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 » Results
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 203-208
 

New insights into anaplastic lymphoma kinase-positive nonsmall cell lung cancer


Department of Medical Oncology, Army Hospital Research and Referral, New Delhi, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. A P Dubey
Department of Medical Oncology, Army Hospital Research and Referral, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_72_17

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 » Abstract 

BACKGROUND: A novel fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has been identified in a subset of non-small-cell lung cancers (NSCLCs). Patients with the ALK-EML4 fusion gene demonstrate unique clinicopathological and physiological characteristics. Here we present an analysis of clinicopathological profile of patients of metastatic adenocarcinoma harboring the ALK-EML4 fusion gene and their response to targeted therapy in the form of crizotinib. METHODS: A retrospective analysis of advanced ALK positive NSCLC, who presented at this tertiary care hospital of armed forces from September 2014 to December 2016 was conducted. The primary goal was to evaluate demographic and clinicopathological profile of ALK positive advanced NSCLC. Detection of ALK fusion was done by IHC on formalin fixed paraffin embedded cell blocks. Out of 20 ALK positive patients, ten patients received upfront cytotoxic chemotherapy, and rest received crizotinib. Patients progressing on cytotoxic chemotherapy received crizotinib as subsequent therapy. RESULTS: Out of 270 patients of NSCLC, fifteen(7.4%) tested positive for ALK-EML4 fusion. Rate of positivity was higher in females(13.7%) than in males (5%). The correlation of the ALK-EML4 fusion gene and clinicopathological characteristics of NSCLC patients demonstrated a significant difference in smoking status, histological types, stage, & metastatic pattern. Median PFS with first line cytotoxic chemotherapy was 5.9 months. Median PFS with upfront crizotinib was not reached, but was significantly superior than cytotoxic chemotherapy. CONCLUSION: Our analysis indicated that ALK-EML4 positive NSCLC comprised a unique subgroup of adenocarcinomas with distinct clinicopathological characteristics. Incidence of ALK positivity was found to be higher in females and never smokers. These patients have distinct pathological and radiological characteristics. Crizotinib, whether used upfront or as subsequent therapy was found to be superior in PFS (not yet reached at the time of writing this article), and maintaining quality of life as compared to cytotoxic chemotherapy.


Keywords: Anaplastic lymphoma kinase-echinoderm microtubule-associated protein-like 4, fluorescence in situ hybridization, immunohistochemistry, nonsmall cell lung cancer


How to cite this article:
Dubey A P, Pathi N, Viswanath S, Rathore A, Pathak A, Sud R. New insights into anaplastic lymphoma kinase-positive nonsmall cell lung cancer. Indian J Cancer 2017;54:203-8

How to cite this URL:
Dubey A P, Pathi N, Viswanath S, Rathore A, Pathak A, Sud R. New insights into anaplastic lymphoma kinase-positive nonsmall cell lung cancer. Indian J Cancer [serial online] 2017 [cited 2019 Oct 18];54:203-8. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/203/219600



 » Introduction Top


For a long time, systemic cytotoxic chemotherapy remained the gold standard in the treatment of patients with advanced nonsmall cell lung cancer (NSCLC). With the discovery of the anaplastic lymphoma kinase (ALK) gene in NSCLC and the development of crizotinib against this subset of NSCLC, an era of targeted therapies took the lead way.[1],[2] The echinoderm microtubule-associated protein-like 4 (EML4)-ALK is a fusion type protein tyrosine kinase, found in 4%–5% of NSCLC.[3] The ALK gene arrangements are largely mutually exclusive with epidermal growth factor receptor (EGFR) or Kirsten-ras mutations.[4] This ALK gene rearrangements can be detected in tumor specimens using immunohistochemistry (IHC), reverse transcription polymerase chain reaction of the complementary DNA, and fluorescence in situ hybridization (FISH).[5] FISH is the gold standard for diagnosing ALK-positive NSCLC. The presence of an ALK fusion oncogene defines a molecular subset of NSCLC with distinct clinical and pathological features. This subset of relatively younger, nonsmokers, or light smoker patients demonstrate mucinous, cribriform, or signet ring cell subtype of adenocarcinoma on histology.[6] Whenever possible, therapy for advanced NSCLC should be individualized based on the molecular and histological features of the tumor. This study was aimed to analyze data and provide a better understanding of patients with ALK-positive advanced NSCLC.

