Background
The most common type of lung cancer is non-small cell lung cancer (NSCLC). About 5% of NSCLC will be driven by a gene mutation known as anaplastic lymphoma kinase (ALK). Targeted treatments for those with advanced (not curable) ALK-mutated NSCLC cancer have been developed and found to be more effective than chemotherapy. The first ALK inhibitor to be developed was crizotinib. Newer ALK-targeted drugs have also been developed and include ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib. In this review we looked at treatments that target ALK-mutated NSCLC to find out how well they work.
Objectives
The primary objective of this review was to find out whether people with ALK-mutated NSCLC given treatments targeted towards ALK live longer without recurrence and have fewer side effects than those treated with chemotherapy. We also planned to evaluate whether newer ALK-targeted drugs achieve this better than crizotinib.
Study characteristics
We searched the main medical databases and records of conferences up to 7 January 2021. We found 11 studies (2874 participants): six studies compared an ALK-targeted drug to chemotherapy, and five studies compared a newer ALK-targeted drug to crizotinib. The studies were conducted in people with advanced ALK-mutated NSCLC using these drugs as their first or later treatment. A total of five different ALK inhibitors were used across studies: alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib.
Results
People treated with ALK-targeted drugs lived longer without their cancer growing than those on chemotherapy. These improvements were also seen in people with cancer that had spread to the brain. People receiving ALK-targeted drugs lived longer overall, even when some had received chemotherapy first. ALK-targeted drugs cause a similar number of side effects as chemotherapy. ALK-targeted drugs caused more tumours to reduce in size and resulted in a longer time until worsening of symptoms when compared to chemotherapy.
People treated with newer ALK-targeted drugs lived longer without their cancer growing than those receiving crizotinib, including in people with cancer involving the brain. People treated with newer ALK-targeted drugs as first treatment were likely to live longer overall with a similar number of overall side effects. Newer ALK-targeted drugs caused more tumours to reduce in size when compared to crizotinib.
The evidence for most reported measures was of moderate or high certainty.
Conclusions
The best first treatment for people with incurable ALK-mutated lung cancer is a newer ALK inhibitor such as alectinib, brigatinib, ceritinib, or lorlatinib. More studies are needed to determine which of these options is best and what treatment should be used when the cancer grows after these medicines have been given.
Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal.
Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines.
To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC.
We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021.
We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC.
Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib’ with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement.
Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement.
ALK inhibitor versus chemotherapy
Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment.
ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence).
ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period.
ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy.
Next-generation ALK inhibitor versus crizotinib
Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases.
Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib.
Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib.
Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting.