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. Author manuscript; available in PMC: 2018 Feb 1.
Published in final edited form as: Hematol Oncol Clin North Am. 2017 Feb;31(1):101–111. doi: 10.1016/j.hoc.2016.08.012

Diagnosis and Treatment of ALK Positive NSCLC

Kathryn C Arbour, Gregory J Riely
PMCID: PMC5154547  NIHMSID: NIHMS826424  PMID: 27912826

Abstract

Anaplastic lymphoma kinase (ALK) gene rearrangements occur in a small portion of patients with non-small cell lung cancer (NSCLC). These gene rearrangements lead to constitutive activation of the ALK kinase and subsequent ALK driven tumor formation. Patients with tumors harboring such rearrangements are highly sensitive to ALK inhibitors such as crizotinib, ceritinib, and alectinib. Resistance to these kinase inhibitors occurs through a number of mechanisms, resulting in ongoing clinical challenges. This review gives an overview of the biology of ALK positive lung cancer, methods for diagnosing ALK positive NSCLC, current FDA approved ALK inhibitors, mechanisms of resistance to ALK inhibition, and potential strategies to combat resistance.

Keywords: EML-ALK rearrangement, Non-small-cell lung cancer (NSCLC), anaplastic lymphoma kinase inhibitors (ALK inhibitors), crizotinib, ceritinb, alectinib

Introduction

Fusions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene were first identified as a likely molecular driver in patients with NSCLC in 2007.1 These rearrangements are observed in approximately 5% of NSCLC. At the time of the discovery of EML4-ALK fusions, crizotinib, a MET and ALK inhibitor was already being evaluated and following a confirmatory phase II trial, crizotinib received accelerated approval for patients with ALK positive NSCLC in 2011. Subsequent clinical trials demonstrated its superiority to first and second-line chemotherapy. Additional ALK inhibitors (such as alectinib and ceritinib), have become crucial therapies as patients often develop resistance to first line therapy within one year of treatment. Numerous ALK dependent and ALK independent mechanisms of resistance have been identified. These individual mechanisms of resistance may have important implications for treatment strategies.

Patient Evaluation

Clinical and radiographic characteristics

ALK rearrangements occur in approximately 5% of patients with NSCLC.1 While initially identified as EML4-ALK,2,3 fusions with a variety of other genes have been reported, all leading to dysregulated over-expression of ALK. Patients with ALK positive tumors tend to be younger and more likely to be never or light smokers3,4 with ALK rearrangements occurring in 12% of never-smokers compared to only 2% of former or current smokers.5 ALK rearrangements almost never co-occur with activating mutations in EGFR or KRAS.6 As compared to patients with EGFR-mutant NSCLC, patients with ALK-positive tumors are more likely to be men7 and radiographically, are associated with larger volume, multifocal thoracic lymphadenopathy.8

Methods for identifying patients with ALK positive lung cancers

ALK-positive tumors represent a subset of adenocarcinomas and may be more likely to exhibit certain histopathological features such as solid growth pattern and signet-ring cell cytomorphology or mucinous cribiform pattern,9,10 however these characteristics are neither sensitive nor specific for ALK rearrangements. Specific testing for the molecular patterns of ALK gene fusion or the resultant ALK protein overexpression are required for diagnosis of ALK positive NSCLC.

During initial evaluation of crizotinib, the ALK break-apart test was used to identify ALK positive patients. This test uses fluorescence in situ hybridization (FISH) and capitalizes on disruption of the ALK gene and was the first test to be FDA-approved. While the FISH test can identify many ALK-rearrangements, routine next generation sequencing (NGS) can identify ALK-rearrangements not previously identified and those with complex fusion partners,11,12,13 thus identifying more patients that would be appropriate for ALK-directed therapy. Furthermore, routine NGS can identify co-occurring mutations, which may provide additional clinical value.14

Since ALK is rarely expressed at significant levels in normal lung tissue and ALK gene rearrangements lead to ALK overexpression, tests looking for ALK protein can also be clinically useful. Immunohistochemical detection of ALK protein has been shown to reliably detect ALK-positive NSCLCs and there are currently two FDA approved commercial assays for this use.15,16 The convenience and widespread availability of immunohistochemistry (IHC) in most pathology labs makes IHC an appealing method for detection of ALK in routine care.