Emerging therapies for anaplastic lymphoma kinase-positive advanced nonsmall cell lung cancer

ALK is a straightforward, biology-based biomarker, predicting a high response rate with targeted agents such as crizotinib, even in heavily pretreated patients and is relatively nontoxic. Crizotinib is an oral, multitargeted, small-molecule tyrosine kinase inhibitor of ALK, hepatocyte growth factor receptor (c-Met), and recepteur d'origine nantais. It shows a concentration dependent inhibition of ALK and c-Met phosphorylation, thereby inducing apoptosis by G1-S phase cell cycle arrest.[7],[8] Randomized Phase III trial PROFILE 1007 demonstrated that when compared with the second-line chemotherapy, crizotinib prolonged progression-free survival (PFS), increased response rates, and improved the quality of life in patients with advanced, previously treated ALK-positive NSCLC.[9] Another randomized Phase III trial PROFILE 1014 demonstrated the superiority of crizotinib over platinum-based chemotherapy as the first-line treatment in the form of significant improvement in objective response rate (ORR), PFS, and quality of life.[10] A dose of 250 mg twice daily is continued until no longer clinically beneficial, with or without food. Significant side effects include nausea (53%), diarrhea (43%), vomiting (40%), visual disturbances (62%), edema (28%), fatigue (20%), and lymphopenia (11%).[11],[12] Although it is clear that crizotinib significantly improves response rates and survival, invariably the disease progresses at some point. Mutations at L1196M and L1152R lead to crizotinib resistance through steric interference. Acquired resistance usually occurs within 1 year of initiating crizotinib. Interesting recent data have also shown benefit for patients with advanced ALK-positive lung cancer to continue ALK inhibition with crizotinib beyond progression in terms of maintaining Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) and may even prolong survival.[13]

Within the first year or two after crizotinib treatment is initiated, resistance typically arises. As mentioned above, mechanisms commonly include secondary mutations within the ALK tyrosine kinase domain and activation of alternative signaling pathways. More potent and structurally different inhibitors are, therefore, developed. A number of next-generation ALK inhibitors with the ability to bypass resistance mutations have recently been reported. Ceritinib is a potent ALK inhibitor compared to crizotinib. This compound is also known to work in patients with central nervous system metastasis as it crosses the blood–brain barrier.[14] Ceritinib (LDK378) is a second-generation ALK inhibitor that was granted an accelerated approval by the Food and Drug Administration (FDA) in April 2014 for the treatment of patients with ALK-positive metastatic NSCLC following treatment with crizotinib. Ceritinib demonstrated efficacy in Phase I trials with a remarkable ORR of 58% (95% confidence interval [CI] = 48–67) and the median PFS was 7.0 months (95% CI = 5.6–9.5).[15] Ceritinib was found to be efficacious in both ALK-positive patients who have previously received crizotinib and crizotinib-naive patients. The side effect profile was less favorable compared to crizotinib but was still manageable with predominantly Grade 1 or 2 gastrointestinal-related adverse effects.

Alectinib is another second-generation ALK inhibitor that has activity in crizotinib-resistant disease with reported activity in brain metastases.[16] It is FDA-approved for the treatment of patients with ALK-positive NSCLC who have progressed on or are intolerant of crizotinib. Two Phase II studies have shown ORR of 50% in patients, disease control rate (objective response and stable disease) of 79%, and median PFS of 11 months, who progressed on crizotinib.

Objective

To evaluate the epidemiological, clinicopathological profile, disease characteristics, and response to crizotinib in advanced EML4-ALK-positive NSCLC patients in a tertiary care hospital for armed forces.


 » Materials and Methods Top


A retrospective analysis of advanced lung cancer patients, who presented to our tertiary care hospital of armed forces from September 2014 to September 2016, was conducted. Those who fulfilled all of the following criteria were taken up for analysis: Advanced NSCLC, positive for ALK rearrangement on IHC or FISH, and those planned for palliative treatment. Patients had a signed written informed consent prior to recording their information as a part of lung cancer audit carried in the department of medical oncology. Patients underwent a complete history, physical examination, and routine blood testing (complete hemogram, renal, and liver function tests). Demographic data including smoking status and tobacco use was noted. Tumor staging was performed by contrast-enhanced computed tomography (CT) of the chest and upper abdomen or whole body positron emission tomography-CT and magnetic resonance imaging brain. Detection of ALK fusion was done by IHC on formalin-fixed, paraffin-embedded cell blocks, performed with the monoclonal antibody D5F3 (Ventana Medical Systems, Tucson, AZ, USA). The presence of strong granular cytoplasmic staining in any percentage of tumor cells is interpreted a positive. Therapy was initiated considering age, comorbidities, ECOG-PS, disease burden requiring emergent initiation of therapy, availability of ALK reports, and feasibility for crizotinib. Patients were started on either upfront chemotherapy or crizotinib. Patients underwent routine blood investigations, including complete hemogram and biochemistry prior to each cycle of chemotherapy and every monthly if on crizotinib. In addition, electrocardiograms were monitored on crizotinib at frequent intervals. Dose reduction was considered as per the standard criteria in setting of toxicity.

