Non–Small Cell Lung Cancer Erminia Massarelli and Vassiliki Papadimitrakopoulou

Published OnlineFirst January 6, 2015; DOI: 10.1158/1078-0432.CCR-14-1291

CCR Drug Updates Clinical Cancer Research Ceritinib for the Treatment of Late-Stage (Metastatic) Non–Small Cell Lung Cancer Erminia Massarelli and Vassiliki Papadimitrakopoulou

Abstract

Over the past decade, the non–smallcelllungcancer including secondary mutation in the ALK gene, eventually therapeutics landscape has been dominated by the increasing result in disease progression, and several second-generation focus on identification and validation of molecular targets, ALK inhibitors, notably ceritinib, have demonstrated evi- as well as the identification of the best candidate agents to dence of clinical activity in this setting. This review discusses address these targets. Among the notable successes have been the data associated with the recent accelerated approval of the approval of erlotinib, gefitinib, and afatinib for the EGFR ceritinib for treatment of patients with ALK-positive, meta- mutation, and more recently crizotinib for anaplastic lym- static lung adenocarcinoma with disease progression on or phoma kinase (ALK) gene rearrangement. Despite the excel- who are intolerant to crizotinib. Clin Cancer Res; 21(4); 670–4. lent efficacy of crizotinib, several mechanisms of resistance, Ó2015 AACR.

Introduction inhibitors (ALKi). Apart from the EML4–ALK fusion gene, 11 other variants have been identified but it is still unclear whether Since the original report by Soda and colleagues that the these result in differential susceptibility to ALKi (3). In addition, anaplastic lymphoma kinase (ALK) gene fuses with the echi- chromosomal rearrangements involving the gene encoding ROS1 noderm microtubule-associated protein like 4 (EML4), result- proto-oncogene receptor tyrosine kinase (ROS1)define a distinct ing in potent transforming activity in non–smallcelllung molecular subgroup of NSCLCs that have shown sensitivity to cancer (NSCLC) limited to the adenocarcinoma histologic ALKi, in particular crizotinib (ref. 7; Table 1). subtype, it is well recognized that between 3% and 7% of The ALK tyrosine kinase inhibitor (ALK-TKI) crizotinib, NSCLC is molecularly defined by the presence of an inversion which is a small-molecule potent inhibitor targeting cMET, or translocation of chromosome 2p involving the ALK gene, ALK, and ROS1 tyrosine kinases, was the first in class shown resulting in a transforming fusion gene and representing a þ to be effective for ALK-positive (ALK ) patients with advanced distinct molecular subset of disease (1, 2). Generally, all the NSCLC demonstrating response rates of about 60% in a single- ALK rearrangements identified so far are constituted by two arm study, which led to accelerated FDA approval in October portions. The first is the highly conserved break point within 2011 (8–10). This study was followed by a randomized trial in ALK, located in the intron immediately upstream of the exons which crizotinib demonstrated superiority over standard che- encodingthekinasedomain;thesecondarethe50-end partners motherapy in patients previously treated with platinum-based containing a coiled-coil or leucine zipper domain responsible chemotherapy. ALK inhibitors can inhibit ROS1 kinase activity for oligomerization of fusion protein and ligand-independent in cell lines, and crizotinib is also associated with clinically activation of the ALK tyrosine kinase (TK) activity. Constitutive significant antitumor activity in patients with ROS1 NSCLC. A activation of downstream signaling pathways, such as the Ras/ study investigating the use of crizotinib in ROS1 rearranged MAPK, PI3K/AKT, and JAK/STAT, results in uncontrolled cancer cancer demonstrated an overall response rate (ORR) of 72% cell proliferation and survival. Thirteen variants of the EML4– [95% confidence intervals (CI), 58–84], with 33 partial ALK fusion have been described, according to the break point responses (PR) and three complete responses (CR). The median on EML4 (from exon 2 to exon 20; ref. 3). Furthermore, in duration of response (DOR) was 17.6 months (95% CI, 14.4 to addition to EML4,theTRK-fused gene (TFG;refs.4–6) and the not reached), with 25 patients (50%) still in follow-up for kinesinfamilymember5B(KIF5B;refs.4–6) have been progression at the time of this report. The pharmacokinetics, described to be fused to ALK in rare cases (Table 1). antitumor activity, and safety profile of crizotinib in this group Mice transduced with NIH3T3 cells forced to express the þ of patients were similar to those observed in patients with ALK EML4–ALK fusion gene can be successfully treated with ALK NSCLC (7). þ Despite dramatic initial activity of crizotinib in ALK NSCLC, invariably crizotinib resistance develops typically within 1 to 2 Department of Thoracic/Head and Neck Medical Oncology, The Uni- years from the beginning of treatment. The central nervous system versity of Texas MD Anderson Cancer Center, Houston, Texas. (CNS) is a particularly common site of progressive disease in Corresponding Author: Vassiliki Papadimitrakopoulou, The University of Texas crizotinib-treated patients, suggesting the need for ALKi that not MD Anderson Cancer Center, Houston, TX 77030. Phone: 713-792-6363; Fax: only can overcome acquired crizotinib resistance, but also pen- 713-792-1220; E-mail: [email protected] etrate the blood–brain barrier (11, 12). This review focuses on the þ doi: 10.1158/1078-0432.CCR-14-1291 use of ceritinib for the treatment of patients with ALK , metastatic Ó2015 American Association for Cancer Research. lung adenocarcinoma.

