karayama1,4 · Hiroyuki Matsuda5 · Koshi Yokomura6 · Naoki Koshimizu7 · Shiro Imokawa8 · Takashi Yamada9 · Toshihiro Shirai3 · Norio Kasamatsu10 · Takafumi Suda1
Received: 28 April 2015 / Accepted: 18 May 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are key drugs in the treatment of nonsmall cell lung cancer (NSCLC) harboring EGFR activating mutations. We assessed the efficacy and safety of one EGFR tyrosine kinase inhibitor, erlotinib, in elderly Japanese patients with EGFR-mutated NSCLC. Methods Elderly patients aged 75 or older with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) were enrolled in this prospective phase II trial. Patients received 150 mg erlotinib per day orally. The primary end point was the overall response rate. Results Between March 2013 and November 2014, 32 patients were enrolled with median age 80 years. All tumors had adenocarcinoma histology, and 20 patients (62.5 %) had an L858R mutation. The response rate was 56.3 % [95 % confidence interval (CI) 39.4–72.0 %], and the disease control rate was 90.6 % (95 % CI 75.2–97.6 %). Median progression-free survival was 15.5 months (95 %
CI 11.2–not reached). Skin disorder was the most common adverse event, and grade 4 drug-related interstitial lung disease occurred in one patient. Conclusions Erlotinib is effective and tolerated in elderly patients with EGFR mutation-positive NSCLC.
* Naoki Inui inui@hama‑med.ac.jp
6
Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara, Hamamatsu 433‑8558, Japan
7
Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4‑1‑11 Surugadai, Fujieda 426‑8677, Japan
8
Department of Respiratory Medicine, Iwata City Hospital, 512‑3 Ohkubo, Iwata 438‑8550, Japan
9
Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10‑93 Otemachi, Shizuoka 420‑8630, Japan
10
Department of Respiratory Medicine, Hamamatsu Medical Center, 328 Tomitsuka, Hamamatsu 432‑8580, Japan
1
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1‑20‑1 Handayama, Higashi‑ku, Hamamatsu 431‑3192, Japan
2
Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan
3
Department of Respiratory Medicine, Shizuoka General Hospital, 4‑27‑1 Kita‑ando, Shizuoka 420‑8527, Japan
4
Department of Clinical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan
5
Department of Respiratory Medicine, Japanese Red Cross Shizuoka Hospital, 8‑2 Otemachi, Shizuoka 420‑0853, Japan
Keywords Elderly · Erlotinib · Epidermal growth factor receptor · EGFR mutation · Non-small cell lung cancer
Introduction Lung cancer, of which non-small cell lung cancer (NSCLC) accounts for almost 80 %, has long been a leading cause of cancer-related death worldwide [1]. Because lung cancer is associated with aging, and the risk of NSCLC increases with advancing age [2], the number of elderly patients with NSCLC is increasing in developed countries due to the aging population. The elderly tend to have impaired organ function, more co-morbidities [3, 4], and an advanced
13
Cancer Chemother Pharmacol
disease stage [5], which necessitate tailored treatment strategies. Recently, molecular-targeted therapeutic strategies have been established in the treatment of NSCLC with gene alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, by inhibition of critical signaling pathways in cancer cells. Approximately 10 % of patients with NSCLC in the USA and 35 % in East Asia have tumors harboring EGFR mutations [6, 7]. Treatment with EGFR tyrosine kinase inhibitors, gefitinib [8, 9], erlotinib [10, 11], and afatinib [12], has given superior anticancer effects than the standard platinum-doublet cytotoxic chemotherapy in patients with advanced NSCLC harboring activating EGFR mutations. However, these clinical trials were usually conducted only or mainly in healthy patients aged 75 years or younger. In elderly patients with advanced EGFR-mutated NSCLC, some reports [13–15] showed the efficacy and safety of gefitinib. However, to our knowledge, the antitumor effects and safety profiles of erlotinib focused on elderly patients have not been evaluated. Erlotinib reversibly inhibits EGFR signaling pathways by competitive binding to the adenosine triphosphate (ATP) site in the tyrosine kinase domain [6]. In addition to patients with EGFR activating mutations, erlotinib has shown efficacy even in molecularly unselected or EGFR wild-type NSCLC patients in second- or third-line settings [16, 17] and maintenance therapy [18]. Drug clearance, lean body mass, and residual organ function usually decrease in elderly patients, which raises the possibility that the relatively high dose of erlotinib might lead to severe or unexpected adverse events. Therefore, we conducted the current prospective phase II study to assess the efficacy and safety of erlotinib in elderly patients with advanced or recurrent NSCLC harboring activating EGFR mutations.