Assessment of radiological response was done every 3 months and at symptomatic progression. Chemotherapy or crizotinib was discontinued at disease progression, intolerable side effects, or patient decision. RECIST 1.1 criteria were used for tumor response evaluation. The adverse events during this period were evaluated in accordance with the Common Terminology Criteria for Adverse Events version 4.02 (CTCAE v 4.02). Standard treatment protocols were followed on evidence of disease progression. Patients were divided into those who received crizotinib upfront, received crizotinib as a subsequent therapy, or were never exposed to crizotinib. Potential reasons for not administering crizotinib upfront or for receiving at a later time were also retrieved.

Statistical analysis

SPSS version 20.0 (Armonk, NY: IBM Corp) was used for analysis. Descriptive statistics was performed. Median value with interquartile range was provided for continuous variables. PFS was calculated in months from the date of start of crizotinib till the date of progression on crizotinib. The overall survival (OS) was calculated in months from the date of start of crizotinib till the date of death. Kaplan–Meier method was used for survival analysis. Univariate analysis of PFS and OS was done using log-rank test. Logistic regression with stepwise forward conditioning method was used for multivariate analysis.


 » Results Top


Of the 270 NSCLC patients evaluated, 20 patients (7.4%) tested positive for ALK rearrangements. The median age of ALK-positive NSCLC cases was 43.9 years (range: 32–63 years), with an equal number of males and females (10 each) testing positive for ALK rearrangement as denoted in [Table 1]. Smoking history was noted in 20% of all ALK-positive cases. There were no female smokers in the study. Fifteen (75%) of ALK-positive patients had an ECOG-PS 0–1. The most common presentation was a cough observed in 75% (15) patients followed by shortness of breath noted in 55% (11) cases. Hemoptysis and neurological deficits were presenting complaints in 15% of cases each. One patient was a diagnosed case of chronic kidney disease Stage IV on maintenance hemodialysis. Four cases were known hypertensives on antihypertensives.
Table 1: Demographic data and baseline tumor characteristics

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Histologically, adenocarcinoma was the dominant subtype found in 70% (14) of all cases and rest about 30% (6) of them were poorly differentiated carcinoma. Nine (64%%) of the adenocarcinoma histology cases were having mucinous or signet ring pattern on histology, rest being poorly differentiated adenocarcinoma. At baseline, all the patients were having Stage IV disease. Thirteen (65%) of the patients had more than two sites of metastases, with a median number of metastasis equal to three. Most common site of metastases was pleural effusion/pleural deposits (90%, n = 18) followed by brain and bony metastasis (55%, n = 8). On radio imaging, all the brain metastases were present in anterior cranial fossa. Primary tumor location was central in 65% (n = 13), whereas peripheral and multiple lesions in 11% (n = 3) and 20% (n = 4), respectively. In patients with multiple lung lesions, the central lesion was present in all of them, in addition to other lesions.

