Case Report
Successful Crizotinib Rechallenge After Crizotinib-Induced Interstitial Lung Disease in Patients With Advanced NoneSmall-Cell Lung Cancer Nobuhiro Asai, Etsuro Yamaguchi, Akihito Kubo Clinical Practice Points Although the development of the anaplastic lym-
Comparing the 2 successfully treated cases, including
phoma kinase tyrosine kinase inhibitor (ALK TKI), as well as epidermal growth factor receptor (EGFR) TKIs, has a great impact and has led to a paradigm shift in the treatment of advanced nonesmall-cell lung cancer (NSCLC), the occurrence of drug-induced interstitial lung disease (ILD) remains problematic. We report a successful rechallenge of crizotinib after crizotinib-induced ILD in a patient with ALK-rearranged NSCLC. To our knowledge, this is the second case successfully treated and the first short review of crizotinib-induced ILD.
ours, with the fatal case previously reported, we found some common characteristics in the successful case and our case, among which was the fact that our patient had no risk of EGFR TKIeinduced ILD. The risk factors for EGFR TKIeinduced ILD may be related to crizotinib-induced ILD. Although crizotinib-induced ILD may be fatal, some patients might benefit from rechallenge of the drug. It is important to elucidate the clinicopathologic characteristics of ALK TKIeinduced ILD and to determine its risk factors.
Clinical Lung Cancer, Vol. 15, No. 3, e33-5 ª 2014 Elsevier Inc. All rights reserved. Keywords: Crizotinib, EML4-ALK, Interstitial lung disease, Lung cancer
Introduction Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene translocation was recently identified in 3% to 5% of unselected nonesmall-cell lung cancer (NSCLC) cases, predominantly in nonsmoking patients with adenocarcinoma.1,2 Crizotinib, the first-in-class ALK tyrosine kinase inhibitor (TKI), showed promising results for treating locally advanced and metastatic lung cancer presenting the ALK rearrangement.3 Although the development of the ALK TKI, as well as epidermal growth factor receptor (EGFR) TKIs, has had a great impact and has led to a paradigm shift in the treatment of advanced
Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan Submitted: Oct 10, 2013; Revised: Dec 19, 2013; Accepted: Dec 23, 2013; Epub: Dec 27, 2013 Address for correspondence: Nobuhiro Asai, MD, Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, 480-1195 1-1 Yazako, Karimata, Nagakute, Aichi, Japan E-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2013.12.004
NSCLC, the occurrence of drug-induced interstitial lung disease (ILD) remains problematic. We report a successful rechallenge of crizotinib after crizotinib-induced ILD in a patient with ALKrearranged NSCLC.
Case Report A 70-year old woman was diagnosed with lung adenocarcinoma (cT4N3M1b, stage IV) with metastatic lesions to the liver, pelvic bone, and contralateral lung. She had neither a history of smoking or allergies. She had quadriparesis caused by cerebral thromboembolism, resulting in an Eastern Cooperative Oncology Group performance status of 2, and she was considered ineligible for cytotoxic chemotherapy. Immunohistochemical analysis for the ALK protein suggested the presence of an ALK rearrangement, and subsequent fluorescence in situ hybridization analysis using break-apart probes confirmed the ALK fusion gene. As first-line chemotherapy, crizotinib was administered orally at a dose of 200 mg twice daily. On day 35, chest radiography and computed tomography (CT) revealed a partial response, although new infiltrates were found in the bilateral upper lobes of the lungs (Fig. 1A) with no symptoms. No
Clinical Lung Cancer May 2014
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Successful Crizotinib Rechallenge After ILD Figure 1 (A) Chest Computed Tomography (CT) Showed Crizotinib-Induced Interstitial Lung Disease (ILD) in the Right Upper Lobe of the Lung (Blue Arrow). (B) Two Weeks After Crizotinib was Discontinued, Chest CT Showed That ILD had Improved (Blue Arrow) and That the Tumor Regrew (Red Arrowhead)
pulmonary pathogens were detected in multiple bacterial culture results on sputum, and we considered the lesions to be consistent with crizotinib-induced ILD. Crizotinib was discontinued. The patient remained asymptomatic, and respiratory failure did not develop after the discontinuation of crizotinib, so we did not prescribe corticosteroid therapy. ILD improved without steroid therapy. On treatment day 49, 2 weeks after discontinuing the medication, crizotinib at a dose of 250 mg once daily was restarted because the tumor had begun growing again and there were no signs of ILD recurrence. Two weeks after restarting the medication, the dose of crizotinib was increased to 400 mg twice daily (Fig. 1B), and the tumor in the left lung started shrinking again. Forty-five days after crizotinib resumption, it was discontinued again because of ILD recurrence in the left upper lobe of the lung (Fig. 2A). The tumor expanded dramatically with ILD (Fig. 2B). The patient was
able to resume crizotinib after 28 days of drug cessation. She maintained stable disease after the second rechallenge of crizotinib with gradual improvement of ILD for another month (Fig. 2C).
