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Research ArticleClinical Studies

Pemetrexed and Cisplatin for Advanced Non-squamous Non-small Cell Lung Cancer in Japanese Patients: Phase II Study

YUKO KAWANO, FUMIYOSHI OHYANAGI, NORIKO YANAGITANI, KEITA KUDO, ATSUSHI HORIIKE, AZUSA TANIMOTO, HIRONARI NISHIZAWA, ATSUO ICHIKAWA, TOSHIO SAKATANI, KATSUMI NAKATOMI, SACHIKO HAGIWARA, HIRONORI NINOMIYA, NORIKO MOTOI, YUICHI ISHIKAWA, TAKESHI HORAI and MAKOTO NISHIO
Anticancer Research August 2013, 33 (8) 3327-3333;
YUKO KAWANO
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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FUMIYOSHI OHYANAGI
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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NORIKO YANAGITANI
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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KEITA KUDO
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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ATSUSHI HORIIKE
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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AZUSA TANIMOTO
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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HIRONARI NISHIZAWA
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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ATSUO ICHIKAWA
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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TOSHIO SAKATANI
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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KATSUMI NAKATOMI
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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SACHIKO HAGIWARA
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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HIRONORI NINOMIYA
2Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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NORIKO MOTOI
2Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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YUICHI ISHIKAWA
2Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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TAKESHI HORAI
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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MAKOTO NISHIO
1Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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  • For correspondence: mnishio@jfcr.or.jp
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  • Errata - September 01, 2013

Abstract

Background: Although pemetrexed/cisplatin (P-C) is a standard treatment for advanced non-squamous non-small cell lung cancer (Nsq-NSCLC), neither its efficacy nor the effects of potential differences between driver mutations, such as the anaplastic lymphoma kinase (ALK) translocation and epidermal growth factor receptor (EGFR) mutations, have been thoroughly examined. Patients and Methods: A single-arm phase II study of P-C was conducted in Japanese patients with chemo-naïve advanced Nsq-NSCLC. Patients received four cycles of pemetrexed (500 mg/m2) combined with cisplatin (75 mg/m2) on day 1 every three weeks. The primary end-point was the response rate (RR) and the secondary end-points were toxicity, progression-free survival (PFS), and overall survival (OS). Results: A total of 50 patients were analyzed (males, 68%; adenocarcinoma, 80%). The RR was 44.0%. The median PFS and OS were 4.3 months and 22.2 months, respectively. Toxicities were mild, and no new toxicity profiles were identified. Among the 39 out of 50 samples, six (15.4%) presented ALK translocation and nine (23.1%) presented EGFR mutations; of the remaining patients, 24 (61.5%) were wild-type for both ALK and EGFR. Objective response was observed in two out of six patients with ALK translocations, six out of nine with EGFR mutations, and in 11 (45.8%) wild-type patients. Conclusion: The combination of pemetrexed and cisplatin was effective and safe in Japanese patients with Nsq-NSCLC. We did not observe obvious differences in the efficacy of P-C between patients with ALK translocation or EGFR mutation and those with wild-type genotype.

  • Pemetrexed
  • cisplatin
  • ALK
  • non-squamous NSCLC
  • Japanese

Lung cancer is the major cause of cancer-related deaths worldwide. Approximately 85% of lung tumors are non-small cell lung cancers (NSCLC), 70% of which are either inoperable, locally advanced or metastatic (1). Two-drug combinations of a third-generation agent (docetaxel, paclitaxel, gemcitabine, vinorelbine, and pemetrexed) with a platinum compound (cisplatin and carboplatin) are the standard treatment options for advanced NSCLC (2-5).

Pemetrexed (Alimuta®; Eli Lilly and Company, Indianapolis, IN, USA) is a multitargeted antifolate that inhibits thymidylate synthase (TYMS), dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase (6).

Randomized phase III clinical trials have demonstrated that pemetrexed is efficacious both in combination with cisplatin (P-C) for first-line treatment of NSCLC–having non-inferior efficacy and better tolerability than for the combination of gemcitabine and cisplatin (4)–and as a single-agent in second-line treatment (7). Moreover, in patients with non-squamous NSCLC (Nsq-NSCLC), pemetrexed has superior efficacy compared with other standard treatments, and the combination therapy with cisplatin leads to superior overall survival (OS) compared with gemcitabine and cisplatin, and is one of the most common regimens for treatment of metastatic Nsq-NSCLC (8).

