Decision Making Between Second- and Third-Generation ALK Inhibitors for Lung Cancer

Detecting ALK gene rearrangements in patients newly diagnosed with advanced, metastatic, or recurrent non-small cell lung cancer (NSCLC) is crucial, as the presence of this oncogenic driver significantly impacts treatment strategies. 

Tumors harboring ALK fusion oncogenes or their variants often present certain clinical characteristics, such as a history of never or light smoking and a younger age profile. However, these typical features are not mandatory for diagnosing ALK-rearranged lung cancer. Testing for this genetic alteration in NSCLC is essential, as tumors classified as “ALK-positive” (those with rearranged ALK genes or fusion proteins) respond particularly well to targeted ALK inhibitor therapies. 

Molecular testing is recommended for all patients with advanced or metastatic nonsquamous NSCLC, regardless of smoking history, and should include an assessment for ALK gene rearrangements. This testing, which can be conducted on tumor tissue or plasma samples, is now considered the standard of care (as discussed here). 

In this scenario, Dr. Gregory Riely, a thoracic oncologist at Memorial Sloan Kettering Cancer Center, says that the next critical decision after the diagnosis of this mutation is to define which ALK inhibitor to use.

“When we diagnose a patient with ALK-positive lung cancer and the patient has metastatic disease, one of the key decisions is which is the first ALK inhibitor that the patient should receive. We have a number of options,” he tells SurvivorNet Connect.

Optimizing Treatment Strategies for ALK-Positive NSCLC

An ALK inhibitor is preferred as the initial therapy for patients whose tumor contains this genetic abnormality. Results of a phase III trial comparing ALK inhibition using the first-generation ALK TKI, crizotinib, with chemotherapy in treatment-naïve patients demonstrated a prolongation in progression-free survival (PFS) and improved response rate and quality of life. Subsequent trials have shown progression-free survival benefits of second-generation ALK inhibitors, including alectinib, and brigatinib over crizotinib. 

“There are multiple approved options in the first-line setting. I think, for the most part, people are considering whether it’s a second-generation drug like alectinib or brigatinib or first-line treatment with lorlatinib,” Dr. Riely says. 

The newer generation of ALK tyrosine kinase inhibitors (TKIs) present distinct toxicity profiles. In the pivotal CROWN trial, lorlatinib demonstrated grade 3 or higher adverse effects in 72% of patients, while brigatinib showed 73% in the ALTA-1L trial, and alectinib reported 50% in the ALEX study. Compared to the other TKIs, lorlatinib was associated with 34% of patients experiencing peripheral neuropathy (all grades) and 21% with cognitive effects (all grades), such as memory impairment, attention disturbance, confusion, amnesia, cognitive disorder, and delirium. 

Brigatinib, while safe and effective, exhibited slightly higher rates of grade 3 or 4 pneumonitis (3%) compared to other ALK inhibitors. Ceritinib, another ALK inhibitor, has its own specific side-effect pattern, with all grades of diarrhea (85%), nausea (69%), vomiting (66%), elevated ALT (60%), and increased AST (53%). 

Brigatinib, alectinib, and lorlatinib have all demonstrated high brain penetration and excellent intracranial response rates. The development of these newer ALK inhibitors has dramatically altered the prognosis of NSCLC with brain metastases, significantly improving patients’ quality of life. 

The choice among these drugs can be challenging, and the literature is still uncertain. In this context, Dr. Riely shares:  “I think both (second or third ALK generation) have their pluses and minuses and many physicians still choose alectinib or brigatinib while others have begun to use lorlatinib as first line therapy.”

The use of second- and third-generation ALK inhibitors as a first-line treatment for patients with limited brain metastases is now a well-established approach, largely because of their strong capacity to penetrate the blood-brain barrier. This strategy is reinforced by the low central nervous system (CNS) progression rates observed with second-generation ALK TKIs, typically under 10% per year. Furthermore, evidence from real-world clinical practice suggests that this benefit may also extend to those with symptomatic brain lesions.

Special Considerations Using ALK-inhibitors 

Drug resistance considerations

Notably, when patients develop resistance to targeted therapies, it presents an opportunity to investigate the underlying mechanisms of resistance and tailor subsequent treatment strategies accordingly. Dr. Riely affirms that in cases of resistance to second-generation ALK inhibitors such as alectinib or brigatinib in ALK-positive lung cancer, sequencing the tumor can often reveal specific mutations that help guide the choice of the next therapeutic option. One of the most frequent mutations identified in this context is the G1202R mutation, which can influence the selection of the next appropriate ALK-targeted therapy.

The G1202R mutation is the most frequent resistance mutation following the administration of second-generation ALK inhibitors, accounting for 40–65% of all acquired resistance mutations. Lorlatinib is considered to be one of ALK inhibitors that may hold promise for overcoming the high frequency of ALK inhibitor resistance mutations, particularly G1202R.

“If we begin with a second generation drug like alectinib or brigatinib, at the time of resistance, there’s an opportunity to use lorlatinib as a drug that can overcome resistance. Additionally, beyond lorlatinib in that setting, chemotherapy can play a role. Chemotherapy has a fairly good response rate and an opportunity to prolong progression-free survival when compared to other drugs,” Dr. Riely explains.

Brain metastases

For both asymptomatic and symptomatic patients, second- or third-generation ALK tyrosine kinase inhibitors (TKIs) are recommended due to their proven ability to penetrate the brain and their effectiveness in controlling central nervous system (CNS) metastases. The majority of patients with brain metastases, whether they are TKI-naïve or previously treated with crizotinib, tend to respond well to these therapies. As a result, the need for surgery or radiation can often be delayed, which may help reduce the morbidity associated with these more invasive local treatments.

Management of toxicities 

ALK inhibitors are generally well tolerated, but they can be associated with significant toxicities that may necessitate dose adjustments or, in some cases, discontinuation of treatment.

Pulmonary toxicity can occur with any of the ALK inhibitors, though it appears to be more frequent with brigatinib. In clinical studies, 4% of patients receiving brigatinib experienced pulmonary toxicity, with grade 3–4 toxicity observed in 3% of patients. Brigatinib is also associated with a distinct early-onset pulmonary toxicity. To mitigate this risk, brigatinib treatment is often initiated at a lower dose of 90 mg for the first seven days, followed by an increase to 180 mg daily if tolerated. If pulmonary toxicity is suspected, brigatinib should be paused to allow for timely evaluation and appropriate management.

Grade 1–2 myalgias are relatively common in patients receiving alectinib, affecting around 16% of patients. While myalgias often resolve without the need to interrupt treatment, in some cases, a dose reduction may be necessary. 

Lorlatinib, on the other hand, is associated with elevated cholesterol and triglyceride levels, with hypercholesterolemia occurring in 70% of patients and hypertriglyceridemia in 64%. These lipid abnormalities should be managed using HMG-CoA reductase inhibitors, such as rosuvastatin, for cholesterol control, and fibrates for managing triglycerides.

The enhanced CNS penetration of lorlatinib is linked to a higher incidence of CNS-related side effects. It is crucial to have proactive discussions with patients and their families about the potential cognitive and mood-related side effects. Reassuring patients that these side effects often resolve or improve with dose reduction or temporary treatment interruption can help manage expectations and improve treatment adherence.