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Crizotinib primary resistance overcome by ceritinib in a patient with ALK-rearranged non-small cell lung cancer

Abstract

We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies. We hypothesize that crizotinib was powerless in controlling disease progression due to its inadequate inhibition of ALK signaling. Although we lack any molecular evidence elucidating the primary crizotinib resistance, we believe that ceritinib treatment led to tumor regression thanks to its superior biological potency.

Tumori 2016; 102(Suppl. 2): e46 - e49

Article Type: CASE REPORT

DOI:10.5301/tj.5000520

Authors

Francesco Facchinetti, Caroline Caramella, Nathalie Auger, David Planchard, Julien Adam, Ludovic Lacroix, Jordi Remon, Christophe Massard, Jean-Charles Soria, Luc Friboulet, Benjamin Besse

Article History

Disclosures

Financial support: Francesco Facchinetti’s experience was supported by a grant from the Italian Association of Thoracic Oncology (AIOT).
Conflict of interest: Jean-Charles Soria declared compensated consultancy for Pfizer, Novartis and Genentech. The other authors have no conflict of interest to declare.

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Introduction

Treatment with crizotinib leads to striking outcomes in patients with advanced non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement (1, 2). Nevertheless, as seen with other tyrosine kinase inhibitors (TKIs), patients who initially respond to crizotinib almost invariably experience tumor progression, leading to median progression-free survival times of 7.7 and 10.9 months in second- and first-line treatment, respectively (1, 2). Exhaustion of crizotinib activity can be explained by acquisition of additional biological events leading to acquired resistance to treatment, together with the emergence of a preexisting clone primarily resistant to the TKI and initially undetectable. Furthermore, not all cancers harboring ALK translocations are sensitive to crizotinib. About 5% to 7% of ALK-rearranged patients enrolled in clinical trials were found to have primary resistance to crizotinib (1-2-3). Second-generation ALK-TKIs have shown meaningful activity in patients with secondary resistance to crizotinib. We describe the first case to our knowledge of an ALK-rearranged advanced NSCLC patient with primary resistance to crizotinib who experienced a partial and durable response to ceritinib (LDK378), a second-generation ALK inhibitor (4).

Case presentation

In October 2012, a 55-year-old never-smoker Caucasian man was diagnosed by endobronchial biopsy with stage IV (liver, spleen and pericardium involvement), TTF-1-positive, poorly differentiated lung adenocarcinoma. A typical break-apart FISH pattern of ALK rearrangement (ALK Break Apart Probe, Vysis, Abbott Molecular) was detected in 84 of 100 (84%) examined cells, while no amplification of the rearranged gene was observed. The histological material available was not sufficient to perform ALK immunohistochemistry (IHC). Targeted next-generation sequencing (NGS) did not reveal any molecular alteration on a panel of 75 cancer genes including EGFR, ALK, HER2, PIK3CA, PTEN, AKT1, KIT, MET, RET, ROS1, BRAF and RAS. No MET amplification was detected by FISH analysis. First-line treatment was delivered within a clinical trial combining carboplatin, taxol and bevacizumab plus a PI3K inhibitor. The first 4 courses of induction treatment, started in November 2012, led to stabilization of the tumor volume, which allowed subsequent administration of 16 maintenance cycles of bevacizumab combined with the PI3K inhibitor.

In January 2014 the appearance of new hepatic lesions together with an increase in mediastinal lymph node involvement was documented by a routine CT scan, and second-line therapy with crizotinib 250 mg orally twice daily was started in February 2014 (Fig. 1A). The first CT scan after 2 months of treatment showed disease progression in the liver with the appearance of a new lesion and a slight increase in the size of the known lesions (+13% according to the RECIST criteria). Crizotinib treatment was maintained because of the lack of significant tumor-related symptoms and the excellent tolerability.

Primary resistance to crizotinib overcome by ceritinib: effect of treatment on liver metastases. Crizotinib did not control liver metastases (Fig. 1A: baseline; Fig. 1B: after 14 weeks of treatment, +30% according to RECIST criteria). After disease progression under crizotinib, ceritinib administration led to regression of the hepatic lesions that persisted over time (-30% and -80% after 2 and 9 months, Fig. 1C and 1D, respectively).

Liver progression (+30%) was confirmed 6 weeks later (Fig. 1B), prompting the interruption of crizotinib. A new liver biopsy was performed which confirmed a metastasis of lung adenocarcinoma. The 75-gene panel targeted analysis on the new specimen, completed by whole exome sequencing and RNA sequencing analyses, did not reveal any remarkable new alterations. In particular, no mutations or other translocations (beside the EML4-ALK variant 5 fusion transcript E2;A20) were identified for ALK, EGFR, KIT, ROS1, RET, MET or other genes involved in the PI3K/mTOR pathway. A diffuse intense ALK-positive signal was obtained by IHC performed with the D5F3 clone (Fig. 2). As priority was given to sequencing analyses, no sufficient material was available to perform ALK FISH on this sample.