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Table 1. Sensitizing and resistance mechanisms to ALKi Among 163 previously crizotinib-treated patients receiving Sensitizing mechanisms 750 mg of ceritinib daily, the ORR was 54.6% (95% CI, 46.6%– ALK ALK-EML4 fusions 62.4%) and PFS was 6.9 months (95% CI, 5.4–8.4). In 83 patients ALK-TRK – ALK-KIF5B without prior ALKi, the ORR was 66.3% (95% CI, 55.1% 76.3%). ROS1 fusions At the time of data cutoff, the majority of these patients were still Resistance mechanisms receiving ceritinib and the median PFS had not been reached. ALK dominant In the 124 patients who started the study with brain metastases, Secondary mutations in the ALK gene (L1196M, ceritinib achieved an ORR of 54.0% (95% CI, 44.9%–63.0%) and G1269A, 1151T-ins, L1152R, C1156Y, G1202R, a median PFS of 6.9 months (95% CI, 5.4–8.4). Tumor shrinkage S120Y, V1180L) ALK copy number gain was seen in patients with brain metastases with (50%; 95% CI, CNS resistance 39.7%–60.3%) and without (69.2%; 95% CI, 48.2%–85.7%) ALK nondominant prior ALK-TKI. Discontinuation of treatment due to adverse events Partially ALK dependent Increased autophosphorylation of EGFR (AE) occurred in 10% of patients, and 59% of patients required at Kit amplification least one dose reduction. The most common AEs, occurring in Transformation to sarcomatoid carcinoma more than half of patients, were diarrhea, nausea, vomiting, MET amplification ALK independent KRAS mutations abdominal pain, and fatigue (15, 16). EGFR mutations The subgroup analysis between Asian and Caucasian patients showed that baseline demographics were similar but ALKi pretreatment had been received by 47 (29%) and 108 (66%) patients, respectively (17). Of 173 patients analyzed for efficacy, Ceritinib the ORR was 69% (95% CI, 55.2–80.9) in Asian patients (38/55) Among the several highly potent next-generation ALK-TKIs and 57% (95% CI, 47.3–65.9) in Caucasian patients (67/118). currently under investigation, LDK378 (ceritinib) has demon- The median DORs among responders were 10.1 months (95% CI, strated promising antitumor activity and was granted FDA 7.3 to not reached) and 6.9 months (95% CI, 4.5–11.4) in the approval in April 2014. Asian and Caucasian patients, respectively. The observed differ- Ceritinib contains modifications in the chemical structure ences between Asians and Caucasians for ORR and DOR were not that promote a more favorable interaction with the mutant explained by differences in ALKi pretreatment (17). lipophilic residues at the gatekeeper position of the kinase Two phase III ongoing randomized trials are currently inves- domain with a 20-fold higher in vitro potency against ALK than tigating the role of ceritinib both in chemotherapy and in þ crizotinib. Ceritinib led to suppression of ALK phosphorylation patients with ALK NSCLS previously treated with crizotinib as well as the downstream PI3K–AKT, MEK–ERK, and mTOR (NCT01828112) versus single-agent chemotherapy (pemetrexed signaling pathways at lower doses than crizotinib. Although or docetaxel), and in previously untreated (NCT01828099) þ ceritinib was potent against the two lung cancer cell lines with ALK NSCLC versus platinum doublet chemotherapy (platinum/ ALK rearrangements, it was not potent against NSCLC or breast pemetrexed). cancer cell lines driven by KRAS, EGFR, PI3K,orHER2 (13). In addition, in treatment-na€ve H228 xenograft models, ceritinib Ceritinib Toxicity Profile demonstrated more durable antitumor activity than crizotinib Adverse reaction data are based on 255 patients treated with (13). The kinase selectivity has been tested in a cellular pro- þ ceritinib, 750 mg daily for ALK malignancies (n ¼ 246 NSCLC; liferation assay against 16 different kinases, and aside from þ n ¼ 9 other ALK diseases; refs. 16, 18). ALK, no inhibition below 100 nmol/L was observed (14). Serious AEs were rare (2%), and included interstitial lung Unlike crizotinib, ceritinib does not inhibit the activity of MET, disease (ILD)/pneumonitis, convulsion, pneumonia, dyspnea, a tyrosine kinase that can be overexpressed, amplified, or dehydration, hyperglycemia, and nausea (18). The most common mutated in NSCLC, leading to cell progression and survival. AEs (1%) that resulted in discontinuation of therapy included However, ceritinib does inhibit insulin-like growth factor 1 ILD/pneumonitis, pneumonia, and anorexia. Fatal AEs were also receptor (IGFIR), insulin receptor (InsR), and ROS1 (15). The rare (5% of patients), resulting from pneumonia (n ¼ 4), respi- chemical architecture of ceritinib, including the chlorine in the ratory failure (n ¼ 1), ILD/pneumonitis (n ¼ 1), pneumothorax 5-position of the pyrimidine, may interact more favorably with (n ¼ 1), gastric hemorrhage (n ¼ 1), general physical health a methionine gatekeeper in crizotinib-resistant ALK and could deterioration (n ¼ 1), pulmonary tuberculosis (n ¼ 1), cardiac explain the activity of this drug against several ALK resistance tamponade (n ¼ 1), and sepsis (n ¼ 1). Neuropathies, including mutations such as L1196M, G1269A, I1171T, and S1206Y. peripheral sensory or motor neuropathy, gait disturbance, pares- However, it does not overcome the ALK resistance mutations thesia, hypoesthesia, dysesthesia, neuralgia, hypotonia, or poly- G1202R and F1174C. neuropathy, occurred in 17% of patients. Vision abnormalities ASCEND-1, the first phase I in-human, single-arm study of (9%) occurred infrequently but were clinically relevant. ILD/ ceritinib at 750 mg daily, included 255 patients, 246 of whom had þ pneumonitis resulted in one death (0.4%). Concentration-depen- ALK NSCLC, 67% with at least two prior treatment regimens, dent QTc prolongation has also occurred (18). and 66% with prior ALKi treatment (16). After a median 7 months of follow-up, patients treated with ceritinib achieved an ORR of 58.5% (95% CI, 52.1%–64.8%) and a median progression-free Mechanisms of Resistance to ALK Inhibitors survival (PFS) of 8.2 months (95% CI, 6.7–10.1). The median Mechanisms of acquired resistance are heterogeneous and may DOR was 9.7 months (95% CI, 7.0–11.4), with a median time to evolve dynamically in response to different ALK-TKIs and may be first response of 6 weeks. divided into two groups: ALK dominant or ALK nondominant

