Treatment of non-small cell lung carcinoma with gefitinib: a case report

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1 Treatment of non-small cell lung carcinoma with gefitinib: a case report A. Lefebure, P. Germonprè Targeted therapy for non-small cell lung carcinoma (NSCLC) is a possible treatment option for patients with tumours expressing an activating mutation of the epidermal growth factor receptor (EGFR). Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that was approved for treatment of EGFR mutation-positive NSCLC in Europe in In Belgium, gefitinib was only approved as a monotherapy for EGFR mutation-positive NSCLC stage IIIB-IV, whatever the line of treatment. When treatment was initiated, limited data were available relating to the use of TKIs for treating Caucasian patients with EGFR mutation-positive NSCLC. Thus, information on EGFR TKI use, in the real-life clinical setting and particularly in Caucasian patients and patients with brain metastases is still needed. Here, we report the case of a patient with NSCLC and brain metastases being treated with gefitinib. After twelve months of treatment, the chest and brain scans still showed improvement with lung function normalising and the patient reporting a good quality of life. As this patient was not previously treated with chemotherapy, there is still an opportunity of treating her later, when the tumour becomes resistant to gefinitib, with cisplatinum-pemetrexed. This is still possible because she remains chemotherapy-naive, which is required to request reimbursement in Belgium of that type of chemotherapy. (Belg J Med Oncol 2012;6: ) Introduction The treatment of non-small cell lung cancer (NSCLC) has progressed significantly in the last fifteen years. 1 The discovery that a proportion of patients with NSCLC have activating mutations of the epidermal growth factor receptor (EGFR) has allowed the development of targeted therapies for NSCLC. 2-4 These therapies act as inhibitors of the tyrosine kinase domain of the EGFR (EGFR-TKI). There are different EGFR-TKIs available with gefitinib (Iressa TM, AstraZeneca) and erlotinib (Tarceva TM, N.V. Roche S.A.) the first to be approved for clinical use. 3 This patient case aims to describe the diagnosis and treatment with gefitinib of a patient with advanced lung cancer. At the time that this patient was treated, gefitinib was the only EGFR-TKI that was reimbursed in Belgium as first-line treatment for NSCLC patients with activating mutations of the EGFR tyrosine kinase domain. Gefitinib is a selective small molecule inhibitor of the EGFR tyrosine kinase, Authors: Ms. A. Lefebure PhD, Department of Respiratory Medicine, Saint Erasmus Hospital, Antwerp Hospital Network, Antwerp, Belgium; P. Germonprè, Department of Respiratory Medicine, Antwerp University Hospital, Antwerp, Belgium. Please send all correspondence to: Ms. A. Lefebure PhD, Saint Erasmus Hospital (ZNA Sint-Erasmus), Department of Respiratory Medicine, Luit. Lippenslaan 55, B-2140 Borgerhout, Belgium tel: +32 (0) , Anneke.Lefebure@zna.be. Conflict of interest: A. Lefebure and P Germonprè have both received unrestricted research grants from AstraZeneca for participation in clinical trials. Keywords: EGFR-TKI, non-small cell lung carcinoma, brain metastasis, therapeutic options. 169

2 Figure 1. Response of metastases throughout treatment. A: Chest CT prior to treatment; B: Brain CT prior to treatment; Abbreviation: CT computerised tomography scan which has been demonstrated to be an effective treatment for patients with tumours containing activating mutations of the EGFR-TKI. 5,6 No clinically relevant activity has been shown in patients with known EGFR mutation-negative tumours. Patient history A 60-year-old female never smoking patient presented with a protracted cough associated with a mild shortness of breath despite the use of antibiotics. She reported symptoms of mild lethargy, tickling cough and headache lasting a couple of days. The clinical examination revealed that she was in good overall condition: PS=1 and normal heart, ear, nose and throat function. The lung examination revealed a normal vesicular respiratory sound but the lung function was restrictive with the Forced Expired Volume (FEV) in 1 second being 65% and Total Lung Capacity was 71%. A mass on the upper left lobe was detected after chest X-ray, which was confirmed by chest computerised tomography (CT) (Figure 1A) and positron emission tomography-ct (PET-CT) scans. Furthermore, a brain CT scan revealed the presence of several metastases with oedema (Figure 1B). Bronchoscopy with biopsies showed a stenosis of the left upper lobe, which proved on anatomopathological examination to be an adenocarcinoma of the lung that was poorly differentiated to undifferentiated, TTF1 positive and CK7 immunohistochemistry were positive. Carcinoembryonic antigen (CEA) level was 45 ng/ml. Three therapeutic options were proposed to the patient: upfront whole brain radiotherapy due to the size of the laesions and the neurological symptoms followed by first-line systemic treatment with cisplatinum-pemetrexed chemotherapy (the first choice for treating a metastatic adenocarcinoma of the lung), or treatment with gefitinib (at that moment, only used in Belgium as part of a compassionate use protocol but not yet reimbursed) in case of an EGFR mutation-positive tumour, or the option to take neither therapy. As the patient preferred the second option, if possible, a second bronchoscopy was performed to obtain new tumour samples, since not enough material was remaining from the first set of biopsies to test for the EGFR mutation status. At the start of the first compassionate use protocol in 2001, EGFR mutation testing was not common practice and initially gefinitib was available as part of the protocol without patient selection being based on EGFR mutation status. However, in the months before reimbursement in Belgium (February- June 2010), the mutation analysis became a necessary requirement for gefitinib treatment. Genetic testing 5 170

