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J Thorac Oncol. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: J Thorac Oncol. 2016 July ; 11(7): e81–e82. doi:10.1016/j.jtho.2016.01.017.
Lazarus-type response to crizotinib in a patient with poor performance status and advanced MET exon 14 skipping mutation-positive lung adenocarcinoma Meghan Shea, MD1, Mark S. Huberman, MD1, and Daniel B. Costa, MD, PhD1,* 1Department
Author Manuscript
of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Keywords mutation; lung cancer; adenocarcinoma; MET; exon 14; crizotinib
Introduction
Author Manuscript
The Cancer Genome Atlas (TCGA) project determined that 4.3% of lung adenocarcinomas harbor MET mutations that lead to exon 14 skipping [1]. Preclinical systems support the use of MET tyrosine kinase inhibitors (TKIs), including crizotinib, in tumors with MET exon 14 skipping mutation; and case series of patients with crizotinib responses have been reported [2, 3]. However, rapid responses leading to improvement in performance status have not been previously reported and patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4 are excluded from registration MET TKI trials.
Case report
Author Manuscript
A 74-year-old white woman with a prior 20 pack-year history of smoking (quit at age 37) presented with recurrent/advanced lung adenocarcinoma six years after resection for stage III disease and adjuvant platinum-based chemotherapy. At initial histologic confirmation of recurrence, the patient had left-sided pulmonary lesions, mediastinal adenopathy, pleural effusion, lymphangitic spread and significant cardio-pulmonary symptoms with an ECOG PS of 2. She was treated with 4 cycles of carboplatin and pemetrexed followed by 1 cycle of maintenance pemetrexed 500mg/m2 with symptomatic improvement and radiographic response before tumor re-progression. The original lung resection specimen was submitted to comprehensive genomic profiling using targeted next-generation sequencing and a
*
Correspondence: Daniel B. Costa, MD, PhD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Av., Boston, MA 02215, Phone: 617-667-9236, Fax: 617-975-5665, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest: DBC has received consulting fees from Pfizer and Ariad pharmaceuticals, and honoraria from Boehringer Ingelheim. No other conflict of interest is stated.
Shea et al.
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Author Manuscript
targeted solid fusion assay [2]; only identifying an intragenic fusion involving MET exon 13 and MET exon 15 - consistent with the result of a MET exon 14 skipping mutation.
Author Manuscript
At time of progression on pemetrexed, the patient had an ECOG PS of 4, hypoxia (requiring 3 liters per minute nasal cannula), significant cardio-pulmonary symptoms and extensive intra-thoracic tumor burden (Figure). Off-label crizotinib 250mg twice daily was commenced and associated with improvement in cardio-pulmonary symptoms within a week of use. However, the TKI led to significant adverse events (gastro-intestinal with CTCAE v. 4.0 grade 3 nausea and diarrhea) that required dose reduction to 250mg once daily at the two-week mark of therapy. The patient tolerated the adjusted dose with tolerable gastrointestinal adverse effects, minor visual changes and some lower extremity edema. Within one month of therapy, the patient had regained an ECOG PS of 1 and was weaned from oxygen support. By two months of therapy, the patient’s ECOG PS had improved to 0 and her cardio-pulmonary symptoms had abated. Re-imaging studies disclosed substantial tumor regression (Figure), consistent with partial response by RECIST v1.1. The patient continues on crizotinib 250mg daily at time of this report (3-month mark of therapy).
Discussion
Author Manuscript
The current report not only supports that MET exon 14 skipping mutated lung adenocarcinomas are oncogene addicted to MET but also discloses that rapid clinical/ radiographic responses can be seen with use of the approved MET TKI crizotinib, even in patients with very poor performance status. The type of response reported here is not uncommon in epidermal growth factor receptor (EGFR) mutated or anaplastic lymphoma kinase (ALK) rearranged lung cancers treated with EGFR and ALK TKIs, respectively; and has been previously dubbed “Lazarus-type” response in analogy to the miraculous rebirth from death of Lazarus in the New Testament of the Bible [4]. Indeed, some clinical guidelines allow for use of EGFR and ALK TKIs even in patients with ECOG PS of 3-4 if a tumor harbors an EGFR activating mutation or an ALK rearrangement, respectively [5]. If and when MET TKIs are fully approved for MET exon 14 skipping mutated lung adenocarcinomas, we hope that future patients with poor performance status may benefit from this type of palliative precision oncology.