Adenocarcinoma is the major histological type of Nsq-NSCLC. More than 75% East Asian never-smokers with lung adenocarcinoma harbor targetable oncogenic mutations, including epidermal growth factor receptor (EGFR) mutations, fusions of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK; 5.8%) (9, 10). Therefore, ethnic differences and driver mutations are important factors in NSCLC (particularly adenocarcinoma) treatment.

Recent reports revealed the impact of EGFR mutations, and ALK translocation on the efficacy of pemetrexed and P-C therapies (11-14). Moreover, ethnicity is a prognostic factor; East and South Asian patients had longer survival compared with that in the entire study population (Whites, African descent, East Asians, and others) in a phase III study (15) –and may be a predictive biomarker of enhanced sensitivity to pemetrexed. Although P-C provided tolerability in a phase I/ II study of malignant pleural mesothelioma in Japan (16), its overall efficacy, and that according to tumor genotype, has not been well-evaluated in Japanese patients with Nsq-NSCLC.

We conducted this prospective study to evaluate the efficacy and safety of P-C in Japanese patients with Nsq-NSCLC, and to determine whether the EGFR mutation or ALK translocation impacted the treatment outcome in these patients.

Patients and Methods

Eligibility. Patients with histologically- or cytologically-confirmed Nsq-NSCLC were eligible for this study. Additional eligibility criteria were as follows: clinical stage IIIB, IV, or recurrent disease, no prior chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow, renal, and hepatic function. Patients with unstable brain metastases, uncontrolled pleural effusion or ascites, active infection, active concomitant malignancy or interstitial pneumonia were excluded. The study protocol was approved by the Institutional Review Board at our center (UMIN000002847). All patients signed written informed consent before enrollment.

Treatment plan. Patients received pemetrexed (500 mg/m2) intravenously (i.v.) for over 10 min followed by cisplatin (75 mg/m2, i.v.) over 2 h on day 1 of a 21-day cycle. This combination therapy was repeated for up to four cycles. Patients were instructed to take oral multivitamin supplement (1 g/day) containing 500 mg folic acid beginning one week before the first treatment until 22 days after the last pemetrexed administration; vitamin B12 (1000 mg) was injected intramuscularly every nine weeks during the same period.

The second and subsequent treatment cycles were initiated only when the following criteria were satisfied on day 1 of the cycle: white blood cells ≥3,000/mm3 or neutrophils ≥1,500/mm3, platelets ≥100,000/mm3, PS ≤1, creatinine ≤1.5 mg/dl, aspartate aminotransferase (AST)/alanine aminotransferase(ALT) ≤100IU/l, total bilirubin ≤1.5 mg/dl, body temperature(BT) <38°C, no interstitial pneumonia, non-hematological toxicity ≤G1. Pemetrexed was reduced to 400 mg/m2 in the subsequent cycles if chemotherapy induced either grade 4 leukopenia or neutropenia for more than five days or grade 4 thrombocytopenia or thrombocytopenia requiring platelet transfusion, grade 3 febrile neutropenia or grade 3 non-hematological toxicities. Cisplatin was reduced to 60 mg/m2 in the subsequent cycles if these toxicities recurred after the dose reduction of pemetrexed or if serum creatinine was more than 2.0 mg/dl. Patients would be withdrawn from the study if these toxicities recurred after the reduction in cisplatin dose, or if the next cycle was delayed because of toxicity for by more than 43 days

Evaluation of tumor response and toxicity. Complete patient histories, physical examinations, complete blood cell counts, serum electrolytes and chemistry were performed before initiation of treatment and before each treatment cycle. Tumor status and response were assessed by radiological examination, including computed tomography, at baseline and after every two treatment cycles. Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.0) (17) were used to define the antitumor effects, and toxicity was assessed based on the National Cancer Institute Common Toxicity Criteria (version 3.0) (18).

Detection of oncogene driver mutations. Genomic DNA was extracted from tumors embedded in paraffin blocks or from tumor cells from aspirates of pleural effusions, or biopsied superficial lymph nodes or subcutaneous metastases. Mutations in EGFR exons 19 and 21 were detected by the Cycleave real-time quantitative PCR technique, and the ALK translocation was examined using fluorescence in situ hybridization or highly sensitive immunohistochemistry (IHC) to detect the ALK fusion protein (19).