3 Figure 1. C: Chest CT after two months gefitinib treatment; D: Brain CT after two weeks of gefitinib treatment; Abbreviation: CT computerised tomography scan of the tumour-dna revealed an EGFR mutation (deletion in exon 19). The patient first received 30 Gy of cerebral radiation therapy in twelve sessions as the initial treatment to reduce the size of the laesions. The radiotherapy was well tolerated but methylprednisolone (Medrol TM, Pfizer) was administered to protect against headaches. Following confirmation of EGFR mutation status, the patient received firstline treatment with 250 mg/day gefitinib (Iressa TM, AstraZeneca), at that moment approved in Belgium for that indication, which was also well tolerated. Over the course of the treatment, the chest CT scans showed improvement (Figure 1C) and the brain CT scans demonstrated a near-total disappearance Figure 1. E: Reduction of CEA levels throughout therapy; F: Brain CT after four months of gefitinib treatment 171

4 Figure 2. Response of metastases at the end of treatment. A: Brain CT after fifteen months of treatment; B: Chest CT after eighteen months of treatment. of the oedema, more pronounced than would be expected from radiotherapy alone (Figures 1D and 1F). Serum CEA levels decreased to 15 ng/ml one month after the start of the therapy and decreased further to 4 ng/ml after two months (Figure 1E). After four months, the brain CT showed further improvement, CEA was 1 ng/ml and lung function had normalised. Although the patient continued to lose weight, she described herself as being full of energy and able to perform normal daily activities. The treatment planned for this patient was a chest CT every other second month until progression and a follow-up of the CEA results. The chest and brain CT scans remained stable during treatment with gefinitib until approximately fourteen months after starting gefinitib. The cerebral metastasis became discretely more prominent (Figure 2A), but as the patient did not have any complaints, gefitinib treatment was continued. By the next consultation, the patient has started to cough a little and, on the chest CT scan, the tumour remained the same. However, there were signs of inflammation of the lymph vessels (lymphangitis carcinomatosa) on the left side. At this time, CEA had risen to 8 ng/ml, and by the following month to 16 ng/ml (Figure 2C). We are presently discussing how to proceed with the treatment and will begin cisplatinum-pemetrexed treatment soon. Discussion Our patient reported a very good quality of life while being treated with an EGFR-TKI and her symptoms were under control for more than fourteen months. After twelve months of treatment, her CEA had remained at 1 ng/ml; after which it started to rise slowly again. Although this patient initially was still suffering from weight loss while in remission, this had stabilised after a few months. The only problem before being able to choose treatment with gefitinib was that it required a new biopsy, as there was not enough tissue remaining from the first biopsy to accurately determine the EGFR mutation status of the patient. Testing for mutations of the EGFR is very important in determining the correct treatment strategy for NSCLC. Lung biopsies are not always easy to do and with new techniques like endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS) obtaining adequate tissue amounts to perform immunohistochemistry and mutation-analyses becomes even more difficult. A subset of patients with NSCLC, approximately 5-20% of patients depending on the population being studied, have activating mutations of the tyrosine kinase domain of the EGFR (in Europe, mostly exon 19 deletion or L858R 5 172