Pharmacologic Treatment Options

Crizotinib

Crizotinib is a potent, orally available, ATP-competitive, small-molecule inhibitor of ALK and Met receptor tyrosine kinases that entered initial clinical trials in 2006 prior to the discovery of ALK rearrangements in NSCLC. In the initial phase I trial, the ALK positive cohort had a response rate (RR) of 61%.17 The most frequently occurring treatment-related adverse events were visual disturbance, gastrointestinal events (nausea, diarrhea, vomiting, and constipation), and peripheral edema. Of note, while visual disturbances were common, occurring in 60% of patients, they were not associated with abnormalities on ophthalmologic examination and did not lead to frequent drug discontinuation.18

Subsequently crizotinib was evaluated in randomized clinical trials in two clinical contexts (Table 1). In patients previously treated with platinum doublet chemotherapy, crizotinib was superior to chemotherapy (either pemetrexed or docetaxel), with an improvement in median progression-free survival (PFS) to 7.7 months as compared to 3.0 months for patients receiving chemotherapy.19 Similarly, crizotinib treatment was associated with an improved RR of 65% compared to only 20% in patients who received chemotherapy. Crizotinib also demonstrated superiority to first-line chemotherapy in a randomized phase III study comparing crizotinib to platinum-pemetrexed as initial therapy. Patients receiving crizotinib had an improved median PFS (10.9 months vs 7.0 months).20

Table 1. Summary of landmark crizotinib clinical trials.

Authors Study Arms N ORR Median PFS (months) Conclusion
Camidge et al. 17 Crizotinib Phase I Study 143 60.8% 9.7 Crizotinb was well tolerated and demonstrated efficacy
Shaw et al. 19 Crizotinib 173 65% 7.7 Crizotinib is superior to chemotherapy in the 2nd line setting
Chemotherapy (Docetaxel or Pemetrexed) 174 20% 3.0
Solomon et al.20 Crizotinib 172 74% 10.9 Crizotinib is superior to chemotherapy in the 1st line setting
Cisplatin or Carboplatin + Pemetrexed 171 45% 7.0
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Identification of Crizotinib Resistance

Clinically apparent drug resistance occurs after a median of 8-11 months of crizotinib treatment through a variety of mechanisms. Broadly, these include alterations of ALK (second-site mutations, alternative splicing, or gene amplification) and reactivation of signaling through alternate pathways. This stands in contrast to EGFR mutant NSCLC where resistance to EGFR inhibitors is associated with the EGFR T790M mutation in the majority of patients.21

A variety of mutations in the ALK kinase domain have been identified in patients at the time of progression on crizotinib (Table 3). One of the most frequently identified mutations, L1196M substitution,22 occurs at the conserved gatekeeper site within the kinase domain and is analogous to EGFR T790M mutation. Even mutations at non-active sites can affect interactions between drug and ALK, as was demonstrated in the case of the C1156Y substitution.23 Further adding to the complexity, multiple separate secondary mutations have been identified in individual crizotinib resistant patients demonstrating either tumor heterogeneity or multiple cooperative mutations.24 Given the diversity of point mutations that occur as resistance mechanisms to ALK inhibition, it will become important to perform repeat biopsy at the time of progression potentially yielding information which may help guide further treatment decisions.

Table 3. Summary of the reported sensitivity and resistance of second generation ALK inhibitors to known crizotinib resistance mutations.
ALK Secondary Mutation Reported Sensitive Inhibitors Reported Resistant Inhibitors
1151Tins Alectinib36 Ceritinib53
L1152R Alectinib36,54 Ceritinib54
C1156Y Alectinib36 Ceritinib53
I1171T Ceritinib33 Alectinib35
F1174L/V/C Alectinib36 Ceritinib33
L1196M Ceritinib33
Alectinib36
G1202R Ceritinib33
Alectinib36
S1206Y Ceritinib33
F1245C Ceritinib55
G12569A Ceritinib33 Alectinib56
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In the majority of patients with progression on crizotinib, no ALK resistance mutations are identified24 and therefore other mechanisms of resistance are likely to be present. One such mechanism is the activation of other pathways such as EGFR and KIT. While EGFR and ALK mutations are thought to be mutually exclusive,6 in crizotinib resistant cell lines increased EFGR activation due to increased EGFR ligand levels has been demonstrated.25,26,24 Crizotinib resistance caused by amplification of the KIT gene has also been reported and treatment with imatinib, a small molecule inhibitor of KIT, reversed the resistance phenotype in vitro.24

In resistance, changes in ALK copy number (ALK amplification or loss) have been observed in patients,27,28 consistent with prior data from cell lines.29 And while there have also been reports of loss of ALK positivity upon re-biopsy, it remains unclear if this reflects a true loss of an ALK-gene fusion or false negative testing.27,30

Second generation ALK inhibitors: ceritinib and alectinib

Ceritinib is a more potent and specific ALK inhibitor that has demonstrated ability to overcome crizotinib resistance mutations in vitro.31,32,33 A phase I/II study including patients who had received crizotinib previously, reported a median PFS of 7.0 months and a RR of 56%. Responses were seen in patients who were found to have a variety of crizotinib resistance mutations and in patients where no resistance mutation was identified.32 On the basis of this clinical activity in patients with ALK positive lung cancer who had become resistant to crizotinib, ceritinib received accelerated FDA approval in April of 2014.