Acknowledgments Funding/Grant Support: This work was funded in part through an American Cancer Society grant RSG 11-186 (DBC) and a National Cancer Institute grant CA090578 (DBC).
Author Manuscript
References 1. Collisson EA, Campbell JD, Brooks AN. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511:543–550. [PubMed: 25079552] 2. Jorge SE, Schulman S, Freed JA, et al. Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation. Lung Cancer. 2015; 90:369–374. [PubMed: 26791794] 3. Paik PK, Drilon A, Yu H, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015; 5:842– 849. [PubMed: 25971939]
J Thorac Oncol. Author manuscript; available in PMC 2017 July 01.
Shea et al.
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Author Manuscript
4. Langer CJ. The "lazarus response" in treatment-naive, poor performance status patients with nonsmall-cell lung cancer and epidermal growth factor receptor mutation. J Clin Oncol. 2009; 27:1350– 1354. [PubMed: 19224840] 5. Ettinger DS, Wood DE, Akerley W, et al. Non-Small Cell Lung Cancer, Version 6.2015. J Natl Compr Canc Netw. 2015; 13:515–524. [PubMed: 25964637]
Author Manuscript Author Manuscript Author Manuscript J Thorac Oncol. Author manuscript; available in PMC 2017 July 01.
Shea et al.
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Figure 1.
The left panel shows features of the computed tomography (CT) of chest at time of tumor progression on pemetrexed (baseline). Note is made to left-sided pleural, parenchymal and bilateral lymphatic lesions. The Eastern Cooperative Oncology Group (ECOG) performance status and oxygen saturation on room air at this time are shown. The right panel discloses the CT of chest after 2 months of crizotinib monotherapy. Note is made of significant improvement of the patient’s to left-sided pleural, parenchymal and bilateral lymphatic lesions. The dose of crizotinib (250mg daily), ECOG PS and oxygen saturation on room air at this time are also shown.
Author Manuscript J Thorac Oncol. Author manuscript; available in PMC 2017 July 01.
J Thorac Oncol. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: J Thorac Oncol. 2016 July ; 11(7): e81–e82. doi:10.1016/j.jtho.2016.01.017.
Lazarus-type response to crizotinib in a patient with poor performance status and advanced MET exon 14 skipping mutation-positive lung adenocarcinoma Meghan Shea, MD1, Mark S. Huberman, MD1, and Daniel B. Costa, MD, PhD1,* 1Department
Author Manuscript
of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Keywords mutation; lung cancer; adenocarcinoma; MET; exon 14; crizotinib
Introduction
Author Manuscript
The Cancer Genome Atlas (TCGA) project determined that 4.3% of lung adenocarcinomas harbor MET mutations that lead to exon 14 skipping [1]. Preclinical systems support the use of MET tyrosine kinase inhibitors (TKIs), including crizotinib, in tumors with MET exon 14 skipping mutation; and case series of patients with crizotinib responses have been reported [2, 3]. However, rapid responses leading to improvement in performance status have not been previously reported and patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4 are excluded from registration MET TKI trials.
Case report
Author Manuscript
A 74-year-old white woman with a prior 20 pack-year history of smoking (quit at age 37) presented with recurrent/advanced lung adenocarcinoma six years after resection for stage III disease and adjuvant platinum-based chemotherapy. At initial histologic confirmation of recurrence, the patient had left-sided pulmonary lesions, mediastinal adenopathy, pleural effusion, lymphangitic spread and significant cardio-pulmonary symptoms with an ECOG PS of 2. She was treated with 4 cycles of carboplatin and pemetrexed followed by 1 cycle of maintenance pemetrexed 500mg/m2 with symptomatic improvement and radiographic response before tumor re-progression. The original lung resection specimen was submitted to comprehensive genomic profiling using targeted next-generation sequencing and a
*
Correspondence: Daniel B. Costa, MD, PhD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Av., Boston, MA 02215, Phone: 617-667-9236, Fax: 617-975-5665, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest: DBC has received consulting fees from Pfizer and Ariad pharmaceuticals, and honoraria from Boehringer Ingelheim. No other conflict of interest is stated.
Shea et al.