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(Table 1). ALK-dominant mechanisms include second mutations Other Second-Generation ALK Inhibitors and C1156Y, within the kinase domain of the EML4–ALK fusion Among the other second-generation ALKi, alectinib and gene in the same patient who acquired resistance to crizotinib AP26113 are in more advanced development. (19). L1196M is a gatekeeper mutation that interferes with the Alectinib is a potent, selective, and orally available ALK-TKI binding of crizotinib. Other resistance mutations in the ALK gene with 10-fold greater potency than crizotinib with activity against have been discovered in the clinical setting or in mutagenesis other kinases, including MET, IGFIR, and ALK with or without the screening, including L1152R, 1151Tins, G1202R, S1206Y, þ gatekeeper mutation (L1196M; ref. 14). A single-arm, open-label, F1174C, D1203N, G1269A, and L1196M. Eleven ALK patients þ phase I/II trial was conducted in ALK NSCLC in Japan and with NSCLC with acquired resistance to crizotinib were reported demonstrated excellent efficacy for alectinib (25). In contrast to exhibit new-onset ALK copy number gain, which may occur in with the trials of crizotinib, positive results based on both FISH combination with resistance mutations. and IHC or RT-PCR analysis were required for enrollment in that The known ALK-nondominant mechanisms leading to cri- study. In the phase I portion, including 24 patients, a dose of 300 zotinib resistance are mutations of other oncogenes such as mg twice daily was chosen as the recommended dose in the phase the EGFR and KRAS genes (19), amplification of the KIT gene II trial, which included 46 patients. (20), increased autophosphorylation of EGFR (20), and trans- In the ongoing phase II portion of the study, 43 of 46 patients formation to sarcomatoid carcinoma (ref. 21; Table 1). Recent- achieved an OR (93.5%; 95% CI, 82.1–98.6), including 2 CRs ly several studies have suggested that ALK rearrangements (4.3%; 0.5–14.8) and 41 PRs (89.1%; 76.4–96.4). Grade 3 treat- cooccur with mutations in EGFR or KRAS at clinically relevant ment-related AEs were recorded in 12 of 46 (26%) patients, frequencies. Gainor and colleagues reported the genotyping þ including 2 patients with decreased neutrophil counts and data from 1,683 patients with NSCLC finding4outof75ALK increased blood creatine phosphokinase. Serious AEs occurred in patients with KRAS mutations (22). Won and colleagues have 5 patients (11%) but no grade 4 AEs or deaths were reported (25). profiled 1,458 cases of lung cancer and found that 4 out of 91 Intriguingly, no progression of CNS lesions was observed in 15 cases had concomitant EGFR and ALK alterations (23). The patients proved to harbor brain metastases by the time of data possibility of coexistence of either EGFR or KRAS mutations cutoff. The PFS rate at 1 year was 83% (95% CI, 68–92), although has profound effect on therapeutic choices and highlights the the median PFS was not reached. need to extend the ALK testing to EGFR and KRAS-mutation Results from 47 patients enrolled in another phase I/II study positive cases. MET receptor expression but not MET gene þ showed alectinib to be well tolerated, with the most common AEs amplification is significantly increased in ALK NSCLC com- being fatigue (30%), myalgia (17%), and peripheral edema pared with ALK-negative counterpart (24). Because crizotinib (17%). Dose-limiting toxic effects were recorded in 2 patients in is a dual inhibitor of MET and ALK, it is possible that the status þ the cohort receiving alectinib, 