Japanese Journal of Clinical Oncology Advance Access published May 19, 2015 Japanese Journal of Clinical Oncology, 2015, 1–2 doi: 10.1093/jjco/hyv074 Editorial
Editorial Chemotherapy for lung cancer: still alive! *For reprints and all correspondence: Katsuyuki Kiura , Okayama University Hospital, 2-5-1 Shikatacho, Okayama 700-8558, Japan. E-mail: kkiura@ md.okayama-u.ac.jp provides a marked substantial advantage for PFS, but not OS (4,6–9). Median OS of cohorts initially treated with chemotherapy were better than those of the initial EGFR TKI cohorts in four of six trials; median OS was similar between cohorts in one of the remaining trials. Additionally, treatment sequence [whether EGFR TKI followed or preceded chemotherapy] had no impact on OS. This conclusion contrasts with the overall results of five RCTs, which showed that initial TKI treatment provides a marked substantial advantage for PFS, but not OS. Median OS of cohorts initially treated with chemotherapy were better than those of the initial EGFR TKI cohorts in four of six trials; median OS was similar between cohorts in one of the remaining trials. Taken together, these results indicate that when EGFR TKIs are employed first, close attention should be given to the timing of chemotherapy initiation, at least in regard to the RECIST PD. Chemotherapy is essential to increase patient survival rates since the OS in patients with advanced NSCLC harboring EGFR gene mutations is currently ∼4 years (10). As Dr Kris described in the ASCO Educational Booklet, ‘in 2014, nearly all persons with lung cancers will receive and benefit from intravenous chemotherapies at some point in their illness. This being the case, it is imperative to understand how to best use and tailor chemotherapies with targeted agents.’ While not stated directly, the paper appears to suggest that in clinical practice, patients with progressive disease might not have the opportunity to switch from gefitinib to chemotherapy because physicians, as well as patients, prefer to use EGFR TKIs due to their moderate adverse events, oral intake and use in an outpatient setting. This treatment strategy tended to show shorter OS than that observed with chemotherapy followed by TKIs (the WJTOG3405 trial showed 36% of patients did not receive platinum doublet chemotherapy) (4,5 in Table 1).
Table 1. Phase III clinical trials comparing EGFR TKIs with chemotherapy in the first-line setting Study
Treatment
N
Median PFS (months)
NEJ002 (2009) (2) 2011 (3) WJTOG3405 (2009) (4) 2014 (5) OPTIMAL (6) EURTAC (7)
Gefitinib versus carboplatin/paclitaxel
230
Gefitinib versus cisplatin/docetaxel
177
10.8 versus 5.4 (P = 0.001) 10.8 versus 5.4 (P = 0.001) 9.2 versus 6.3 (P = 0.0001)
Erlotinib versus carboplatin/gemcitabine Erlotinib versus platinum-based chemotherapy Afatinib versus cisplatin/pemetrexed Afatinib versus cisplatin/gemcitabine
165 174
LUX-Lung 3 (8) LUX-Lung 6 (9)
Median OS (months)
30.5 versus 23.6 (P = 0.31) HR 0.798 27.7 versus 26.6 (P = 0.48) HR 0.887 30.9 versus NR HR 1.64 34.8 versus 37.3 HR 1.25 13.1 versus 4.6 (P = 0.0001) HR 1.065 (P = 0.65) 9.7 versus 5.2 (P = 0.0001) 19.3 versus 19.5 (P = 0.87)
345 11.1 versus 6.9 (P = 0.0004) 28.2 versus 28.2 HR 0.88 (P = 0.385) 364 (2 : 1) 11.0 versus 5.6 (P = 0.0001) 23.1 versus 23.5 HR 0.93 (P = 0.614)
HR, hazard ratio; OS, overall survival; PFS, progression-free survival; EGFR, epidermal growth factor receptor: TKI, tyrosine kinase inhibitor; NEJ, North-East Japan; WJTOG, West Japan Thoracic Oncology Group; EURTAC, European Tarceva versus chemotherapy; OPTIMAL, open label, Phase III study comparing first-line Tarceva versus cisplatin plus gemcitabine in Chinese advanced/metastatic non-small-cell lung cancer patients with EGFR activating mutations. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
1
Downloaded from http://jjco.oxfordjournals.org/ at Mount Royal University on July 14, 2015