Statistical analysis. This study was a prospective, single-center, single-arm study (UMIN000002847) of first-line combination therapy withP-C. The primary end-point was the response rate (RR) and the secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS).

A Simon's minimax two-stage phase II design (20) was used to define minimum sample sizes for statistical significance: assuming an expected overall RR of ≥50% and a minimum acceptable RR of 30%, 22 patients would be required as the first step. Our plan further stipulated that if at least seven out of the 22 patients responded to the therapy, another 24 patients would be required as the second step. If at least 17 of the 46 patients responded, the treatment would be declared sufficiently promising. OS was recorded as the time from registration until either death or conclusion of the analysis; PFS was the time from registration to documented progression or death from any cause, whichever occurred first. Survival analyses were performed using the Kaplan-Meier method. All statistical analyses were performed using the SPSS 17.0 statistical software (Dr SPSS II for Windows, Standard version 17.0; SPSS Inc., Chicago, IL, USA).

Results

Patients' characteristics. From November 2009 until January 2010, 50 patients with Nsq-NSCLC were enrolled. Patients' characteristics are listed in Table I. The median age was 60 years (range 28-74), and there were 34 males and 16 females. Thirty-one patients had PS 0 and 19 patients had PS 1. Forty-one patients (82.0%) had adenocarcinoma. EGFR mutation status was analyzed in 46 patients; nine patients (19.6%) harbored an activating mutation in EGFR. ALK-translocation was identified in six (15.4%) out of 39 patients analyzed. Six patients were positive by FISH, five out of six patients were positive by IHC, but the remaining patients were not evaluable by IHC.

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Table I.

Patients' characteristics.

Response and survival. Fifty patients were analyzed. There were no complete responses, 22 partial responses, 17 cases of stable disease, 10 of progressive disease, and one case was non-evaluable because of grade 5 pneumonitis during the first treatment cycle. Thus, the overall RR was 44.0% [95% confidence interval (CI)=30.0%-58.0%], and the disease control rate (DCR) was 78.0% (95% CI=66.0%-90.0%; Table II). At the median follow-up period of 19.0 months (range=1.4-35.2 months), the median PFS and OS were 4.3 months (95% CI=3.9-4.8 months; Figure 1A) and 22.2 months (95% CI=13.4-31.0 months; Figure 2B), respectively.

Treatment delivery. Thirty-three (66.0%) patients completed four cycles of P-C therapy. The median number of chemotherapy cycles administered throughout the study was four (range=1-4 cycles). However, one patient had dose reduction of cisplatin because of elevated serum creatinine level, two patients had dose reduction of pemetrexed because of infection (one patient) and fatigue (one patient).

Toxicity. Toxicity was evaluated in all patients in all cycles (Table III). Grade 3 or 4 neutropenia was observed in eight patients (16%) and grade 3 infection in three (6%), but there were no cases of febrile neutropenia. In addition, grade 3 or 4 anemia was observed in eight patients (16%), and grade 3 elevations of serum creatinine level were observed in two patients. Furthermore, one patient (2%) experienced grade 5 pneumonitis after one cycle.

Subgroup analysis by ALK fusion status and EGFR mutation status. Among the 39 out of 50 patients, we identified ALK translocations in six patients (15.4%), EGFR mutations in nine (23.1%), and wild-type ALK and EGFR in 24 patients (61.5%) (referred to as WT/WT). However, we were unable to examine ALK translocation in 11 patients and EGFR mutations in four patients because of insufficient material. Objective responses were observed in two patients with ALK translocation, six with EGFR mutation, and 11 (45.8%) of the WT/WT group. However, there were no significant differences in PFS by genotype. The median PFS in the ALK translocation, EGFR mutation and WT/WT subgroups were 3.0 months (95% CI=0.0-8.3 months), 5.5 months (95% CI=4.7-6.4 months) and 4.0 months (95% CI=2.9-5.1 months), respectively (Figure 1B). Median OS had not yet been reached in the patients with EGFR mutation and ALK translocation, and was 15.8 months in WT/WT patients (95% CI=2.9-28.8 months; Figure 2B).

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Table II.

Response rates.