Discussion Although a fatal case of crizotinib-induced ILD, for which the risk factors remain unclear, has recently been reported,4 Yanagisawa et al reported successful crizotinib retreatment after crizotinibinduced ILD.5 Comparing the 2 successfully treated cases, including ours, with the fatal case as shown in Table 1, we found some common characteristics in the successful case and ours. In 2 cases, the patients were women with ALK-positive adenocarcinoma. They had neither a smoking history nor preexisting pulmonary disease such as interstitial pneumonia. Both received crizotinib as first-line chemotherapy. Ando et al documented male
Figure 2 (A) Forty-Five Days After Restarting Crizotinib, Chest Computed Tomography (CT) Showed Crizotinib-Induced Interstitial Lung Disease (ILD) in the Left Upper Lobe of the Lung (Blue Arrow). (B) Four Weeks After Cessation of Crizotinib, Chest CT Showed That the Tumor had Expanded Dramatically, Which Seems to be a Disease Flare, and ILD Remained (Blue Arrow). (C) Chest CT Revealed no Exacerbation of Crizotinib-Induced ILD in the Left Upper Lobe of the Lung (Blue Arrow), Although the Anterior Part of the Tumor Shrank (Yellow Arrowhead) and the Posterior Part of the Tumor did not Regrow (Red Arrowhead), Resulting in Stable Disease According to Response Evaluation Criteria in Solid Tumors
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Clinical Lung Cancer May 2014
Nobuhiro Asai et al Table 1 Comparison of 3 Cases of Crizotinib-Induced ILD Pathologic Type
Smoking History
Chemotherapy Line
Time to Occurrence of ILD (Days)
Author
Sex
Age (Years)
Tamiya et al4
Male
39
Adenocarcinoma
Current smoker
Second
9
Yanagisawa et al5 Female
53
Adenocarcinoma
Never smoker
First
14
Asai (current)
70
Adenocarcinoma
Never smoker
First
35
Female
Treatment for ILD Cessation of crizotinib and PSL Cessation of crizotinib and PSL Cessation of crizotinib
Outcome Death
Cure
Cure
Abbreviations: ILD ¼ interstitial lung disease; PSL ¼ prednisolone.
sex, history of smoking, and coexistence of interstitial pneumonia as independent risk factors for EGFR TKIeinduced ILD.6 In the fatal case caused by crizotinib-induced ILD mentioned previously, the patient was a man who was a current smoker. The patient experienced rapidly progressive dyspnea with severe hypoxia, although he had no preexisting ILD or chronic obstructive pulmonary disease.4 In contrast, Nakamichi et al reported a successful case of EGFR TKI rechallenge in advanced lung adenocarcinoma after gefitinib-induced ILD.7 This patient had no risk factors for EGFR TKI induced ILD. The successful rechallenge of ALK TKI for both Yanagisawa et al’s case and our case had some clinical characteristics in common, among which neither of the patients had any risk factors for EGFR TKIeinduced ILD. One can speculate that these characteristics might be related to successful retreatment with crizotinib in these patients. Currently, however, the mechanism of crizotinib-induced ILD remains unclear. It remains to be seen whether risk factors for ALK TKIeinduced ILD may be similar to those for EGFR TKIeinduced ILD. It is also unknown which cases of crizotinib-induced ILD could be fatal and which could be cured. With the inevitable cessation of crizotinib, such as seen in our patient, rapid exacerbation of the tumor (or disease flare) is a major concern after discontinuation of crizotinib. It has been reported that rapid progression can occur after discontinuation of crizotinib, similar to the case of EGFR TKIs, although the exact mechanism of this phenomenon remains unknown.8,9 In our patient, the tumor regrew after discontinuation of crizotinib, as in previous reports. Continuation of crizotinib beyond disease progression might be considered in patients with ALK-rearranged NSCLC.
