Elsevier

Lung Cancer

Volume 84, Issue 2, May 2014, Pages 110-115
Lung Cancer

Review
Overcoming the resistance to Crizotinib in patients with Non-Small Cell Lung Cancer harboring EML4/ALK translocation

https://doi.org/10.1016/j.lungcan.2014.02.001Get rights and content

Abstract

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.

Introduction

Non-small cell lung cancer (NSCLC) has not been exempted of the successes seen in tumor biology and molecular medicine. The disease is now being targeted by several different small molecules and inhibitors of different pathways. Lung cancer continues to be the first cancer-related mortality in the United States. In 2013, a total of 228,190 new lung cancer cases are expected and 159,480 deaths have been estimated [1]. In the recent years, clinicians are starting to routinely include molecular analyses of tumors from patients with NSCLC since cumulative data has shown more favorable toxicity profile, response rate and progression-free survival (PFS) in favor of targeted therapy over conventional, cytotoxic and “blind or untargeted” chemotherapy. Thus, it is crucial to test our patients for those targets such as epidermal growth factor receptor (EGFR) mutations, echinoderm microtubule associated protein like-4/anaplastic lymphoma kinase (EML-4/ALK) translocations, and recently ROS-1 translocations. EGFR exon 19 deletion and L858R mutations, EML-4/ALK translocation, EGFR exon 20 insertions, and ROS-1 translocations are found more commonly in similar phenotypic population: adenocarcinoma, younger patients, Asian ethnicity, and never smokers [2], [3], [4]. Thus, we cannot treat those patients appropriately if we do not perform these genetic tests.

In this manuscript we are reviewing how crizotinib was established as a targeted agent in NSCLC and how to overcome the resistance to this therapeutic agent with several new agents in development. Today, the term “alk-omas” has been coined to those tumors regardless of the histologic type which harbor ALK translocation. The EML-4 and ALK (already known in anaplastic non-Hodgkin's lymphoma) genes were identified in NSCLC by Soda et al. [5]. This alteration occurs from chromosome 2p inversion and is found in 3–13% of NSCLC patients [6]. The inversion of chromosome 2 leads to the fusion gene, and subsequently, a fusion protein that induces a constitutive activation of the intracellular domain of ALK; therefore, a downstream cascade of events that lead to carcinogenesis (Fig. 1) [5]. Most of the patients harboring EML4-ALK rearranged tumors are younger than other patients with lung cancer, usually never smokers or light smokers (less than 10 pack/year) [5], [7], [8], most of the cases are adenocarcinomas and do not simultaneously carry other genetic abnormalities such as EGFR mutations which are also seen in never smokers or light smokers. [6]. Histologically, these ALKomas tend to have a mucinous cribiform pattern in 56% of the cases and as much as 43% had a solid signet-ring pattern sometimes seen in gastrointestinal tumors [9]. Lung adenocarcinomas which have these histologic characteristics and are negative for EGFR and K-Ras should be tested for EML-4/ALK translocation. Nonetheless, not a single histologic parameter was still completely sensitive or specific to predict ALK rearrangement. IHC has proven to be a reliable way for screening specimens in a daily routine practice because is less time consuming and cheaper than performing FISH analysis on the specimens [10]. However, FISH still remains the standard and only FDA approved tool for testing for EML-4/ALK rearrangement.

Section snippets

Crizotinib in NSCLC – the beginning

Crizotinib (formerly known as PF-01241066), an inhibitor of ALK and c-MET receptor kinases, was the first ALK-targeted therapy tested in the clinical practice. A phase I, international, multicenter trial was conducted to investigate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of crizotinib in patients with advanced cancer [11]. That trial was already enrolling patients in the dose escalation phase when EML4-ALK in NSCLC was first reported in 2007. There were two

Clinical trials using crizotinib – post-marketing approval

In the Phase III trial PROFILE 1007 crizotinib was compared against pemetrexed or docetaxel in the second line setting [13]. Patients with stage IIIB/IV ALK-positive NSCLC previously treated with one prior platinum-based doublet (n = 347) were randomized to receive crizotinib (n = 173) at 250 mg orally twice a day or chemotherapy (n = 174; 41% received docetaxel and 57% pemetrexed at standard doses). Patients with progressive disease on chemotherapy were offered crizotinib on another trial known as

Mechanism of resistance to crizotinib

Unfortunately, PFS in patients on crizotinib are short-lived despite of great clinical and radiographic responses, although cases with more than 24 months of clinical benefit have been reported [12]. Patients exposed to crizotinib may have an intrinsic resistance, demonstrated sometimes by a fast progression of the disease while on therapy, or acquired resistance to inhibitors after an initial response [11]. Several mechanisms of acquired resistance to ALK inhibitors have been described, but

AUY922

A novel isoxazole-based heat shock protein 90 (Hsp90) inhibitor has been shown to cause the degradation of multiple oncogenic cellular proteins. Preclinical data suggest broad antitumor activity including xenografts for breast, ovarian, prostate cancer, melanoma, glioblastoma, and multiple myeloma. This novel compound not only causes tumor regression but decreases invasion and angiogenesis. Hsp90 is a molecular chaperone which supports multiple client proteins essential for apoptosis,

Conclusion

Certainly, the accelerated approval of crizotinib has benefited many patients whose tumors harbor this novel translocation EML4/ALK. In this period of time, when researchers have developed novel agents which are active against previously treated crizotinib patients or patients progressing on this agent, this ALK inhibitor has also shown activity on another translocation that shares 90 percent of its biological pathway and signaling, ROS-1. To date, patients with adenocarcinoma histology former

Conflict of interest statement

Dr. Raez has received research funding from Pfizer, Novartis, Genentech/Roche, Syntha and Aztra-Zeneca. Dr. Santos is part of the speaker bureau of Pfizer, Lilly, Genentech, Millenium, Celgene, Amgen and Boehringer-Ingelheim. Dr. Perez and Dr. Velez have no potential conflicts of interest.

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