Page 2
Author Manuscript
targeted solid fusion assay [2]; only identifying an intragenic fusion involving MET exon 13 and MET exon 15 - consistent with the result of a MET exon 14 skipping mutation.
Author Manuscript
At time of progression on pemetrexed, the patient had an ECOG PS of 4, hypoxia (requiring 3 liters per minute nasal cannula), significant cardio-pulmonary symptoms and extensive intra-thoracic tumor burden (Figure). Off-label crizotinib 250mg twice daily was commenced and associated with improvement in cardio-pulmonary symptoms within a week of use. However, the TKI led to significant adverse events (gastro-intestinal with CTCAE v. 4.0 grade 3 nausea and diarrhea) that required dose reduction to 250mg once daily at the two-week mark of therapy. The patient tolerated the adjusted dose with tolerable gastrointestinal adverse effects, minor visual changes and some lower extremity edema. Within one month of therapy, the patient had regained an ECOG PS of 1 and was weaned from oxygen support. By two months of therapy, the patient’s ECOG PS had improved to 0 and her cardio-pulmonary symptoms had abated. Re-imaging studies disclosed substantial tumor regression (Figure), consistent with partial response by RECIST v1.1. The patient continues on crizotinib 250mg daily at time of this report (3-month mark of therapy).
Discussion
Author Manuscript
The current report not only supports that MET exon 14 skipping mutated lung adenocarcinomas are oncogene addicted to MET but also discloses that rapid clinical/ radiographic responses can be seen with use of the approved MET TKI crizotinib, even in patients with very poor performance status. The type of response reported here is not uncommon in epidermal growth factor receptor (EGFR) mutated or anaplastic lymphoma kinase (ALK) rearranged lung cancers treated with EGFR and ALK TKIs, respectively; and has been previously dubbed “Lazarus-type” response in analogy to the miraculous rebirth from death of Lazarus in the New Testament of the Bible [4]. Indeed, some clinical guidelines allow for use of EGFR and ALK TKIs even in patients with ECOG PS of 3-4 if a tumor harbors an EGFR activating mutation or an ALK rearrangement, respectively [5]. If and when MET TKIs are fully approved for MET exon 14 skipping mutated lung adenocarcinomas, we hope that future patients with poor performance status may benefit from this type of palliative precision oncology.
Acknowledgments Funding/Grant Support: This work was funded in part through an American Cancer Society grant RSG 11-186 (DBC) and a National Cancer Institute grant CA090578 (DBC).
Author Manuscript
References 1. Collisson EA, Campbell JD, Brooks AN. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511:543–550. [PubMed: 25079552] 2. Jorge SE, Schulman S, Freed JA, et al. Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation. Lung Cancer. 2015; 90:369–374. [PubMed: 26791794] 3. Paik PK, Drilon A, Yu H, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015; 5:842– 849. [PubMed: 25971939]
J Thorac Oncol. Author manuscript; available in PMC 2017 July 01.
Shea et al.
Page 3
Author Manuscript
4. Langer CJ. The "lazarus response" in treatment-naive, poor performance status patients with nonsmall-cell lung cancer and epidermal growth factor receptor mutation. J Clin Oncol. 2009; 27:1350– 1354. [PubMed: 19224840] 5. Ettinger DS, Wood DE, Akerley W, et al. Non-Small Cell Lung Cancer, Version 6.2015. J Natl Compr Canc Netw. 2015; 13:515–524. [PubMed: 25964637]
Author Manuscript Author Manuscript Author Manuscript J Thorac Oncol. Author manuscript; available in PMC 2017 July 01.
Shea et al.
Page 4
Author Manuscript Author Manuscript Author Manuscript
Figure 1.
The left panel shows features of the computed tomography (CT) of chest at time of tumor progression on pemetrexed (baseline). Note is made to left-sided pleural, parenchymal and bilateral lymphatic lesions. The Eastern Cooperative Oncology Group (ECOG) performance status and oxygen saturation on room air at this time are shown. The right panel discloses the CT of chest after 2 months of crizotinib monotherapy. Note is made of significant improvement of the patient’s to left-sided pleural, parenchymal and bilateral lymphatic lesions. The dose of crizotinib (250mg daily), ECOG PS and oxygen saturation on room air at this time are also shown.
Author Manuscript J Thorac Oncol. Author manuscript; available in PMC 2017 July 01.