Conclusion Although crizotinib-induced ILD may be fatal, some patients might benefit from rechallenge of the drug. It is important to
elucidate the clinicopathologic characteristics of ALK TKIeinduced ILD and to determine its risk factors.
Acknowledgments We are grateful for the diligent and thorough critical reading of our manuscript by Dr Yoshihiro Ohkuni, Chief Physician, Taiyo and Mr John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Kameda Medical Center (Japan).
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448:561-6. 2. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. 2. J Thorac Oncol 2009; 4:1450-4. 3. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693-703. 4. Tamiya A, Okamoto I, Miyazaki M, Shimizu S, Kitaichi M, Nakagawa K. Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALKpositive non-small-cell lung cancer. J Clin Oncol 2013; 31:e15-7. 5. Yanagisawa S, Inoue A, Koarai A, Ono M, Tamai T, Ichinose M. Successful crizotinib retreatment after crizotinib-induced interstitial lung disease. J Thorac Oncol 2013; 8:e73-4. 6. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24:2549-56. 7. Nakamichi S, Kubota K, Horinouchi H, et al. Successful EGFR-TKI rechallenge of leptomeningeal carcinomatosis after gefitinib-induced interstitial lung disease. Jpn J Clin Oncol 2013; 43:422-5. 8. Kuriyama Y, Kim YH, Nagai H, Ozasa H, Sakamori Y, Mishima M. Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase-positive lung cancer. Case Rep Oncol 2013; 14:430-3. 9. Pop O, Pirvu A, Toffart AC, Moro-Sibilot D. Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol 2012; 7:e1-2.
Clinical Lung Cancer May 2014
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Successful Crizotinib Rechallenge After Crizotinib-Induced Interstitial Lung Disease in Patients With Advanced NoneSmall-Cell Lung Cancer Nobuhiro Asai, Etsuro Yamaguchi, Akihito Kubo Clinical Practice Points Although the development of the anaplastic lym-
Comparing the 2 successfully treated cases, including
phoma kinase tyrosine kinase inhibitor (ALK TKI), as well as epidermal growth factor receptor (EGFR) TKIs, has a great impact and has led to a paradigm shift in the treatment of advanced nonesmall-cell lung cancer (NSCLC), the occurrence of drug-induced interstitial lung disease (ILD) remains problematic. We report a successful rechallenge of crizotinib after crizotinib-induced ILD in a patient with ALK-rearranged NSCLC. To our knowledge, this is the second case successfully treated and the first short review of crizotinib-induced ILD.
ours, with the fatal case previously reported, we found some common characteristics in the successful case and our case, among which was the fact that our patient had no risk of EGFR TKIeinduced ILD. The risk factors for EGFR TKIeinduced ILD may be related to crizotinib-induced ILD. Although crizotinib-induced ILD may be fatal, some patients might benefit from rechallenge of the drug. It is important to elucidate the clinicopathologic characteristics of ALK TKIeinduced ILD and to determine its risk factors.
Clinical Lung Cancer, Vol. 15, No. 3, e33-5 ª 2014 Elsevier Inc. All rights reserved. Keywords: Crizotinib, EML4-ALK, Interstitial lung disease, Lung cancer
Introduction Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene translocation was recently identified in 3% to 5% of unselected nonesmall-cell lung cancer (NSCLC) cases, predominantly in nonsmoking patients with adenocarcinoma.1,2 Crizotinib, the first-in-class ALK tyrosine kinase inhibitor (TKI), showed promising results for treating locally advanced and metastatic lung cancer presenting the ALK rearrangement.3 Although the development of the ALK TKI, as well as epidermal growth factor receptor (EGFR) TKIs, has had a great impact and has led to a paradigm shift in the treatment of advanced
Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan Submitted: Oct 10, 2013; Revised: Dec 19, 2013; Accepted: Dec 23, 2013; Epub: Dec 27, 2013 Address for correspondence: Nobuhiro Asai, MD, Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, 480-1195 1-1 Yazako, Karimata, Nagakute, Aichi, Japan E-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2013.12.004
NSCLC, the occurrence of drug-induced interstitial lung disease (ILD) remains problematic. We report a successful rechallenge of crizotinib after crizotinib-induced ILD in a patient with ALKrearranged NSCLC.