Discussion

The impact of ethnicity and oncogene driver mutations on advanced NSCLC treatment has only recently begun to be considered. Although there have been several phase II and III studies of P-C for Nsq-NSCNC worldwide, there are no data for Japanese patients. In our phase II study of Japanese patients with Nsq-NSCLC, we observed that the efficacy of P-C in terms of overall RR and median PFS was comparable to those for other ethnicities, and we did not identify any new safety concerns. In our study, the overall RR was 44.0%, and the median PFS was 4.3 months, whereas in global studies, these values were 30.9%-45% and 5.3-6.3 months, respectively (4, 21, 22). Toxicities were mostly very mild; the major toxicities were myelosuppression, and the incidence of either grade 3 or grade 4 neutropenia or anemia were 16%. However, the toxicity profile was similar to that of previous studies: grade 3 or grade 4 neutropenia, 15.1%-58.3%; anemia, 5.6%-20% (4, 21, 22).

The median OS of our whole-patient sample was 22.2 months, which is significantly longer than that in previous reports (8.9-11.8 months) (4, 21, 22). Ethnic differences might have resulted in this discrepancy. Similar results were observed in a subset analysis of a previous global phase III study reporting that East Asian patients with Nsq-NSCLC (Taiwan and Korea) had longer median OS (21.2 months) than that of the population overall (23). In subset analysis of our study, patients with EGFR mutations or ALK translocations exhibited longer median OS compared with that in WT/WT patients. The driver mutation status and target therapy after the discontinuation of P-C may be related to prolonged survival. All patients with ALK translocations received ALK inhibitors for second-line or third-line treatment, and all patients with EGFR mutations received EGFR tyrosine kinase inhibitor for second-line treatment.

Figure 1.
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Figure 1.

Kaplan-Meier curves for progression-free survival (PFS) (N=50). The median PFS (N=50) was 4.3 months (A). The median PFS in subgroups of with patients with anaplastic lymphoma kinase (ALK) translocation, epidermal growth factor receptor (EGFR) mutation, wild-type for both ALK and EGFR (WT/WT) were 3.0, 5.5 and 4.0 months, respectively (B).

Figure 2.
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Figure 2.

Kaplan–Meier curves for overall survival (OS) (N=50). The overall median OS (N=50) was 22.2 months (A). The median OS had not yet been reached in the patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocation, but was 15.8 months in wild-type for both ALK and EGFR (WT/WT) patients (B).

Some reports correlate EGFR mutations with the efficacy of pemetrexed. NSCLC cells with activating mutations in EGFR had lower TYMS expression than those with wild-type EGFR (24). In one study, patients with EGFR mutations receiving pemetrexed monotherapy responded more favorably and also had longer PFS than those with wild-type EGFR (14). TYMS is key folate enzyme targeted by pemetrexed and TYMS levels may correlate inversely with sensitivity to pemetrexed (25). In our study, the RR was higher in the nine patients with EGFR mutations than in the entire study population (6/9 vs. 44.0%), although there were no differences in PFS.

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Table III.

Hematological and non-hematological toxicities (N=50) experienced with pemetrexed-cisplatin therapy.

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Table IV.

Patients' characteristics by genotype.

ALK translocation has been identified as a driver mutation in NSCLC (26), and ALK tyrosine kinase inhibitors such as crizotinib have had a profound impact on the treatment of advanced NSCLC (27). Several retrospective studies report conflicting results on the efficacy of pemetrexed in ALK-positive patients. Camidge et al. reported that ALK-positive patients respond to pemetrexed with a better RR and longer PFS than WT patients (11). However, one of the largest retrospective analyses of pemetrexed-based chemotherapy documented no difference in PFS with respect to ALK status (13). In the phase III study of ALK-positive NSCLC comparing crizotinib, pemetrexed and docetaxel, overall RR and PFS were higher in the pemetrexed arm than in the docetaxel arm: 29.3% vs. 6.9% and 4.2 months vs. 2.6 months, respectively (28). Moreover, patients with ALK re-arrangements had lower TYMS expression than those with normal ALK loci. In our study, RR was lower in the six patients with ALK translocations than in the entire study population (6/9 vs. 44.0%), but there were no differences in PFS.

However, it is difficult to conclude on the mechanism of sensitivity to P-C therapy on the basis of the TYMS level in tumor tissue because of the lack of TYMS evaluation in our study. In addition, our study was too small to conclude whether particular genotypes correlate with the efficacy of P-C.