I recently read a very interesting article entitled ‘Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation positive advanced non-small-cell lung cancer—data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002)’ (1). The NEJ002 trial is the first report to demonstrate the superiority of gefitinib over the standard care of platinum doublet chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) gene mutations. Gefitinib was more effective in improving progression-free survival (PFS) and quality of life, but surprisingly did not provide a greater overall survival (OS) benefit because of the crossover setting (2,3). Based on the sub-analysis of the preceding paper, the authors conclude that first-line treatment with gefitinib would not affect chemotherapy, despite several study limitations, including small sample size and retrospective design. I agree with their interpretation; however, very disappointingly, the authors only showed similar response rates between the initial chemotherapy and after the initial gefitinib treatment, but did not describe response duration or the number of chemotherapy cycles. In addition, multiple types of chemotherapy were evaluated as a single group. Although this manuscript has substantial limitations, it suggests that patients treated with gefitinib as a first-line treatment can undergo full-powered intact chemotherapy for progressive disease according to the response evaluation criteria in solid tumors (RECIST). Additionally, treatment sequence [whether EGFR tyrosine kinase inhibitor (TKI) followed or preceded chemotherapy] had no impact on OS. This conclusion contrasts with the overall results of five randomized controlled trials (RCTs), which showed that initial TKI treatment
2
Editorial
Conflict of interest statement Katsuyuki Kiura received honoraria from Chugai Pharmaceutical Co., Ltd, F. Hoffmann-La Roche AG, Genentech Eli Lilly Japan AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd.
Disclaimer
4.
5.
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7.
8.
9.
10.
The opinions expressed above are those of the author and do not necessarily represent the views of the editors or the journal. 11.
References 1. Miyauchi E, Inoe A, Kobayashi K, et al. Efficacy of chemotherapy after firstline gefitinib therapy in EGFR mutation positive advanced non-small cell lung cancer—data from a randomized phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002); doi: 10.1093/jjco/hyv054. 2. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380–8. 3. Inoue A, Kobayashi K, Maemondo M, et al. North-East Japan Study Group. Updated overall survival results from a randomized phase III trial
12.
comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54–9. Mitsudomi T, Morita S, Yatabe Y, et al. West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121–8. Yoshioka H, Mitsudomi T, Morita S, et al. Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with nonsmall cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR). J Clin Oncol 2014;32(suppl; abstr 8117):5s. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735–42. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13: 239–46. 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 2013;31:3327–34. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213–22. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311: 1998–2006. Horinouchi H, Kubota K, Itani H, et al. Short hydration in chemotherapy containing cisplatin (≥75 mg/m2) for patients with lung cancer: a prospective study. Jpn J Clin Oncol 2013;43:1105–9. Hotta K, Takigawa N, Hisamoto-Sato A, et al. Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy: results of a prospective feasibility study in advanced lung cancer in the Okayama Lung Cancer Study Group Trial 1002. Jpn J Clin Oncol 2013;43: 1115–23.
Katsuyuki Kiura* Department of Allergy and Respiratory Medicine (Thoracic Oncology), Okayama University Hospital, Okayama, Japan
Downloaded from http://jjco.oxfordjournals.org/ at Mount Royal University on July 14, 2015
Even now, there is a deep-rooted antipathy to chemotherapy despite the availability of drugs to control the nausea and vomiting induced by cisplatin and the fact that it may now be implemented in an outpatient setting (11,12). In addition, NSCLC harboring EGFR gene mutations are sensitive to chemotherapies. Response rates in mutation + versus − are as follows: docetaxel 46 versus 0% (V-15-32), 21 versus 10% (INTEREST), carboplatin/paclitaxel 47 versus 27% (IPASS), 30% versus none (NEJ002). In Japanese subset analysis of LUXlung 3, afatinib followed by cisplatin plus pemetrexed produced 46.9-month of median OS. In patients where an effective TKI can be found for the gene driving the cancer, such as gefitinib for the activating EGFR gene mutation, TKIs are routinely effective for ∼1 year. Rather than continuing to treat clinical PD, TKIs are most appropriate in combination with sequencing and other treatments, such as chemotherapy, immunotherapy, radiotherapy and/or surgery. Now we should aim for a 5-year survival rate, and if possible, a long-term and complete remission. These factors should be considered when constructing a comprehensive treatment plan for patients with advanced NSCLC harboring driver oncogenes.