erlotinib for elderly patients with NSCLC harboring activating EGFR mutations. Eligible patients were aged ≥75 years and had pathologically confirmed advance stage IIIB, stage IV or recurrent NSCLC [based on the seventh tumor–node–metastasis (TNM) staging system] harboring activating EGFR mutations. In this study, EGFR mutations were restricted to exon 19 deletions or L858R mutations in exon 21. They also had an Eastern Cooperative Oncology Group performance status of 0–3 and adequate organ function. Chemotherapy-naïve patients and patients treated with first-line systemic chemotherapy were included. Patients were excluded if they had interstitial lung disease, uncontrolled symptomatic brain metastases, active infection, or other severe uncontrolled complications. Patients were not eligible if the T790M mutation was detected in their tumors.
Materials and methods
Evaluation of response and toxicity
Ethical approval of the study protocol
Evaluation of treatment response was repeated every 4 weeks according to Response Evaluation Criteria in Solid Tumors version 1.1. The response was assessed in reference to the CT findings that had initially been used to define tumor extent. Adverse events were graded based on the National Cancer Institute Common Toxicity Criteria version 4.0.
This study was undertaken in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of each participating institution. Informed consent was obtained from all individual participants included in the study. This study was registered at the UMIN Clinical Trials Registry as UMIN000010525 (http:// www.umin.ac.jp/ctr/). Study design and patient selection This study was a single-arm, open-label, multi-center, phase II trial of first-line or second-line treatment with
13
EGFR mutation screening EGFR mutation analysis was performed in all patients in commercial clinical laboratories, such as SRL in Tokyo (cycleave method), LSI Medience in Tokyo (peptide nucleic acid-locked nucleic acid PCR clamp method), or BML, Inc. in Tokyo (PCR invader method). Treatment schedule Patients were treated orally with erlotinib at a dose of 150 mg daily. Erlotinib was continued until disease progression, unacceptable toxic events, interstitial lung disease, or withdrawal of consent to participate in the study occurred. Dose reduction was permitted to 100 mg when severe toxicity was observed. If recovery of such toxicities could not be confirmed at a reduced dose, the patient was withdrawn from the study. Further therapy after progression of disease was permitted in the protocol.
Statistical analyses The primary end point of the study was the overall response rate (ORR): partial response (PR) plus complete response (CR). Secondary end points were planned to include progression-free survival (PFS), overall survival (OS), and safety.