900 mg twice a day. At data cutoff of MET expression may affect the efficacy of crizotinib in ALK (median follow-up of 126 days), investigator-assessed ORs were NSCLC under therapy. However, second-generation ALKi has noted in 24 of 44 (55%) patients, with a confirmed CR in 1 (2%), a selective activity against ALK-TK and does not demonstrate confirmed PR in 14 (32%), and an unconfirmed PR in 9 (20%). activity against MET-TK. Sixteen (36%) patients had stable disease (SD); the remaining 4 Second-generation ALKi, such as alectinib (25, 26) and ceritinib (14), have been shown to be effective not only in crizotinib-na€ve (9%) had PD. Of 21 patients with CNS metastases at baseline, 11 fi patients, but also in those resistant to crizotinib. (52%) OR, 6 (29%) CR (3 uncon rmed), 5 (24%) PR (1 uncon- fi Unfortunately ceritinib resistance has already been reported rmed), 8 (38%) SD, and the remaining 2 (10%) PD were þ in 11 ALK NSCLC cases by FISH, showing mutations in two reported. Alectinib, 600 mg twice a day, was chosen as the residues, G1202R and F1174C, respectively, in 3 out of 11 and recommended dose for phase II (28). 2 out of 11 post-ceritinib biopsies (13). In vitro resistance AP26113 is a novel TKI that potently inhibits mutant activated ALK EGFR to both crizotinib and ceritinib was reported in less com- forms of the and genes as well as TKI-resistant forms, ALK EGFR mon ALK-resistance mutations such as C1156Y, 1151T-ins, including L1196M of the gene and T790M of the gene fi and L1152P (13). (29). Preliminary data for an ongoing dose- nding phase I/II A novel ALK V1180L gatekeeper mutation from a cell line study of AP26113 for advanced malignancy refractory to standard fi model and a second novel I1171T mutation from a patient who treatment showed the ef cacy and safety of the compound in patients with NSCLC previously treated with ALKi or EGFR-TKIs. developed resistance to alectinib were recently reported (27). þ Among 57 evaluable ALK NSCLC patients, 41 (72%) responded. Both mutations demonstrated structural alterations with subse- þ quent decrease binding affinity with alectinib and crizotinib. Among 51 evaluable ALK NSCLC patients with prior crizotinib However, both mutations were sensitive to ceritinib and other exposure, 35 (69%) responded. The DOR was 1.6 to 14.7 months ongoing at the time of data cutoff. Among 49 patients with follow- next-generation ALK-TKIs and treatment of the patient with þ ceritinib led to a marked response. up scans, the median PFS was 10.9 months. Nine out of 13 ALK After the acquisition of resistance to ALKi, regardless of the patients with untreated progressing CNS lesions at baseline and use of crizotinib or second-generation ALKi, specifictreatment with follow-up scans showed evidence of radiographic improve- strategies should be considered directed to inhibition of the ment in CNS disease, including 1 patient with improvement in specific resistance mechanisms. The association of an ALKi leptomeningeal disease (30). The antitumor activity of at least two beyond the state of progressive disease (PD) and an inhibitor other second-generation ALKi, ASP3026 and X-396, has been in vitro of the specific resistance pathways (i.e., EGFR-TKI or KIT-TKI) shown in studies, and these agents are currently under would be appropriate. Also, chemotherapy with pemetrexed clinical investigation (NCT01401504 and NCT01625234). Table þ should be considered for ALK patients with any possible 2 summarizes the trials with novel second-generation ALKi in mechanism of resistance to crizotinib. clinical development.