Of the twenty patients, 18 patients received crizotinib during the study period. Crizotinib was used as first line therapy in ten(50%) patients, whereas cytotoxic chemotherapy was used as first line therapy in the remainig half of patients as shown in [Table 2]. Cytotoxic chemotherapy used in all of remaining ten patients was platinum doublet, with either pemetrexed or paclitaxel as per the recommended dosage guidelines. Eight out of ten patients receiving cytotoxic chemotherapy received crizotinib as subsequent therapy, whereas rest two patients did not. Sixteen of 18 patients receiving crizotinib responded to the therapy in the form of partial response or stable disease, and thus disease control rate of 89% was achieved. Median PFS and OS of the entire group of patients was not reached, though median PFS at the time of writing of this article was 9.2 months for upfront crizotinib and 8.0 months for crizotinib as subsequent therapy. The maximum PFS reached was 26 months. Younger patients, and those with good PS (<2), were associated with significantly superior PFS as compared to those who were elderly, frail, and with poor PS. The median PFS of patients on the first-line cytotoxic chemotherapy was inferior to the subset of patients receiving upfront crizotinib (5.9 months vs. 9.2 months) as shown in [Table 3]. In addition, the median PFS till date for the entire group of patients receiving crizotinib either as upfront or subsequent therapy was significantly higher than those receiving the first- or second-line cytotoxic chemotherapy. Patients with brain metastasis were found to have significantly superior PFS than those with no brain metastasis (10.5 months vs. 6.5 months).
Table 2: Treatment data

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Table 3: Response rate, survival, and pattern of progression on crizotinib

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Crizotinib was tolerated well by the entire group of patients. Grade 3 or 4 toxicities were seen in two patients in the form of gastrointestinal side effects in one and symptomatic bradycardia in the other. GI side effects were managed with symptomatic and supportive care, and patient continued the therapy, whereas interruption of therapy followed by reintroduction resulting in relief of cardiovascular effects. Among Grade 1 or 2 toxicities, anemia was seen in 30% of patients, followed by transaminitis in 25% of patients receiving crizotinib. One patient with chronic kidney disease on maintenance hemodialysis was started with crizotinib 250 once daily which initially resulting in spiking of serum creatinine levels, followed by reverting to baseline in next 6 weeks.


 » Discussion Top


Lung cancer is the most prevalent cancer and leading cause of cancer-related deaths worldwide.[17] Despite improvements in therapeutic methodology, including surgery, chemotherapy, and radiotherapy, the average prognosis of lung carcinoma still remains unsatisfactory and the 5-year survival rate is merely 15%.[18] Among those lung cancer patients, NSCLC accounted for approximately 80%–85% of lung cancer cases.[19] Increased attention has been garnered in the development and application of drugs that target-specific molecules which expressed on NSCLC cells which include signaling transduction and angiogenesis inhibitors, such as the EGFR- and ALK-targeted drugs.[1],[20],[21]

We analyzed 270 (197 males and 73 females) patients with advanced NSCLC for the presence of EGFR mutations and ALK rearrangement during the April 2014 to December 2016. ALK testing was done with IHC on formalin-fixed, paraffin-embedded blocks. Twenty (7.4%) patients tested positive for ALK-EML4 translocation, which was consistent with the previous published reports.[22],[23] Although our study had an equal number of males and females testing positive for ALK translocation, the incidence was higher in females (13.7%), whereas incidence in males was found to be 5%, which was statistically significant (10/141 vs. 10/73, P = 0.03). This finding was incontrast with prior studies which found male preponderance in patients with ALK-positive NSCLC, those being light or never smokers. All females were never smokers in our study, whereas smoking history was present in around 42% of males. The incidence of ALK positivity was independent of smoking status in males. The median age of ALK-positive patients is less than that of non-ALK translocated patients that was consistent with our study finding it to be 43.9 years but it was lower than other studies where they found median age to be 52 years.[24] The most common symptoms were cough (75%) and dyspnea (55%) which were similar to non-ALK-positive patients of carcinoma lung.[25]

Adenocarcinoma was the predominant histologic type seen in 14 (70%) patients. Poorly differentiated carcinoma was seen in the remaining patients. Mucinous and signet ring pattern together combined was present in 9 (64%) of 11 patients of adenocarcinoma, with rest 5 (45%) being adenocarcinoma of poorly differentiated type. The majorities of ALK-positive NSCLCs are adenocarcinomas with only a few reports of squamous cell pathology. The solid growth pattern with signet ring cell component, a feature not often seen with EGFR mutant or wild-type NSCLC, and mucinous cribriform pattern with extracellular mucinous materials are the major histological findings published in literature.[26],[27],[28] The anatomical location of ALK-positive lung cancers appears to be more central and subsequently bronchoscopic cytology positivity is more common in the ALK-positive group of patients as compared to non-ALK-positive group of adenocarcinoma patients. Thirteen (65%) of patients had central location on radio imaging, rest 3 (15%), and 4 (20%) had peripheral and multiple lesions, respectively. This finding was consistent with the study conducted by Kang et al., who observed central location of ALK-positive tumors in comparison to EGFR mutant or wild type NSCLC. Yang et al. found higher incidence of extrathoracic metastasis in ALK-positive cases, which was consistent in our study group with extrathoracic disease present in 18 (90%) of 20 patients.[29] Thirteen (65%) patients had disseminated disease with >2 sites of metastasis. Most ALK-positive patients have predilection for cerebral and skeletal metastases in addition to pleural and pericardial effusions.[23],[26] This finding was not significantly different in our patients, with pleural effusion being most common site of metastasis, followed by brain and bony metastasis. Pleural involvement in the form of moderate to massive pleural effusion or pleural deposits was the most common site of metastasis found in 14 (93%) patients. Other common sites of metastasis were bone and brain in eight (53%) patients each. In contrast, liver metastasis was present only in one patient of our study group.