Cancer Chemother Pharmacol
The minimum sample size enrolled in the present study was 27, assuming that the 95 % confidence interval (CI) would be 10 % below the conditions of an α error of 0.05 and a β error of 0.20, and assuming an expected RR of 55 % [10, 13, 19] and a threshold RR of 30 % [20, 21] based on the Simon selection design. According to the design, we aimed for 30 patients, after taking patients who dropped out of the study into consideration. The Fisher exact test was used to determine the association of the type of EGFR mutations with treatment response. PFS and OS were estimated using the Kaplan–Meier method. PFS was calculated as the time from the date of treatment initiation to the date of occurrence of progressive disease or death by any cause. OS was calculated as the time from the date of treatment initiation to the date of death by any cause. Outcomes were censored if an end point was not reached by the time of last follow-up or if a patient was lost to follow-up. The statistical analyses were performed using the software EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 3.0.2) [22]. P values
ORIGINAL ARTICLE
Phase II study of erlotinib in elderly patients with non‑small cell lung cancer harboring epidermal growth factor receptor mutations Yusuke Inoue1 · Naoki Inui1,2 · Kazuhiro Asada3 · Masato Karayama1,4 · Hiroyuki Matsuda5 · Koshi Yokomura6 · Naoki Koshimizu7 · Shiro Imokawa8 · Takashi Yamada9 · Toshihiro Shirai3 · Norio Kasamatsu10 · Takafumi Suda1
Received: 28 April 2015 / Accepted: 18 May 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are key drugs in the treatment of nonsmall cell lung cancer (NSCLC) harboring EGFR activating mutations. We assessed the efficacy and safety of one EGFR tyrosine kinase inhibitor, erlotinib, in elderly Japanese patients with EGFR-mutated NSCLC. Methods Elderly patients aged 75 or older with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) were enrolled in this prospective phase II trial. Patients received 150 mg erlotinib per day orally. The primary end point was the overall response rate. Results Between March 2013 and November 2014, 32 patients were enrolled with median age 80 years. All tumors had adenocarcinoma histology, and 20 patients (62.5 %) had an L858R mutation. The response rate was 56.3 % [95 % confidence interval (CI) 39.4–72.0 %], and the disease control rate was 90.6 % (95 % CI 75.2–97.6 %). Median progression-free survival was 15.5 months (95 %
CI 11.2–not reached). Skin disorder was the most common adverse event, and grade 4 drug-related interstitial lung disease occurred in one patient. Conclusions Erlotinib is effective and tolerated in elderly patients with EGFR mutation-positive NSCLC.
* Naoki Inui inui@hama‑med.ac.jp
6
Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara, Hamamatsu 433‑8558, Japan
7
Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4‑1‑11 Surugadai, Fujieda 426‑8677, Japan
8
Department of Respiratory Medicine, Iwata City Hospital, 512‑3 Ohkubo, Iwata 438‑8550, Japan
9
Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10‑93 Otemachi, Shizuoka 420‑8630, Japan
10
Department of Respiratory Medicine, Hamamatsu Medical Center, 328 Tomitsuka, Hamamatsu 432‑8580, Japan
1
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1‑20‑1 Handayama, Higashi‑ku, Hamamatsu 431‑3192, Japan
2
Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan
3
Department of Respiratory Medicine, Shizuoka General Hospital, 4‑27‑1 Kita‑ando, Shizuoka 420‑8527, Japan
4
Department of Clinical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan
5
Department of Respiratory Medicine, Japanese Red Cross Shizuoka Hospital, 8‑2 Otemachi, Shizuoka 420‑0853, Japan
Keywords Elderly · Erlotinib · Epidermal growth factor receptor · EGFR mutation · Non-small cell lung cancer
Introduction Lung cancer, of which non-small cell lung cancer (NSCLC) accounts for almost 80 %, has long been a leading cause of cancer-related death worldwide [1]. Because lung cancer is associated with aging, and the risk of NSCLC increases with advancing age [2], the number of elderly patients with NSCLC is increasing in developed countries due to the aging population. The elderly tend to have impaired organ function, more co-morbidities [3, 4], and an advanced
13
Cancer Chemother Pharmacol
disease stage [5], which necessitate tailored treatment strategies. Recently, molecular-targeted therapeutic strategies have been established in the treatment of NSCLC with gene alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, by inhibition of critical signaling pathways in cancer cells. Approximately 10 % of patients with NSCLC in the USA and 35 % in East Asia have tumors harboring EGFR mutations [6, 7]. Treatment with EGFR tyrosine kinase inhibitors, gefitinib [8, 9], erlotinib [10, 11], and afatinib [12], has given superior anticancer effects than the standard platinum-doublet cytotoxic chemotherapy in patients with advanced NSCLC harboring activating EGFR mutations. However, these clinical trials were usually conducted only or mainly in healthy patients aged 75 years or younger. In elderly patients with advanced EGFR-mutated NSCLC, some reports [13–15] showed the efficacy and safety of gefitinib. However, to our knowledge, the antitumor effects and safety profiles of erlotinib focused on elderly patients have not been evaluated. Erlotinib reversibly inhibits EGFR signaling pathways by competitive binding to the adenosine triphosphate (ATP) site in the tyrosine kinase domain [6]. In addition to patients with EGFR activating mutations, erlotinib has shown efficacy even in molecularly unselected or EGFR wild-type NSCLC patients in second- or third-line settings [16, 17] and maintenance therapy [18]. Drug clearance, lean body mass, and residual organ function usually decrease in elderly patients, which raises the possibility that the relatively high dose of erlotinib might lead to severe or unexpected adverse events. Therefore, we conducted the current prospective phase II study to assess the efficacy and safety of erlotinib in elderly patients with advanced or recurrent NSCLC harboring activating EGFR mutations.