Similarly, alectinib is a potent and specific ALK inhibitor that has in vitro activity against a variety of ALK mutations that are observed in patients with resistance to crizotinib. After an initial phase I trial in ALK inhibitor naïve patients, investigators conducted global phase I clinical trials which included patients who had progressed or were intolerant to crizotinib, demonstrating a RR of 55%.34 This response rate was confirmed in another phase II study (RR 52%) with patients experiencing a median PFS of 8.1 months. Based on these data, alectinib received an accelerated approval by the FDA in December of 2015 for patients resistant to or intolerant of crizotinib. Table 2 summarizes the currently FDA approved ALK inhibitors and the associated toxicity profiles which have been reported for each agent.

Table 2. Recommended dosing and side effect profiles of FDA approved ALK inhibitors.
Drug Starting Dose Common Toxicities (any grade) Most common Grade 3 or 4 treatment AEs Reference
Crizotinib 250mg BID Vision Disorder (60%)
Diarrhea (60%)
Nausea (55%)
Vomiting (47%)		 Elevated AST/ALT (16%)
Dyspnea (4%)
Neutropenia (13%)		 Camidge et al.17
Ceritinib 750mg once a day Nausea (82%)
Diarrhea (75%)
Vomiting (65%)
Fatigue (47%)
ALT Elevation (35%)		 ALT increase (21%)
AST increase (11%)
Diarrhea (7%)
Lipase increase (7%)		 Shaw et al.32
Alectinib 600mg BID Constipation (36%)
Fatigue (33%)
Myalgia (24%)
Peripheral Edema (23%)		 CPK increase (8%)
ALT increase (6%)
AST increase (5%)		 Shaw et al.42
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Identification of individual ALK resistance mutations may have important implications for treatment as these resistance mutations can confer variable sensitivity to second generation inhibitors. For example, cell lines expressing the I1171T secondary mutation were found to be sensitive to ceritinib33 but resistant to alectinib,35 whereas the F1174C mutation appears to confer resistance to ceritinib33 but sensitivity to alectinib.36 Notably, the ALK secondary mutation G1202R appears to confer resistance to both ceritinib and alectinib37 (and therefore all currently FDA approved ALK inhibitors), representing a particular challenge. Lorlatinib, a newer ALK inhibitor currently in clinical development, may have efficacy in patients with this mutation. The sensitivity of such mutations to currently FDA approved ALK inhibitors are summarized in Table 3.

Resistance patterns to second generation inhibitors

Only 20% of patients who become resistant to crizotinib will have an ALK resistance mutation identified.38 However, this rate appears to be higher following treatment with newer ALK inhibitors. A recent analysis identified resistance mutations in 54% of patients who progressed following ceritinib therapy and 53% following alectinib therapy. The most frequent resistance mutation identified following treatment with a second generation inhibitor was G1202R. The proportion of patients without identifiable resistance mutations following progression on a second generation inhibitor continues to be substantial, suggesting that additional mechanisms beyond ALK point mutations are driving resistance for some patients.

Special considerations for patients with central nervous system disease

The management of brain metastases and leptomeningeal disease is an important consideration in the treatment of ALK-positive NSCLC, as 26% of patients have brain metastases at the time of presentation.20 A pooled analysis of patients from clinical trials demonstrated modest central nervous system (CNS) responses to crizotinib therapy in patients with untreated brain metastases. However, in patients with CNS disease at the start of therapy, it remained the most common site of progression of disease,39 raising the concern that CNS penetration of the drug is low.40 Ceritinib and alectinib appear to have improved CNS activity. Ceritinib demonstrated a CNS RR of 45% in patients with measurable CNS disease.41 Alectinib has also demonstrated high CNS RRs in both the phase I (52%)34 and phase II trials (75%) including 25% of patients who achieved a complete CNS response.42 Additional reports have also described significant clinical and radiographic improvements in leptomeningeal disease with alectinib treatment.43

Optimal sequence of therapy

With three ALK inhibitors currently approved by the FDA, the appropriate sequence of the use of these agents is unclear. It has been traditionally posited that one could extend overall survival using them in sequence (crizotinib followed by a second generation ALK-inhibitor as opposed to second-generation ALK inhibitor as initial therapy). To explore this question, investigators have compared alectinib to crizotinib as initial therapy, with preliminary presentation of the data suggesting that initial alectinib is associated with a markedly improved median PFS, which was longer than historical experience with crizotinib followed by a second generation inhibitor and a more favorable toxicity profile.44 We look forward to final results of the trial and results from a global trial with the same comparator arms. If these data are supported by the ongoing global study, they may lead to a paradigm shift in the treatment of ALK-positive NSCLC. Multiple promising ALK inhibitors are also currently in clinical development and are summarized in Table 4.