In conclusion, P-C therapy was effective and well-tolerated in Japanese patients with Nsq-NSCLC. We did not observe any obvious differences in the efficacy of P-C treatment between patients with ALK translocation or EGFR mutation status and these wild-type for these genes.

Acknowledgements

The Authors thank all the patients and investigators who participated in this study.

Footnotes

  • Disclosure

    The Authors have declared no conflicts of interest.

  • Received May 29, 2013.
  • Revision received June 27, 2013.
  • Accepted June 28, 2013.
  • Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

References

  1. ↵
    1. Breathnach OS,
    2. Freidlin B,
    3. Conley B,
    4. Green MR,
    5. Johnson DH,
    6. Gandara DR,
    7. O'Connell M,
    8. Shepherd FA,
    9. Johnson BE
    : Twenty-two years of phase III trials for patients with advanced non-small cell lung cancer: Sobering results. J Clin Oncol 19: 1734-1742, 2001.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Non-small Cell Lung Cancer Collaborative Group
    : Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311: 899-909, 1995.
    OpenUrlAbstract/FREE Full Text
    1. Ohe Y,
    2. Ohashi Y,
    3. Kubota K,
    4. Tamura T,
    5. Nakagawa K,
    6. Negoro S,
    7. Nishiwaki Y,
    8. Saijo N,
    9. Ariyoshi Y,
    10. Fukuoka M
    : Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 18: 317-323, 2007.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Scagliotti GV,
    2. Parikh P,
    3. von Pawel J,
    4. Biesma B,
    5. Vansteenkiste J,
    6. Manegold C,
    7. Serwatowski P,
    8. Gatzemeier U,
    9. Digumarti R,
    10. Zukin M,
    11. Lee JS,
    12. Mellemgaard A,
    13. Park K,
    14. Patil S,
    15. Rolski J,
    16. Goksel T,
    17. de Marinis F,
    18. Simms L,
    19. Sugarman KP,
    20. Gandara D
    : Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small cell lung cancer. J Clin Oncol 26: 3543-3551, 2008.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Schiller JH,
    2. Harrington D,
    3. Belani CP,
    4. Langer C,
    5. Sandler A,
    6. Krook J,
    7. Zhu J,
    8. Johnson DH,
    9. Eastern Cooperative Oncology G
    : Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 346: 92-98, 2002.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Kut V,
    2. Patel JD,
    3. Argiris A
    : Pemetrexed: A novel antifolate agent enters clinical practice. Expert Rev Anticancer Ther 4: 511-522, 2004.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Hanna N,
    2. Shepherd FA,
    3. Fossella FV,
    4. Pereira JR,
    5. De Marinis F,
    6. von Pawel J,
    7. Gatzemeier U,
    8. Tsao TC,
    9. Pless M,
    10. Muller T,
    11. Lim HL,
    12. Desch C,
    13. Szondy K,
    14. Gervais R,
    15. Shaharyar,
    16. Manegold C,
    17. Paul S,
    18. Paoletti P,
    19. Einhorn L,
    20. Bunn PA Jr..
    : Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 22: 1589-1597, 2004.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Kubota K,
    2. Niho S,
    3. Enatsu S,
    4. Nambu Y,
    5. Nishiwaki Y,
    6. Saijo N,
    7. Fukuoka M
    : Efficacy differences of pemetrexed by histology in pretreated patients with stage IIIB/IV non-small cell lung cancer: Review of results from an open-label randomized phase II study. J Thorac Oncol 4: 1530-1536, 2009.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Mitsudomi T
    : Advances in target therapy for lung cancer. Jpn J Clin Oncol 40: 101-106, 2010.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Sun Y,
    2. Ren Y,
    3. Fang Z,
    4. Li C,
    5. Fang R,
    6. Gao B,
    7. Han X,
    8. Tian W,
    9. Pao W,
    10. Chen H,
    11. Ji H
    : Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol 28: 4616-4620, 2010.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Camidge DR,
    2. Kono SA,
