Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?

Abstract

Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in this subset of NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.

Figure 1. Radiographic findings in patient 1. (A) An initial CT-scan of the chest showed a large tumor arising from the left lower lobe of the lung. (B) An initial staging PET CT-scan showed diffuse FDG avidity suggestive of widespread metastases involving the skeleton. (C) After 6 mo of Crizotinib monotherapy, the patient had a partial response with remarkable improvement in Fluorodeoxyglucose (FDG) avidity seen in a PET CT-scan. (D) An MRI of the brain at 6 mo showed development of 12 brain metastases, two of which are visible in this axial T1-post contrast image.

Figure 2. Histopathologic features of the EML4-ALK translocation positive tumor from patient 1. (A) An FNA of the patients left lung tumor showed malignant cells with hematoxylin and eosin (H&E) staining. (B) A core needle biopsy of the primary left lower lobe lung tumor showed moderately-differentiated adenocarcinoma. (C) The tumor cells exhibited nuclear expression of TTF-1 by IHC. (D) A biopsy of a nasal bone lesion confirmed metastatic disease which similarly expressed TTF-1 by IHC.

Figure 3. Radiographic findings in patient 2. (A) An initial CT-scan of the brain showed 3 large lesions, one of which is seen in this axial image abutting the posterior right lateral ventricle. (B) The primary tumor likely arised from the right middle lobe adjacent to the hilum. (C) After 6 mo of Crizotinib monotherapy, the tumor in the right lower lobe exhibited a significant partial response. (D) An MRI of the brain after undergoing 8 mo of Crizotinib showed the interval development of multiple new metastases.

Figure 4. Radiographic findings in patient 3. (A) an initial CT-scan of the chest showed a large right hilar tumor with bilateral pleural effusions. (B) A biopsy of her right hilar tumor showed moderately-differentiaed adenocarcinoma. (C) Sn axial image and (D), a frontal/coronal image from a brain MRI showing development of multiple large metastases.

Figure 5. Working model for the role of EML4-ALK chimeric kinase in driving the progression of NSCLC through activation of the EGFR pathway. The EML4-ALK protein phosphorylates and activates Ras signaling leading to a cascade of events driving cellular proliferation and growth. There are multiple redundancies in this pathway susceptible to targeted small molecule therapy. We propose that using agents such as Sorafenib with good CNS penetration distal to ALK-signaling represents an opportunity to overcome therapeutic resistance and reduce CNS failure. EGFR, epidermal growth factor receptor dimer; AKT, a serine/threonine-specific protein kinase; ERK, extracellular-signal related kinases; IKK, IκB kinase; NFκB, nuclear transcription factor kappa B; MEK, mitogen-activated protein kinase; RAF, protein serine/threonine protein kinase. →, activates; —|, inhibits.