Case Report A 70-year old woman was diagnosed with lung adenocarcinoma (cT4N3M1b, stage IV) with metastatic lesions to the liver, pelvic bone, and contralateral lung. She had neither a history of smoking or allergies. She had quadriparesis caused by cerebral thromboembolism, resulting in an Eastern Cooperative Oncology Group performance status of 2, and she was considered ineligible for cytotoxic chemotherapy. Immunohistochemical analysis for the ALK protein suggested the presence of an ALK rearrangement, and subsequent fluorescence in situ hybridization analysis using break-apart probes confirmed the ALK fusion gene. As first-line chemotherapy, crizotinib was administered orally at a dose of 200 mg twice daily. On day 35, chest radiography and computed tomography (CT) revealed a partial response, although new infiltrates were found in the bilateral upper lobes of the lungs (Fig. 1A) with no symptoms. No
Clinical Lung Cancer May 2014
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Successful Crizotinib Rechallenge After ILD Figure 1 (A) Chest Computed Tomography (CT) Showed Crizotinib-Induced Interstitial Lung Disease (ILD) in the Right Upper Lobe of the Lung (Blue Arrow). (B) Two Weeks After Crizotinib was Discontinued, Chest CT Showed That ILD had Improved (Blue Arrow) and That the Tumor Regrew (Red Arrowhead)
pulmonary pathogens were detected in multiple bacterial culture results on sputum, and we considered the lesions to be consistent with crizotinib-induced ILD. Crizotinib was discontinued. The patient remained asymptomatic, and respiratory failure did not develop after the discontinuation of crizotinib, so we did not prescribe corticosteroid therapy. ILD improved without steroid therapy. On treatment day 49, 2 weeks after discontinuing the medication, crizotinib at a dose of 250 mg once daily was restarted because the tumor had begun growing again and there were no signs of ILD recurrence. Two weeks after restarting the medication, the dose of crizotinib was increased to 400 mg twice daily (Fig. 1B), and the tumor in the left lung started shrinking again. Forty-five days after crizotinib resumption, it was discontinued again because of ILD recurrence in the left upper lobe of the lung (Fig. 2A). The tumor expanded dramatically with ILD (Fig. 2B). The patient was
able to resume crizotinib after 28 days of drug cessation. She maintained stable disease after the second rechallenge of crizotinib with gradual improvement of ILD for another month (Fig. 2C).
Discussion Although a fatal case of crizotinib-induced ILD, for which the risk factors remain unclear, has recently been reported,4 Yanagisawa et al reported successful crizotinib retreatment after crizotinibinduced ILD.5 Comparing the 2 successfully treated cases, including ours, with the fatal case as shown in Table 1, we found some common characteristics in the successful case and ours. In 2 cases, the patients were women with ALK-positive adenocarcinoma. They had neither a smoking history nor preexisting pulmonary disease such as interstitial pneumonia. Both received crizotinib as first-line chemotherapy. Ando et al documented male
Figure 2 (A) Forty-Five Days After Restarting Crizotinib, Chest Computed Tomography (CT) Showed Crizotinib-Induced Interstitial Lung Disease (ILD) in the Left Upper Lobe of the Lung (Blue Arrow). (B) Four Weeks After Cessation of Crizotinib, Chest CT Showed That the Tumor had Expanded Dramatically, Which Seems to be a Disease Flare, and ILD Remained (Blue Arrow). (C) Chest CT Revealed no Exacerbation of Crizotinib-Induced ILD in the Left Upper Lobe of the Lung (Blue Arrow), Although the Anterior Part of the Tumor Shrank (Yellow Arrowhead) and the Posterior Part of the Tumor did not Regrow (Red Arrowhead), Resulting in Stable Disease According to Response Evaluation Criteria in Solid Tumors
e34
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Clinical Lung Cancer May 2014
Nobuhiro Asai et al Table 1 Comparison of 3 Cases of Crizotinib-Induced ILD Pathologic Type
Smoking History
Chemotherapy Line
Time to Occurrence of ILD (Days)
Author
Sex
Age (Years)
Tamiya et al4
Male
39
Adenocarcinoma
Current smoker
Second
9
Yanagisawa et al5 Female
53
Adenocarcinoma
Never smoker
First
14
Asai (current)
70
Adenocarcinoma
Never smoker
First
35
Female
Treatment for ILD Cessation of crizotinib and PSL Cessation of crizotinib and PSL Cessation of crizotinib
Outcome Death
Cure
Cure
Abbreviations: ILD ¼ interstitial lung disease; PSL ¼ prednisolone.