    3. Lu X,
    4. Okuyama S,
    5. Baron AE,
    6. Oton AB,
    7. Davies AM,
    8. Varella-Garcia M,
    9. Franklin W,
    10. Doebele RC
    : Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 6: 774-780, 2011.
    OpenUrlCrossRefPubMed
    1. Lee JO,
    2. Kim TM,
    3. Lee SH,
    4. Kim DW,
    5. Kim S,
    6. Jeon YK,
    7. Chung DH,
    8. Kim WH,
    9. Kim YT,
    10. Yang SC,
    11. Kim YW,
    12. Heo DS,
    13. Bang YJ
    : Anaplastic lymphoma kinase translocation: A predictive biomarker of pemetrexed in patients with non-small cell lung cancer. J Thorac Oncol 6: 1474-1480, 2011.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Shaw AT,
    2. Varghese AM,
    3. Solomon BJ,
    4. Costa DB,
    5. Novello S,
    6. Mino-Kenudson M,
    7. Awad MM,
    8. Engelman JA,
    9. Riely GJ,
    10. Monica V,
    11. Yeap BY,
    12. Scagliotti GV
    : Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer. Ann Oncol 24: 59-66, 2013.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Wu SG,
    2. Yang CH,
    3. Yu CJ,
    4. Lee JH,
    5. Hsu YC,
    6. Chang YL,
    7. Shih JY,
    8. Yang PC
    : Good response to pemetrexed in patients of lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Lung Cancer 72: 333-339, 2011.
    OpenUrlPubMed
  13. ↵
    1. Syrigos KN,
    2. Vansteenkiste J,
    3. Parikh P,
    4. von Pawel J,
    5. Manegold C,
    6. Martins RG,
    7. Simms L,
    8. Sugarman KP,
    9. Visseren-Grul C,
    10. Scagliotti GV
    : Prognostic and predictive factors in a randomized phase III trial comparing cisplatin-pemetrexed versus cisplatin-gemcitabine in advanced non-small-cell lung cancer. Ann Oncol 21: 556-561, 2010.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Nakagawa K,
    2. Yamazaki K,
    3. Kunitoh H,
    4. Hida T,
    5. Gemba K,
    6. Shinkai T,
    7. Ichinose Y,
    8. Adachi S,
    9. Nambu Y,
    10. Saijo N,
    11. Fukuoka M
    : Efficacy and safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: A phase I/II study in Japanese patients. Jpn J Clin Oncol 38: 339-346, 2008.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Therasse P,
    2. Arbuck SG,
    3. Eisenhauer EA,
    4. Wanders J,
    5. Kaplan RS,
    6. Rubinstein L,
    7. Verweij J,
    8. Van Glabbeke M,
    9. van Oosterom AT,
    10. Christian MC,
    11. Gwyther SG
    : New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205-216, 2000.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    The National Cancer Institute Common Toxicity Criteria: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.
  17. ↵
    1. Takeuchi K,
    2. Choi YL,
    3. Togashi Y,
    4. Soda M,
    5. Hatano S,
    6. Inamura K,
    7. Takada S,
    8. Ueno T,
    9. Yamashita Y,
    10. Satoh Y,
    11. Okumura S,
    12. Nakagawa K,
    13. Ishikawa Y,
    14. Mano H
    : KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15: 3143-3149, 2009.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Simon R
    : Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10: 1-10, 1989.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Manegold C,
    2. Gatzemeier U,
    3. von Pawel J,
    4. Pirker R,
    5. Malayeri R,
    6. Blatter J,
    7. Krejcy K
    : Front-line treatment of advanced non-small cell lung cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: A multicenter phase II trial. Ann Oncol 11: 435-440, 2000.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Shepherd FA,
    2. Dancey J,
    3. Arnold A,
    4. Neville A,
    5. Rusthoven J,
    6. Johnson RD,
    7. Fisher B,
    8. Eisenhauer E
    : Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: A study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 92: 595-600, 2001.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Yang CH,
    2. Simms L,
    3. Park K,
    4. Lee JS,
    5. Scagliotti G,