Crizotinib is an oral, multitargeted, small-molecule tyrosine kinase inhibitor of ALK, which has shown superiority in PFS, over cytotoxic chemotherapy as the first-line as well as subsequent therapy in ALK translocated, advanced NSCLC. Randomized Phase III trials PROFILE 1014 and PROFILE 1007 have proven its significant ORR, PFS, and quality of life over platinum-based cytotoxic chemotherapy. Ten (50%) of our patients received upfront cytotoxic chemotherapy, and rest 10 (50%) received upfront crizotinib. Eight of ten patients who progressed on cytotoxic chemotherapy received crizotinib as subsequent therapy, remaining two patients lost to follow-up. Median PFS of patients who were started on upfront crizotinib was not reached at the time of writing this article but was significantly higher than those on upfront cytotoxic therapy. A total of 18 patients received crizotinib, out of which 2 progressed during the therapy (1 in first 3 months and other after a PFS of 26 months) and rest 16 (89%) patients responded in the form of partial response/stable disease. ORR to crizotinib in our study was 89%, which was comparatively higher than PROFILE 1007 and PROFILE 1014 (89% vs. 74%). Median PFS or OS neither of subgroup which was started with upfront crizotinib nor of subgroup which received crizotinib as subsequent therapy was not reached till the time of article. Only two patients (1 in first 3 months and other after a PFS of 26 months) progressed on crizotinib therapy. Median PFS till date (at the time of writing this article) was 9.3 months for patients with upfront crizotinib, and 8 months for crizotinib as subsequent therapy.

Crizotinib was shown to be tolerable with a good safety profile in published literature. The main adverse effects included visual disturbances, gastrointestinal side effects (nausea, 56%; diarrhea, 50%; vomiting, 39%; and liver function abnormalities, 12%), and pneumonitis reduced levels of testosterone and potential hypogonadism have been observed and may also be related to the potential central effects of crizotinib on the hypothalamus/pituitary axis.[30] Crizotinib was tolerated well by the entire group of patients. Grade 3 or 4 toxicities were seen in only 2 (11%) patients. None of our patients had visual side effects, whereas transaminitis and diarrhea were observed in 25% and 20% of the patients, respectively.

Limitations of our study

Instead of a smaller sample size of 270 patients and a further smaller cohort of about 20 ALK-positive cases, a bigger sample analysis might have brought out many more significant observations in addition to those observed. In addition, the ratio of males to females in our study may not be truly representative of real world scenario, due to hospital administration logistics at our center. Most of the patients on crizotinib are still progression free and require long-term follow-up for detailed PFS and OS data.


 » Conclusion Top


Our analysis indicated that ALK-EML4-positive NSCLC comprised a unique subgroup of adenocarcinomas with distinct clinicopathological characteristics. Compared to non-ALK-positive NSCLC, this group is significantly enriched for nonsmoking patients, mucinous, and signet ring histopathology. ALK-positive tumors tend to have central lesion, disseminated disease at presentation and typical metastatic pattern with pleura, brain, and bone being the most common sites of involvement. The detection of ALK fusion genes in NSCLC has led to significant progress in the clinical care of patients with advanced lung cancer. While ALK-positive NSCLC is associated with a poorer clinical outcome in the absence of treatment with a targeted agent, the emergence of several different inhibitors and the development of therapeutic strategies to abrogate resistance promise to improve clinical outcome in these patients. We observed crizotinib as an effective therapy in ALK positive advanced NSCLC, both as the first-line and subsequent therapy, resulting in superior response rates, PFS, and quality of life, compared to cytotoxic therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3]

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