ALK immunohistochemistry was performed on the liver metastasis biopsy obtained at the time of progression on crizotinib. ALK protein expression was evaluated with the D5F3 clone on the BenchMark XT platform (Ventana), showing positive staining of tumor cells.

Ceritinib was then administered within an expanded access program at the scheduled dose of 750 mg orally once daily from June 2014. At 2 months, a CT scan revealed regression of the metastatic mediastinal lymph nodes and a marked decrease in the size of the liver metastases (RECIST -30%). After 6 months of ceritinib treatment, additional tumor response was observed both in the primary tumor and liver lesions (-80%, Fig. 1C and 1D), and was confirmed after 9 months of ceritinib administration. After 18 months of ceritinib treatment, no radiological or clinical signs of progression were observed and the patient was still receiving the drug (Fig. 3).

Tumor burden evaluation over time and related molecular features of the tumor. First-line carboplatin + taxol + bevacizumab + PI3K inhibitor and maintenance treatment with the latter 2 compounds led to prolonged tumor control. When progression was documented, crizotinib was administered given the rearranged ALK signal of the diagnostic specimen. As crizotinib did not show any efficacy, ceritinib treatment was started and was successful. The information in the black boxes refers to known molecular clues potentially explaining the crizotinib resistance, evaluated on the diagnostic biopsy specimen and the post-crizotinib liver specimen. NGS = next-generation sequencing; CNG = copy number gain; WES = whole-exome sequencing; RNA-seq = RNA sequencing.

Discussion

Whereas the acquired resistance mechanisms regarding both EGFR and ALK inhibition have been elucidated (5), primary resistance in ALK-rearranged patients has not been extensively studied yet. In EGFR-mutated lung cancer, pretreatment T790M gatekeeper mutation or MET gene amplification (6, 7) concur to explain primary resistance to EGFR-TKIs in a large percentage of cases. It may therefore be presumed that detectable or undetectable clones harboring these resistance-inducing alterations, present before TKI treatment, will sooner or later elude pharmacological suppression.

In the last few years, several studies have addressed the molecular mechanisms of acquired resistance to crizotinib, associating clinical evidence with preclinical models (5). Amplification of the rearranged ALK allele or mutations within the ALK kinase domain explain failure of crizotinib treatment in about 20% to 40% of cases. The emergence of ALK, KIT or EGFR gene amplification can explain another significant part of the acquired crizotinib resistance. Up to 50% of cases do not harbor any detectable mechanism explaining treatment failure.

In the present report, a patient affected by advanced NSCLC harboring an ALK translocation did not show any response to crizotinib but benefited from ceritinib treatment. None of the previously described resistance mechanisms to ALK-TKIs nor any other molecular alterations pertained to the patient’s samples. No mutations or amplifications of the rearranged ALK gene and no EGFR, KIT, SRC or IGF-1R molecular abnormalities were detected in the diagnostic or post-crizotinib biopsies.

A putative role of false ALK positivity in the FISH analysis of the first biopsy was refuted both by the ALK protein expression detected by IHC in the second sample and the ceritinib response itself. Pharmacokinetics issues and interpatient variability in drug bioavailability may have an impact on crizotinib’s efficacy. Interestingly, using patient-derived in vitro models, Friboulet and colleagues provided evidence for the potential benefit exercised by ceritinib in terms of the potency of ALK inhibition (8). Assuming a clinical scenario similar to what Friboulet and collaborators depicted in vitro, we believe that the lack of crizotinib efficacy can be explained by persistence of ALK signaling, which was successfully interrupted by the more potent compound ceritinib.

The current availability of a wide spectrum of ALK-TKIs makes it imperative to expose patients affected by NSCLC harboring ALK rearrangements to the most extended possibilities of oncogene-directed therapies. Indeed, preclinical evidence (9) and preliminary clinical data (10) suggest the new next-generation ALK-TKI PF-06463922 (lorlatinib) would hopefully allow longer disease control. Although unexplained at the molecular level, this first report of primary resistance to crizotinib reversed by ceritinib strongly supports the concept of administering next-generation ALK-TKIs to patients who do not respond to the first-generation inhibitor.

Disclosures

Financial support: Francesco Facchinetti’s experience was supported by a grant from the Italian Association of Thoracic Oncology (AIOT).
Conflict of interest: Jean-Charles Soria declared compensated consultancy for Pfizer, Novartis and Genentech. The other authors have no conflict of interest to declare.
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Authors

Affiliations

  • Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif - France
  • Medical Oncology Unit, University Hospital, Parma - Italy
  • INSERM, U981, Gustave Roussy Cancer Campus, Villejuif - France
  • Department of Medicine, University Paris-Sud, Kremlin Bicetre/Chatenay-Malabry - France
  • Department of Radiology, Gustave Roussy Cancer Campus, Villejuif - France
  • Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif - France
  • Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif - France

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