erlotinib for elderly patients with NSCLC harboring activating EGFR mutations. Eligible patients were aged ≥75 years and had pathologically confirmed advance stage IIIB, stage IV or recurrent NSCLC [based on the seventh tumor–node–metastasis (TNM) staging system] harboring activating EGFR mutations. In this study, EGFR mutations were restricted to exon 19 deletions or L858R mutations in exon 21. They also had an Eastern Cooperative Oncology Group performance status of 0–3 and adequate organ function. Chemotherapy-naïve patients and patients treated with first-line systemic chemotherapy were included. Patients were excluded if they had interstitial lung disease, uncontrolled symptomatic brain metastases, active infection, or other severe uncontrolled complications. Patients were not eligible if the T790M mutation was detected in their tumors.
Materials and methods
Evaluation of response and toxicity
Ethical approval of the study protocol
Evaluation of treatment response was repeated every 4 weeks according to Response Evaluation Criteria in Solid Tumors version 1.1. The response was assessed in reference to the CT findings that had initially been used to define tumor extent. Adverse events were graded based on the National Cancer Institute Common Toxicity Criteria version 4.0.
This study was undertaken in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of each participating institution. Informed consent was obtained from all individual participants included in the study. This study was registered at the UMIN Clinical Trials Registry as UMIN000010525 (http:// www.umin.ac.jp/ctr/). Study design and patient selection This study was a single-arm, open-label, multi-center, phase II trial of first-line or second-line treatment with
13
EGFR mutation screening EGFR mutation analysis was performed in all patients in commercial clinical laboratories, such as SRL in Tokyo (cycleave method), LSI Medience in Tokyo (peptide nucleic acid-locked nucleic acid PCR clamp method), or BML, Inc. in Tokyo (PCR invader method). Treatment schedule Patients were treated orally with erlotinib at a dose of 150 mg daily. Erlotinib was continued until disease progression, unacceptable toxic events, interstitial lung disease, or withdrawal of consent to participate in the study occurred. Dose reduction was permitted to 100 mg when severe toxicity was observed. If recovery of such toxicities could not be confirmed at a reduced dose, the patient was withdrawn from the study. Further therapy after progression of disease was permitted in the protocol.
Statistical analyses The primary end point of the study was the overall response rate (ORR): partial response (PR) plus complete response (CR). Secondary end points were planned to include progression-free survival (PFS), overall survival (OS), and safety.
Cancer Chemother Pharmacol
The minimum sample size enrolled in the present study was 27, assuming that the 95 % confidence interval (CI) would be 10 % below the conditions of an α error of 0.05 and a β error of 0.20, and assuming an expected RR of 55 % [10, 13, 19] and a threshold RR of 30 % [20, 21] based on the Simon selection design. According to the design, we aimed for 30 patients, after taking patients who dropped out of the study into consideration. The Fisher exact test was used to determine the association of the type of EGFR mutations with treatment response. PFS and OS were estimated using the Kaplan–Meier method. PFS was calculated as the time from the date of treatment initiation to the date of occurrence of progressive disease or death by any cause. OS was calculated as the time from the date of treatment initiation to the date of death by any cause. Outcomes were censored if an end point was not reached by the time of last follow-up or if a patient was lost to follow-up. The statistical analyses were performed using the software EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 3.0.2) [22]. P values