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Table 2. Trials with novel second-generation ALK inhibitors in clinical development Authors/trial Prior Patient ORR in patients

Drug Cmax (ng/mL) T 1/2 (h) NCT number Phase ALK-TKI no. ORR PFS with CNS disease Ceritinib 800 205 41 ASCEND-1 (16) I Yes for 163 246 58% Median ORR ¼ 54% PFS ¼ 8.2 mo NCT 01828112 III Yes Ongoing NCT 01828099 III No Ongoing Alectinib 676 186 20 Seto et al. (25) I/II No Phase I ¼ 24 93% 1-y PFS 83%; NA Phase II ¼ 46 median PFS not reached Gadgeel et al. (28) I/II Yes Phase I ¼ 47 55% NA ORR ¼ 52% AP26113 402 29 Gettinger et al. (30) I/II Yes 57 evaluable 72% Median 9 out of 13 (69%) patients PFS ¼ 10.9 mo with improved CNS disease ASP3026 3,150 (at MTD 21.8 to 84.6 NCT 01401504 I Ongoing 525 mg dose) X-396 NA 23 (at 200 mg NCT 01625234 I Ongoing dose) Abbreviations: h, hours; mo, months; NA, not available; y, years.

ALK Fusion Detection Methods promote personalized medicine (32). However, molecular diagnostic testing is complex and several assays with different merits ALK gene fusion can be detected by several methods, may be suitable in that regard especially when testing molecularly including RT-PCR, the first published method used (2); FISH, heterogeneous tumors such as NSCLC. the currently accepted method approved by the FDA; and IHC. þ FISH is a relatively expensive assay that can detect all types When to Use Ceritinib in ALK NSCLC of ALK rearrangements known to date; however, its interpre- þ The optimal choice for first-line therapy for ALK patients tation could be challenging even in the hands of experienced and the optimal sequence for therapies after progression to specialists. IHC is relatively inexpensive, fast, and familiar first-line therapy aiming at maximizing survival benefitand to most pathologists, and can also be used universally, strategies to prevent or delay resistance remain to be deter- similar to FISH, as it can potentially detect overexpressed mined. Although it is not clear at present whether crizotinib or ALK chimeric protein produced by any rearrangement type. þ second-generation ALKi will be the superior treatment for ALK However, the variability of chimeric proteins with different patients, a head-to-head study comparing crizotinib with the levels of expression raises questions about the correct choice second-generation ALKi would clarify this point. In fact, a of antibody and signal enhancement system to avoid false- randomized phase III trial comparing alectinib with crizotinib negative results. Artifacts that may lead to false-positive is currently being performed to address this issue results are also relatively frequent and cannot be underesti- (NCT02075840). The activity demonstrated by ceritinib and mated. RT-PCR is a highly sensitive and specific technique that alectinib in patients with CNS disease involvement suggests the allows the detection of even a few molecules of chimeric ALK use of these agents preferentially in this clinical scenario. On transcripts. However, the use of RT-PCR as a screening method the basis of already described mechanisms of resistance to first- for detecting ALK rearrangements may not be completely and second-generation ALKi-specific treatment strategies, com- reliable for several reasons, including poor quality of RNA bination therapy with EGFR-TKI, KIT-TKI, MET-TKI, or peme- obtained from formalin-fixed, paraffin-embedded tissues, trexed-based therapy could be explored. which are mostly available in the clinical setting, and the necessity of PCR multiplexing because of the wide variation in fusion types. Conclusions and Challenges It is clear that each method has advantages and pitfalls, and The challenge of future studies is in the identification of the an agreement about the optimal protocol for ALK testing has mechanisms underlying