CHAPTER 8A. High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases one with a remarkable thoracic response as well

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1 CHAPTER 8A High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases one with a remarkable thoracic response as well J.L. Kuiper, E.F. Smit Lung Cancer 2013 Apr;80(1):102-5

2 Chapter 8A ABSTRACT A considerable number of patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) develop leptomeningeal metastases. Leptomeningeal metastases are associated with deterioration of clinical symptoms and poor survival. Traditionally, treatment of metastases in the central nervous system consists of radiotherapy and less frequently, surgery. The role of systemic therapy is limited due to the blood-brain barrier inhibiting pharmacological doses to be reached in the central nervous system. Several case reports have described high-dose, pulsatile tyrosine kinase inhibitors as an effective treatment of leptomeningeal metastases, based on the hypothesis that higher concentrations in the cerebrospinal fluid can be reached by higher systemic concentrations. Here, we describe two patients with EGFR-mutated non-small cell lung cancer, with both clinical and radiological response to this high-dose, pulsatile regimen. Interestingly, one patient showed a remarkable response of intrathoracic response as well. 132

3 High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases INTRODUCTION EGFR-mutated NSCLC is associated with a favourable prognosis, high rate of response to EGFR-TKI s and consequently improved overall survival when compared to other subtypes of NSCLC. However, after an initial response to EGFR-TKI s, progression of disease is inevitable. A substantial number of patients develop central nervous system (CNS) metastases, in some series up to 30%. CNS metastases are associated with disabling neurological symptoms, deterioration of performance status and poor survival. Traditionally, treatment of CNS metastases consists of radiotherapy and in selected cases, surgery. Systemic treatment is believed to have a limited role, due to the blood-brain barrier (BBB). Since EGFR TKI s are a substrate of P-glycoprotein, the BBB is preventing pharmacological dose of EGFR TKI s at standard dosing regimes to be reached in the CNS. Due to this lower drug concentration, selective pressure in the CNS is different and acquired resistance mechanisms that are often demonstrated in metastases outside the CNS are believed to be less common in CNS metastases. Hence, these metastases would still be sensitive to EGFR-TKI-treatment, if only sufficient penetration of these drugs into the CNS could be achieved. Theoretically, administering TKI s in a higher dose could achieve higher concentrations in the cerebrospinal fluid. This strategy has been applied before, with encouraging results (1-6). Here, we report two EGFR-mutated NSCLC-patients with leptomeningeal metastases successfully treated with high-dose, weekly erlotinib, one with a remarkable response of intrathoracic disease as well. Case 1 A 49-year old, Creole female underwent a lobectomy of the left upper lobe in 2006 because of adenocarcinoma followed by adjuvant radiotherapy. In 2009 a local recurrence was diagnosed and mutational analysis showed an EGFR mutation exon 21 (L858R). She was treated with erlotinib on which she maintained stable disease for twelve months. In 2010 she developed single-site progression of a left supraclavicular lymph node. Biopsy revealed adenocarcinoma, with weak detection of the former L858R mutation, for which she was treated with radiotherapy (5x5Gy) while erlotinib therapy was maintained. In November 2011, a gastroduodenoscopy was performed because of persistent, progressive pain in the upper abdomen and evident compression of the proximal duodenum was observed. A CT abdomen revealed a big retro- and intraperitoneal mass. Because of the clinical situation and the high suspicion of abdominal metastasis, chemotherapy consisting of pemetrexed and cisplatin at standard dose, was initiated before pathological confirmation was obtained. One month later, she experienced headache and vomiting. MRI-cerebrum showed diffuse leptomeningeal metastases (Figure 1a). Erlotinib pulsatile therapy was started at a dose of 1000 mg once a week in conjunction with chemotherapy, which was increased to 1500 mg once a week after the first dose. This treatment regimen was well tolerated. Side effects 8A 133

4 Chapter 8A were mild malaise on day of taking the high dose and skin toxicity grade 1. Follow-up MRIcerebrum demonstrated evident response of the leptomeningeal metastases (Figure 1b) and months after initiation of high dose erlotinib, she remains free of neurological symptoms. Follow-up CT-scans showed control of both intrathoracic and intra-abdominal disease as well. Case 2 The second patient is a female patient of 51 years old diagnosed with stage IV NSCLC in An EGFR mutation was detected in exon 19 (del (P753S)). She has been treated with erlotinib in combination with sorafenib, single agent erlotinib and afatinib in combination with cetuximab chronologically. After progression on the latter regimen in March 2012 she was treated with 2 cycles of cisplatin and pemetrexed at standard dose. A CT-scan showed stable disease of the intrathoracic lesions (Figure 3a-b) but she developed neurological symptoms. An MRI-scan showed leptomeningeal metastases (Figure 2a) pathologically confirmed by lumbar punction from which an identical activating exon 19 mutation was detected. She was then treated with erlotinib 1500 mg once weekly and cytotoxic chemotherapy was continued. Surprisingly after 3 weeks of treatment with the high dose erlotinib regimen there was significant decrease of the intrathoracic disease (Figure 3c). The neurological symptoms improved drastically, confirmed by an MRI-cerebrum that showed decrease of leptomeningeal metastases (Figure 2b). At time of writing, she is still on erlotinib pulsatile therapy and chemotherapy. DISCUSSION Up to one third of EGFR-mutated NSCLC patients develop metastases in the CNS after initial successful treatment with an EGFR-TKI. Forty percent of these CNS metastases are leptomeningeal metastases (7). Whereas leptomeningeal metastasis in EGFR-wild type NSCLC is associated with a dismal prognosis with a median survival of 3-4 months, median survival in EGFR-mutated NSCLC patients with leptomeningeal metastases is 7-14 months (8, 9). Often, leptomeningeal metastases are diagnosed while other disease sites are still in remission. Due to different selection mechanisms, resistance mutations that are frequently encountered in the primary tumour and systemic metastases, are not demonstrated in synchronous or metachronous CNS metastases (10-12). Theoretically, these metastases would still be sensitive to TKI-therapy, however, due to the blood-brain barrier; intrathecal drug concentrations from standard doses EGFR-TKI s in the CNS are much lower than systemic concentrations (6, 13). As illustrated in these two cases, therapeutic concentrations of TKI s in CSF can be achieved by pulsatile, weekly, high-dose erlotinib. It has been demonstrated that erlotinib up to doses of 2000 mg weekly is tolerable and toxicity is manageable (14). Side 134