5 Figure 2.C: Evolution of CEA levels throughout therapy; Abbreviation: CEA carcinoembryonic antigen; point mutation in exon 21) which may be targeted by TKIs such as gefitinib or erlotinib. 3,4 Along with having an adenocarcinoma, our patient was a woman who had never smoked; these three factors (adenocarcinoma, female, non-smoker) are known to be associated with a higher frequency of EGFR mutations in the tumour. The presence of an EGFR mutation increases the likelihood of a clinical response to EGFR-TKI. 7 Routine screening for some mutations, including MET gene overexpression and the T790M mutation of the EGFR (which renders the tumour resistant to TKIs), is becoming more widespread. 8 Most patients will have some sort of mutation. Some of them are already known, such as the activating BRAF and K-Ras mutations, PIK3CA, HER2, AKT1, and mutations of the EML4-ALK fusion gene; however, some are niche mutations, which have no specific treatments currently available. 8,9 For others, therapy is or will become available, e.g. crizonitib for treating NSCLC associated with an ALK fusion gene. 10 Brain metastases develop in approximately 25% of patients with lung cancer and 60% of all brain metastases may be attributable to lung cancer. 11 In comparison to NSCLC, determining the treatment for brain metastases is more straightforward. For patients with symptomatic metastases, steroids in conjunction with radiation therapy are the standard approach until the metastases are under control and there is an improvement in symptoms. If the brain metastases are asymptomatic, there are usually three treatment options: systemic chemotherapy, surgery or radiotherapy. 11 The main issue is, which treatments to use after radiation therapy. Different trials have used different first-line treatments. Interestingly, the brain metastases of our patient continued to decrease in size throughout gefitinib treatment (Figure 1F versus 1D), raising the question about the efficacy of EGFR-TKIs on brain metastases. Previous studies have also suggested an effect of gefitinib on brain metastases, but the question remains whether previous radiotherapy is needed to render the blood brain barrier more accessible to these drugs. 12,13 Although it should be noted that normally the CT scans of the brain are not monitored as frequently as occurred in this case. This patient case provides a real-life case in a Caucasian woman that confirms many of the trial results Furthermore, this patient has been stable 173

6 Key Messages for clinical practice 1. Typical fast and prolonged response of EGFR-TKI in EGFR mutant lung cancer. 2. Good symptom control. 3. Well-tolerated and linked with an improved quality of life. with up to twelve months of gefitinib treatment, which is close to the median progression-free survival (PFS) seen in most phase III trials There are still good treatment options available if there is disease progression due to the patient becoming resistant to EGFR-TKI treatment. Cisplatinumpemetrexed treatment could be the preferential firstline chemotherapy given the adenomatous histology of the tumour, and this patient is still chemo-naive, a requirement in Belgium to give this therapy Furthermore, it is known that tumours with an EGFR mutation are more sensitive to chemotherapy than wild-type tumours. 23 Acquired resistance is the main limiting factor to prolonged treatment with TKIs. Many patients developing acquired resistance to gefitinib express an EGFR mutation, T790M, that confers resistance to TKIs. 4 If resistance develops to an EGFR-TKI, it would be of interest to repeat the tissue biopsy. A recent study by Sequist and colleagues in a population of female patients who had never smoked reported a switch from NSCLC to small cell carcinoma in 14% of patients, which was then responsive to standard small-cell lung cancer treatments. 24 Furthermore, additional biopsies indicated a loss of the resistance conferring EGFR mutation in three patients after the treatment with TKIs was stopped for a period of time; these cancers were sensitive to a second round of TKI treatment. 2 This finding, the loss of the resistance confirming mutation after cessation of TKI treatment, has also been reported by other groups, mainly in case reports This raises the possibility of rechallenging the tumour with a TKI. If the patient is still in good health after other treatments and there are no other treatment options, an additional biopsy may confirm that treatment with an EGFR-TKI is again an option. Unfortunately, it is not easy to biopsy all lung cancers, certainly not after treatment. References 1. Socinski MA, Stinchcombe TE. Duration of First-Line Chemotherapy in Advanced Non-Small-Cell Lung Cancer: Less Is More in the Era of Effective Subsequent Therapies. J Clin Oncol 2007;25(33): D Addario G, Fruh M, Reck M, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21 Suppl 5:v Eck MJ, Yun CH. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 2010;1804(3): Gazdar AF. Activating and resistance mutations of EGFR in non-smallcell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009;28(Suppl 1):S24-S Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29(21): Pal SK, Figlin RA, Reckamp K. Targeted therapies for non-small cell lung cancer: an evolving landscape. Mol Cancer Ther 2010;9(7): Janne PA, Johnson BE. Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res 2006;12(14 Pt 2):4416s-20s. 8. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 2011;22(12): Hurwitz JL, Scullin P, Campbell L. Afatinib treatment in advance nonsmall cell lung cancer. Lung Cancer: Targets and Therapy 2011;2: Tiseo M, Gelsomino F, Bartolotti M, et al. Anaplastic lymphoma kinase as a new target for the treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther 2011;11(11): Chamberlain MC. Brain metastases: a medical neuro-oncology perspective. Expert Rev Neurother 2010;10(4): Nishi N, Kawai S, Yonezawa T, Fujimoto K, Masui K. Effect of gefitinib on brain metastases from non-small cell lung cancer. Neurol Med Chir (Tokyo) 2006;46(10): Shimato S, Mitsudomi T, Kosaka T, et al. EGFR mutations in patients with brain metastases from lung cancer: Association with the efficacy of gefitinib. Neuro-Oncology 2006;8(2):

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