Table 4. Selected ALK tyrosine-kinase inhibitors currently in clinical development.
Clinical Trial Drug Status of Relevant Trials
NCT02737501 Brigatinib

  • Phase I/II completed

  • Phase III study of brigatinib vs crizotinib in TKI-naïvepatients currently ongoing
NCT01970865 Lorlatinib

  • Phase I completed

  • Phase II ongoing
NCT01625234 X-396

  • Phase I completed

  • Phase II ongoing
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Potential Role of Adjuvant Treatment with ALK-TKIs

Historically, effective agents for metastatic cancer have been tested in the early stage setting to assess whether these can improve the cure rate compared to today's multimodality therapy. All clinical trials with ALK inhibitors have treated only patients with metastatic disease. A large phase III prospective clinical trial, Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST Treatment Trial), is currently enrolling patients and looking to address this question. Patients with ALK rearrangements will be randomly assigned to receive the drug crizotinib or placebo for 2 years. The primary outcome measure of the ALCHEMIST treatment trial is overall survival and disease free survival, with toxicity as secondary outcomes and is expected to be completed in 2022.45

Non-TKI therapy: role of chemotherapy and immunotherapy

In addition to molecularly targeted therapy, there is still an important role for cytotoxic chemotherapy in the treatment of ALK-positive NSCLC. Multiple series have identified a longer PFS with pemetrexed-based treatment regimens (monotherapy or combination therapy) in ALK-positive crizotinib-naive tumors compared with ALK negative tumors.46 In the pivotal phase II study comparing crizotinib to single agent chemotherapy, pemetrexed monotherapy demonstrated a 29% ORR compared to 7% with docetaxel monotherapy.19 The place of pemetrexed in the sequence of ALK positive treatment still needs to be further elucidated, as small retrospective studies comparing the outcomes of patients who received pemetrexed before or after crizotinib have suggested it may be less effective following crizotinib.47

While immune checkpoint blockade has been a major advance in the treatment of NCSLC, its role for patients with ALK-positive tumors is less clear. Preclinical data suggested that over expression of ALK fusion protein increased PDL-1 expression raising the possibility that PD-L1 antibodies may be effective in the treatment of ALK positive NSCLC.48,49 Retrospective data, however, indicates that patients with ALK rearrangements have lower response rates to PD-1/PD-L1 inhibitors compared to patients with ALK negative tumors.50

Role of Non-pharmacologic Therapy in the management of ALK positive NSCLC

Data regarding the appropriate role of surgery and or radiation for patients with ALK positive disease is limited, in part because routine testing for ALK rearrangements is not often performed in early stage disease. For patients with metastatic disease, radiation therapy can play an important role particularly when progression occurs at a limited number of sites (oligoprogressive) as opposed to widespread disease. A retrospective analysis reviewed outcomes of patients who developed oligoprogressive disease while on therapy with an ALK inhibitor (including patients with isolated CNS progression) and were treated with local ablative therapy and subsequently resumed the same ALK TKI. The median PFS observed after local therapy was 6.2 months, essentially extending the time on an individual therapy from 9.0 months to 15.2 months.51 These results are similar to prior published experience of local therapy for EGFR-mutant NSCLC.52 For patients with oligoprogressive disease, this strategy could meaningfully extend courses of treatment thus providing clinical benefit. While this data is promising, further prospective clinical studies are warranted to validate this approach.

Summary and Future Directions

ALK positive NSCLC is a distinct subset of lung cancer with a different natural history and response to therapies. Routine testing for ALK rearrangements should be performed in all patients with newly diagnosed NSCLC. Efforts to identify mechanisms of resistance to ALK inhibitors have demonstrated a multitude of point mutations (demonstrating variable sensitivity to second generation inhibitors) as well as alternative signaling pathways that likely contribute to cancer growth. As the duration of response to each ALK-directed TKI is limited, future clinical trials will need to be focused on the development of not just more potent ALK inhibitors but also formally assess the effectiveness of other strategies such as immunotherapy.

Key Points.

  • - ALK rearrangements occur in approximately 5% of patients diagnosed with NSCLC, are more frequently found in patients with no significant smoking history, and can be identified with routine testing (fluorescence in situ hybridization, immunohistochemistry, or next generation sequencing).

  • - Crizotinib, the first-available ALK-inhibitor, is superior to chemotherapy as both initial treatment and for patients who have progressed following platinum-doublet therapy.

  • - Resistance to crizotinib develops after a median of 8-11 months with numerous resistance mechanisms identified.

  • - Ceritinib and alectinib are second generation ALK inhibitors that have been approved for patients who have become resistant to or are intolerant of crizotinib.

  • - Additional ALK inhibitors are currently in clinical development.

Footnotes

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