5 High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases effects of the high, weekly dose schedule are similar to the daily standard schedule; mainly rash, diarrhoea, nausea and fatigue. Grade of toxicity is usually mild; in a study evaluating nine patients, no grade 3 toxicities were observed (3). As other therapeutic options are lacking for this category of patients, this treatment schedule could be considered in EGFR-mutated patients with leptomeningeal metastases. Results from prospective trials are awaited for. Evidence of adding EGFR-TKI s to chemotherapy is controversial. While the initial phase III studies combining cytotoxic chemotherapy with EGFR-TKI s were negative (15, 16), recent randomized phase II and phase III studies found a significant survival benefit both in unselected (17) and selected (18) patients. In the described patients, the administration of chemotherapy (directed towards extracerebral lesions) and pulsatile erlotinib (directed towards CNS-lesions) simultaneously proved to be an effective treatment strategy. In the second patient, an MRI-cerebrum confirmed partial response of leptomeningeal metastases after pulsatile erlotinib therapy. Interestingly, thoracic disease in this heavily TKIpretreated patient responded evidently to the high-dose, pulsatile regimen as well, while response to recent chemotherapy was stable disease at best. Several acquired resistance mechanisms have been identified, for example the T790M mutation and MET-amplification. However in approximately 30% the underlying resistance mechanism remains indistinct (19). Tissue from the thoracic lesions for pathological analysis was not obtained, precluding a molecular explanation for the radiological response. Nevertheless, it is known that for example the T790M mutation increases the affinity of the EGFR tyrosine kinase for ATP, thereby restoring signal transduction through this pathway. By increasing plasma concentrations of erlotinib, which is a competitive inhibitor of EGF signalling, sensitivity of EGFR for erlotinib might theoretically be restored. If high-dose pulsatile erlotinib were effective in patients experiencing systemic progression of disease while on EGFR-TKI treatment, this would provide a new and relatively uncomplicated treatment potential in this category of patients lacking therapeutic opportunities. A prospective trial is planned, evaluating the effect of high-dose, weekly erlotinib on systemic progression of disease after treatment with standard doses EGFR-TKI in EGFR-mutated NSCLC patients. 8A Informed consent of both patients was acquired. 135

6 Chapter 8A REFERENCE LIST (1) Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 2010 Sep,99(2), (2) Dhruva N, Socinski MA. Carcinomatous meningitis in non-small-cell lung cancer: response to high-dose erlotinib. J Clin Oncol 2009 Aug 1,27(22), e31-e32. (3) Grommes C, Oxnard GR, Kris MG, et al. Pulsatile high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011 Dec,13(12), (4) Hata A, Kaji R, Fujita S, Katakami N. High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. J Thorac Oncol 2011 Mar,6(3), (5) Jackman DM, Holmes AJ, Lindeman N, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 2006 Sep 20,24(27), (6) Togashi Y, Masago K, Fukudo M, et al. Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol 2011 Oct,68(4), (7) Omuro AM, Kris MG, Miller VA, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 2005 Jun 1,103(11), (8) Morris PG, Reiner AS, Szenberg OR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol 2012 Feb,7(2), (9) Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer 2012 Jul,77(1), (10) Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006 Nov 1,12(21), (11) Hata A, Katakami N, Yoshioka H, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations. Cancer 2013 Dec 15,119(24), (12) Ruppert AM, Beau-Faller M, Neuville A, et al. EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up. Eur Respir J 2009 Feb,33(2), (13) Togashi Y, Masago K, Fukudo M, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol 2010 Jul,5(7), (14) Milton DT, Azzoli CG, Heelan RT, et al. A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer 2006 Sep 1,107(5), (15) Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--intact 2. J Clin Oncol 2004 Mar 1,22(5), (16) Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI- 774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005 Sep 1,23(25),

7 High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases (17) Aerts JG, Codrington H, Lankheet NA, et al. A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study. Ann Oncol 2013 Nov,24(11), (18) Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol 2013 Jul,14(8), (19) Sequist LV, Waltman BA, as-santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011 Mar 23,3(75), 75ra26. 8A 137

8 Chapter 8A Figure 1 and 2 1a: Axial contrast-enhanced T1-weighted MRI-cerebrum shows widespread contrast enhancement of leptomeninges suspect for leptomeningeal metastases. 1b: Follow-up axial contrast-enhanced T1-weighted MRI-cerebrum shows decreased contrast enhancement of leptomeninges, suggesting response of leptomeningeal metastases. 2a: Axial contrast-enhanced T1-weighted MRI-cerebrum shows widespread contrast enhancement of leptomeninges suspect for leptomeningeal metastases. 2b: Follow-up axial contrast-enhanced T1-weighted MRI-cerebrum shows decrease contrast enhancement of leptomeninges, suggesting decrease of leptomeningeal metastases. Figure 3 Serial Thoracic CT scans at progression: - after afatinib-cetuximab combination therapy (A) - after 2 courses of polychemotherapy (cisplatin-pemetrexed) (B) - after 3 courses of pulsatile erlotinib (C) 138