sex, history of smoking, and coexistence of interstitial pneumonia as independent risk factors for EGFR TKIeinduced ILD.6 In the fatal case caused by crizotinib-induced ILD mentioned previously, the patient was a man who was a current smoker. The patient experienced rapidly progressive dyspnea with severe hypoxia, although he had no preexisting ILD or chronic obstructive pulmonary disease.4 In contrast, Nakamichi et al reported a successful case of EGFR TKI rechallenge in advanced lung adenocarcinoma after gefitinib-induced ILD.7 This patient had no risk factors for EGFR TKI induced ILD. The successful rechallenge of ALK TKI for both Yanagisawa et al’s case and our case had some clinical characteristics in common, among which neither of the patients had any risk factors for EGFR TKIeinduced ILD. One can speculate that these characteristics might be related to successful retreatment with crizotinib in these patients. Currently, however, the mechanism of crizotinib-induced ILD remains unclear. It remains to be seen whether risk factors for ALK TKIeinduced ILD may be similar to those for EGFR TKIeinduced ILD. It is also unknown which cases of crizotinib-induced ILD could be fatal and which could be cured. With the inevitable cessation of crizotinib, such as seen in our patient, rapid exacerbation of the tumor (or disease flare) is a major concern after discontinuation of crizotinib. It has been reported that rapid progression can occur after discontinuation of crizotinib, similar to the case of EGFR TKIs, although the exact mechanism of this phenomenon remains unknown.8,9 In our patient, the tumor regrew after discontinuation of crizotinib, as in previous reports. Continuation of crizotinib beyond disease progression might be considered in patients with ALK-rearranged NSCLC.
Conclusion Although crizotinib-induced ILD may be fatal, some patients might benefit from rechallenge of the drug. It is important to
elucidate the clinicopathologic characteristics of ALK TKIeinduced ILD and to determine its risk factors.
Acknowledgments We are grateful for the diligent and thorough critical reading of our manuscript by Dr Yoshihiro Ohkuni, Chief Physician, Taiyo and Mr John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Kameda Medical Center (Japan).
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448:561-6. 2. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. 2. J Thorac Oncol 2009; 4:1450-4. 3. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693-703. 4. Tamiya A, Okamoto I, Miyazaki M, Shimizu S, Kitaichi M, Nakagawa K. Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALKpositive non-small-cell lung cancer. J Clin Oncol 2013; 31:e15-7. 5. Yanagisawa S, Inoue A, Koarai A, Ono M, Tamai T, Ichinose M. Successful crizotinib retreatment after crizotinib-induced interstitial lung disease. J Thorac Oncol 2013; 8:e73-4. 6. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24:2549-56. 7. Nakamichi S, Kubota K, Horinouchi H, et al. Successful EGFR-TKI rechallenge of leptomeningeal carcinomatosis after gefitinib-induced interstitial lung disease. Jpn J Clin Oncol 2013; 43:422-5. 8. Kuriyama Y, Kim YH, Nagai H, Ozasa H, Sakamori Y, Mishima M. Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase-positive lung cancer. Case Rep Oncol 2013; 14:430-3. 9. Pop O, Pirvu A, Toffart AC, Moro-Sibilot D. Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol 2012; 7:e1-2.
Clinical Lung Cancer May 2014
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