Editorial Chemotherapy for lung cancer: still alive! *For reprints and all correspondence: Katsuyuki Kiura , Okayama University Hospital, 2-5-1 Shikatacho, Okayama 700-8558, Japan. E-mail: kkiura@ md.okayama-u.ac.jp provides a marked substantial advantage for PFS, but not OS (4,6–9). Median OS of cohorts initially treated with chemotherapy were better than those of the initial EGFR TKI cohorts in four of six trials; median OS was similar between cohorts in one of the remaining trials. Additionally, treatment sequence [whether EGFR TKI followed or preceded chemotherapy] had no impact on OS. This conclusion contrasts with the overall results of five RCTs, which showed that initial TKI treatment provides a marked substantial advantage for PFS, but not OS. Median OS of cohorts initially treated with chemotherapy were better than those of the initial EGFR TKI cohorts in four of six trials; median OS was similar between cohorts in one of the remaining trials. Taken together, these results indicate that when EGFR TKIs are employed first, close attention should be given to the timing of chemotherapy initiation, at least in regard to the RECIST PD. Chemotherapy is essential to increase patient survival rates since the OS in patients with advanced NSCLC harboring EGFR gene mutations is currently ∼4 years (10). As Dr Kris described in the ASCO Educational Booklet, ‘in 2014, nearly all persons with lung cancers will receive and benefit from intravenous chemotherapies at some point in their illness. This being the case, it is imperative to understand how to best use and tailor chemotherapies with targeted agents.’ While not stated directly, the paper appears to suggest that in clinical practice, patients with progressive disease might not have the opportunity to switch from gefitinib to chemotherapy because physicians, as well as patients, prefer to use EGFR TKIs due to their moderate adverse events, oral intake and use in an outpatient setting. This treatment strategy tended to show shorter OS than that observed with chemotherapy followed by TKIs (the WJTOG3405 trial showed 36% of patients did not receive platinum doublet chemotherapy) (4,5 in Table 1).
Table 1. Phase III clinical trials comparing EGFR TKIs with chemotherapy in the first-line setting Study
Treatment
N
Median PFS (months)
NEJ002 (2009) (2) 2011 (3) WJTOG3405 (2009) (4) 2014 (5) OPTIMAL (6) EURTAC (7)
Gefitinib versus carboplatin/paclitaxel
230
Gefitinib versus cisplatin/docetaxel
177
10.8 versus 5.4 (P = 0.001) 10.8 versus 5.4 (P = 0.001) 9.2 versus 6.3 (P = 0.0001)
Erlotinib versus carboplatin/gemcitabine Erlotinib versus platinum-based chemotherapy Afatinib versus cisplatin/pemetrexed Afatinib versus cisplatin/gemcitabine
165 174
LUX-Lung 3 (8) LUX-Lung 6 (9)
Median OS (months)
30.5 versus 23.6 (P = 0.31) HR 0.798 27.7 versus 26.6 (P = 0.48) HR 0.887 30.9 versus NR HR 1.64 34.8 versus 37.3 HR 1.25 13.1 versus 4.6 (P = 0.0001) HR 1.065 (P = 0.65) 9.7 versus 5.2 (P = 0.0001) 19.3 versus 19.5 (P = 0.87)
345 11.1 versus 6.9 (P = 0.0004) 28.2 versus 28.2 HR 0.88 (P = 0.385) 364 (2 : 1) 11.0 versus 5.6 (P = 0.0001) 23.1 versus 23.5 HR 0.93 (P = 0.614)
HR, hazard ratio; OS, overall survival; PFS, progression-free survival; EGFR, epidermal growth factor receptor: TKI, tyrosine kinase inhibitor; NEJ, North-East Japan; WJTOG, West Japan Thoracic Oncology Group; EURTAC, European Tarceva versus chemotherapy; OPTIMAL, open label, Phase III study comparing first-line Tarceva versus cisplatin plus gemcitabine in Chinese advanced/metastatic non-small-cell lung cancer patients with EGFR activating mutations. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
1
Downloaded from http://jjco.oxfordjournals.org/ at Mount Royal University on July 14, 2015
I recently read a very interesting article entitled ‘Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation positive advanced non-small-cell lung cancer—data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002)’ (1). The NEJ002 trial is the first report to demonstrate the superiority of gefitinib over the standard care of platinum doublet chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) gene mutations. Gefitinib was more effective in improving progression-free survival (PFS) and quality of life, but surprisingly did not provide a greater overall survival (OS) benefit because of the crossover setting (2,3). Based on the sub-analysis of the preceding paper, the authors conclude that first-line treatment with