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Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

in Non-Small Cell Lung Cancer

Kuiper, J.L.

2016

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citation for published version (APA)

Kuiper, J. L. (2016). Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in

Non-Small Cell Lung Cancer.

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High-dose, pulsatile erlotinib in two NSCLC patients with

leptomeningeal metastases – one with a remarkable

thoracic response as well

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ABSTRACT

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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

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were mild malaise on day of taking the high dose and skin toxicity grade 1. Follow-up MRI-cerebrum 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 2008. An EGFR mutation was detected in exon 19 (del 747-752 (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

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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 TKI-pretreated 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.

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(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), 6494-6501.

(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), 4325-4332.

(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), 436-440.

(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), 950-955.

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(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), 785-794.

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(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), 2860-2865.

(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), 777-786.

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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 1 and 2

1b: Follow-up axial contrast-enhanced T1-weighted MRI-cerebrum shows decreased contrast enhancement of leptomeninges, suggesting response of 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)

Figure 3

Serial Thoracic CT scans at progression:

- after afatinib-cetuximab combination therapy (A)