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
AuthorsFrancesco Facchinetti, Caroline Caramella, Nathalie Auger, David Planchard, Julien Adam, Ludovic Lacroix, Jordi Remon, Christophe Massard, Jean-Charles Soria, Luc Friboulet, Benjamin Besse
- • Accepted on 14/04/2016
- • Available online on 13/05/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
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).
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 (
Primary resistance to crizotinib overcome by ceritinib: effect of treatment on liver metastases. Crizotinib did not control liver metastases (
Liver progression (+30%) was confirmed 6 weeks later (
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%,
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.
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
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.
- Facchinetti, Francesco [PubMed] [Google Scholar] 1, 2, 3, 4
- Caramella, Caroline [PubMed] [Google Scholar] 5
- Auger, Nathalie [PubMed] [Google Scholar] 6
- Planchard, David [PubMed] [Google Scholar] 1
- Adam, Julien [PubMed] [Google Scholar] 6
- Lacroix, Ludovic [PubMed] [Google Scholar] 4, 6
- Remon, Jordi [PubMed] [Google Scholar] 1
- Massard, Christophe [PubMed] [Google Scholar] 7
- Soria, Jean-Charles [PubMed] [Google Scholar] 3, 4, 6
- Friboulet, Luc [PubMed] [Google Scholar] 3, 4, * Corresponding Author (email@example.com)
- Besse, Benjamin [PubMed] [Google Scholar] 1, 4
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