gefitinib would not affect chemotherapy, despite several study limitations, including small sample size and retrospective design. I agree with their interpretation; however, very disappointingly, the authors only showed similar response rates between the initial chemotherapy and after the initial gefitinib treatment, but did not describe response duration or the number of chemotherapy cycles. In addition, multiple types of chemotherapy were evaluated as a single group. Although this manuscript has substantial limitations, it suggests that patients treated with gefitinib as a first-line treatment can undergo full-powered intact chemotherapy for progressive disease according to the response evaluation criteria in solid tumors (RECIST). Additionally, treatment sequence [whether EGFR tyrosine kinase inhibitor (TKI) followed or preceded chemotherapy] had no impact on OS. This conclusion contrasts with the overall results of five randomized controlled trials (RCTs), which showed that initial TKI treatment
2
Editorial
Conflict of interest statement Katsuyuki Kiura received honoraria from Chugai Pharmaceutical Co., Ltd, F. Hoffmann-La Roche AG, Genentech Eli Lilly Japan AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd.
Disclaimer
4.
5.
6.
7.
8.
9.
10.
The opinions expressed above are those of the author and do not necessarily represent the views of the editors or the journal. 11.
References 1. Miyauchi E, Inoe A, Kobayashi K, et al. Efficacy of chemotherapy after firstline gefitinib therapy in EGFR mutation positive advanced non-small cell lung cancer—data from a randomized phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002); doi: 10.1093/jjco/hyv054. 2. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380–8. 3. Inoue A, Kobayashi K, Maemondo M, et al. North-East Japan Study Group. Updated overall survival results from a randomized phase III trial
12.
comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54–9. Mitsudomi T, Morita S, Yatabe Y, et al. West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121–8. Yoshioka H, Mitsudomi T, Morita S, et al. Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with nonsmall cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR). J Clin Oncol 2014;32(suppl; abstr 8117):5s. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735–42. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13: 239–46. 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 2013;31:3327–34. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213–22. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311: 1998–2006. Horinouchi H, Kubota K, Itani H, et al. Short hydration in chemotherapy containing cisplatin (≥75 mg/m2) for patients with lung cancer: a prospective study. Jpn J Clin Oncol 2013;43:1105–9. Hotta K, Takigawa N, Hisamoto-Sato A, et al. Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy: results of a prospective feasibility study in advanced lung cancer in the Okayama Lung Cancer Study Group Trial 1002. Jpn J Clin Oncol 2013;43: 1115–23.
Katsuyuki Kiura* Department of Allergy and Respiratory Medicine (Thoracic Oncology), Okayama University Hospital, Okayama, Japan
Downloaded from http://jjco.oxfordjournals.org/ at Mount Royal University on July 14, 2015
Even now, there is a deep-rooted antipathy to chemotherapy despite the availability of drugs to control the nausea and vomiting induced by cisplatin and the fact that it may now be implemented in an outpatient setting (11,12). In addition, NSCLC harboring EGFR gene mutations are sensitive to chemotherapies. Response rates in mutation + versus − are as follows: docetaxel 46 versus 0% (V-15-32), 21 versus 10% (INTEREST), carboplatin/paclitaxel 47 versus 27% (IPASS), 30% versus none (NEJ002). In Japanese subset analysis of LUXlung 3, afatinib followed by cisplatin plus pemetrexed produced 46.9-month of median OS. In patients where an effective TKI can be found for the gene driving the cancer, such as gefitinib for the activating EGFR gene mutation, TKIs are routinely effective for ∼1 year. Rather than continuing to treat clinical PD, TKIs are most appropriate in combination with sequencing and other treatments, such as chemotherapy, immunotherapy, radiotherapy and/or surgery. Now we should aim for a 5-year survival rate, and if possible, a long-term and complete remission. These factors should be considered when constructing a comprehensive treatment plan for patients with advanced NSCLC harboring driver oncogenes.