    6. Orlando M
    : Efficacy and safety of cisplatin/pemetrexed versus cisplatin/gemcitabine as first-line treatment in East Asian patients with advanced non-small cell lung cancer: Results of an exploratory subgroup analysis of a phase III trial. J Thorac Oncol 5: 688-695, 2010.
    OpenUrlPubMed
  22. ↵
    1. Giovannetti E,
    2. Lemos C,
    3. Tekle C,
    4. Smid K,
    5. Nannizzi S,
    6. Rodriguez JA,
    7. Ricciardi S,
    8. Danesi R,
    9. Giaccone G,
    10. Peters GJ
    : Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small cell lung cancer cells. Mol Pharmacol 73: 1290-1300, 2008.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Takezawa K,
    2. Okamoto I,
    3. Okamoto W,
    4. Takeda M,
    5. Sakai K,
    6. Tsukioka S,
    7. Kuwata K,
    8. Yamaguchi H,
    9. Nishio K,
    10. Nakagawa K
    : Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer 104: 1594-1601, 2011.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Soda M,
    2. Choi YL,
    3. Enomoto M,
    4. Takada S,
    5. Yamashita Y,
    6. Ishikawa S,
    7. Fujiwara S,
    8. Watanabe H,
    9. Kurashina K,
    10. Hatanaka H,
    11. Bando M,
    12. Ohno S,
    13. Ishikawa Y,
    14. Aburatani H,
    15. Niki T,
    16. Sohara Y,
    17. Sugiyama Y,
    18. Mano H
    : Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 448: 561-566, 2007.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Camidge DR,
    2. Bang YJ,
    3. Kwak EL,
    4. Iafrate AJ,
    5. Varella-Garcia M,
    6. Fox SB,
    7. Riely GJ,
    8. Solomon B,
    9. Ou SH,
    10. Kim DW,
    11. Salgia R,
    12. Fidias P,
    13. Engelman JA,
    14. Gandhi L,
    15. Janne PA,
    16. Costa DB,
    17. Shapiro GI,
    18. Lorusso P,
    19. Ruffner K,
    20. Stephenson P,
    21. Tang Y,
    22. Wilner K,
    23. Clark JW,
    24. Shaw AT
    : Activity and safety of crizotinib in patients with ALK-positive non-small cell lung cancer: Updated results from a phase I study. Lancet Oncol 13: 1011-1019, 2012.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Shaw AT,
    2. Kim DW,
    3. Nakagawa K,
    4. Seto T,
    5. Crino L,
    6. Ahn MJ,
    7. De Pas T,
    8. Besse B,
    9. Solomon BJ,
    10. Blackhall F,
    11. Wu YL,
    12. Thomas M,
    13. O'Byrne KJ,
    14. Moro-Sibilot D,
    15. Camidge DR,
    16. Mok T,
    17. Hirsh V,
    18. Riely GJ,
    19. Iyer S,
    20. Tassell V,
    21. Polli A,
    22. Wilner KD,
    23. Janne PA
    : Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368: 2385-2394, 2013.
    OpenUrlCrossRefPubMed
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Anticancer Research: 33 (8)
Anticancer Research
Vol. 33, Issue 8
August 2013
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Pemetrexed and Cisplatin for Advanced Non-squamous Non-small Cell Lung Cancer in Japanese Patients: Phase II Study
YUKO KAWANO, FUMIYOSHI OHYANAGI, NORIKO YANAGITANI, KEITA KUDO, ATSUSHI HORIIKE, AZUSA TANIMOTO, HIRONARI NISHIZAWA, ATSUO ICHIKAWA, TOSHIO SAKATANI, KATSUMI NAKATOMI, SACHIKO HAGIWARA, HIRONORI NINOMIYA, NORIKO MOTOI, YUICHI ISHIKAWA, TAKESHI HORAI, MAKOTO NISHIO
Anticancer Research Aug 2013, 33 (8) 3327-3333;

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Pemetrexed and Cisplatin for Advanced Non-squamous Non-small Cell Lung Cancer in Japanese Patients: Phase II Study
YUKO KAWANO, FUMIYOSHI OHYANAGI, NORIKO YANAGITANI, KEITA KUDO, ATSUSHI HORIIKE, AZUSA TANIMOTO, HIRONARI NISHIZAWA, ATSUO ICHIKAWA, TOSHIO SAKATANI, KATSUMI NAKATOMI, SACHIKO HAGIWARA, HIRONORI NINOMIYA, NORIKO MOTOI, YUICHI ISHIKAWA, TAKESHI HORAI, MAKOTO NISHIO
Anticancer Research Aug 2013, 33 (8) 3327-3333;
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Keywords

  • pemetrexed
  • cisplatin
  • ALK
  • non-squamous NSCLC
  • Japanese
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