acquired resistance to ceritinib and not yet been reached. IHC, FISH, and multiplex RT-PCR meth- new ALKi. In addition, combinations between ALKi and other odologies showed good sensitivity, specificity, and concor- therapeutic strategies, such as inhibition of escape survival dance when artifacts were characterized and excluded in a study pathways and immunotherapy agents, are potential alterna- thatprospectivelytested36patientswithNSCLCwhohad þ þ tives to increase survival in ALK NSCLC patients. adenocarcinoma and 10 ALK samples. However, all ambigu- ouscaseshadtobeconfirmed as ALK rearranged by at least two of the three methods. Blackhall and colleagues have recently Disclosure of Potential Conflicts of Interest reported a prevalence of 6.2% of IHC positivity with a 2.2% of V. Papadimitrakopoulou reports receiving commercial research grants FISH positivity in 1,281 European patients with NSCLC, show- from Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Clovis Oncol- fi ingthatascreeningstrategybasedonIHCorH-scoremightbe ogy, Genentech, Janssen, MedImmune, Merck, and P zer and is a con- sultant/advisory board member for AstraZeneca, Clovis Oncology, Eli feasible (31). Lilly, Genentech, GlaxoSmithKline, Janssen, MedImmune, Merck, and The concept of coapproval of therapeutic product and com- Novartis. No potential conflicts of interest were disclosed by the other panion diagnostics has been encouraged as part of the strategy to author.

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Authors' Contributions Writing, review, and/or revision of the manuscript: E. Massarelli, V. Conception and design: E. Massarelli, V. Papadimitrakopoulou Papadimitrakopoulou Development of methodology: V. Papadimitrakopoulou Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): E. Massarelli Analysis and interpretation of data (e.g., statistical analysis, biostatistics, Received October 1, 2014; revised December 8, 2014; accepted December 9, computational analysis): E. Massarelli, V. Papadimitrakopoulou 2014; published OnlineFirst January 6, 2015.

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674 Clin Cancer Res; 21(4) February 15, 2015 Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Correction Clinical Cancer Correction: Ceritinib for the Treatment of Research Late-Stage (Metastatic) Non–Small Cell Lung Cancer

In this article (Clin Cancer Res 2015;21:670–4), which was published in the February 15, 2015, issue of Clinical Cancer Research (1), the authors' interpretation of the study in reference 22 has led to confusion among readers. In response, the authors have provided clarification. The sentence in the first paragraph on page 672 that reads "Gainor and colleagues reported the genotyping data from 1,683 patients with þ NSCLC finding 4 out of 75 ALK patients with KRAS mutations (22)" should now read "Gainor and colleagues reported the genotyping data from 1,683 patients with NSCLC finding 4 patients with KRAS mutations and abnormal ALK FISH patterns, however, with negative ALK expression by IHC in the 3 out of 4 samples with available tissue (22)." The authors regret this error.

Reference 1. Massarelli E, Papadimitrakopoulou V. Ceritinib for the treatment of late-stage (metastatic) non– small cell lung cancer. Clin Cancer Res 2015;21:670–4.

Published online May 15, 2015. doi: 10.1158/1078-0432.CCR-15-0482 Ó2015 American Association for Cancer Research.

2412 Clin Cancer Res; 21(10) May 15, 2015 Published OnlineFirst January 6, 2015; DOI: 10.1158/1078-0432.CCR-14-1291

Ceritinib for the Treatment of Late-Stage (Metastatic) Non−Small Cell Lung Cancer

Erminia Massarelli and Vassiliki Papadimitrakopoulou

Clin Cancer Res 2015;21:670-674. Published OnlineFirst January 6, 2015.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-14-1291

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