ALK-Positive Metastatic Non–Small Cell Lung Cancer:
Optimizing Therapy in the First-Line Setting

The advent of ALK TKIs has led to improved outcomes compared to chemotherapy for patients with ALK-positive mNSCLC,3,4 but CNS metastasis remains a significant clinical challenge.5-9 Using more effective next-generation ALK TKIs as first-line treatments may help delay the development and progression of brain metastases in patients with ALK-positive mNSCLC.10,11

Among the genetic alterations identified in patients with non–small cell lung cancer (NSCLC), 3% to 7% comprise rearrangements involving the anaplastic lymphoma kinase (ALK) gene. The most frequent ALK fusion partner is the echinoderm microtubule-associated protein-like 4 (EML4) gene, resulting in EML4-ALK fusion kinases that are constitutively activated and act as potent oncogenic drivers.1,2 The advent of ALK tyrosine kinase inhibitors (TKIs) targeting these kinases has led to improved response rates and longer progression-free survival compared to chemotherapy for patients with ALK-positive metastatic NSCLC (mNSCLC).3,4 Crizotinib was the first ALK TKI approved for the treatment of ALK-positive mNSCLC, but resistance to this inhibitor often develops.2 Several next-generation ALK inhibitors—alectinib, brigatinib, ceritinib, and lorlatinib—have demonstrated clinical efficacy and are now approved for treatment of patients with ALK-positive mNSCLC (Table 1).

Table 1. Pivotal First-Line Trials of Next-Generation ALK Inhibitors for ALK-Positive Advanced or Metastatic NSCLC

aPatients were chemotherapy naive or had received one prior chemotherapy regimen.
bMedian follow-up for PFS indicated for ALK TKI treatment arms. Outcomes listed are for selected time points; not all time points for each trial are included.
cIC ORR not reported, but cumulative incidence analysis indicated alectinib reduced the risk of progression compared with crizotinib in both CNS and non-CNS lesions.
dIn patients with measurable baseline brain metastases.
NOTE: This table presents a summary of efficacy data for representation purposes only and not for comparative analysis.
Abbreviations: CI = confidence interval; HR = hazard ratio; IC = intracranial; NSCLC = non–small cell lung cancer; NE = not estimable; NR = not reached; NS = not significant; ORR = objective response rate; PFS = progression-free survival; TKI = tyrosine kinase inhibitor.

ALK-positive mNSCLC is associated with a high frequency of central nervous system (CNS) metastasis, and such patients have a particularly poor prognosis, with a short survival and reduced quality of life.5-7 The incidence of brain metastases is approximately 25% at the time of diagnosis of ALK-positive mNSCLC but can increase to 58% by 3 years.7,8 In a study of U.S. Medicare patients with ALK-positive mNSCLC who received a second-generation ALK TKI in the first-line setting, 28% had baseline brain metastases, and the cumulative incidence of brain metastases was 50% to 60% after approximately 5 years of follow-up.9 Moreover, patients with baseline brain metastases may experience subsequent CNS progression. CNS metastasis thus remains a significant clinical challenge in patients with ALK-positive mNSCLC. According to Vincent Lam, MD, Assistant Professor at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, “ALK-positive mNSCLC presents such a high risk for CNS metastasis and progression that there's a critical need for TKIs with good CNS activity.” Next-generation ALK inhibitors like alectinib, brigatinib, ceritinib, and lorlatinib demonstrate improved CNS penetration and intracranial efficacy compared to the first-generation ALK inhibitor crizotinib, which has poor CNS penetrance.2 As a result, using more effective next-generation ALK TKIs as first-line treatments may help delay the development and progression of brain metastases in patients with ALK-positive mNSCLC.10,11 It therefore makes sense to utilize the most effective ALK inhibitor from the beginning to maximize patient responses, regardless of whether they have baseline brain metastases.11 Five-year follow-up data from a phase III trial of lorlatinib in this setting were recently presented that may have clinical implications for optimizing first-line therapy.

ALK-positive mNSCLC presents such a high risk for CNS metastasis and progression that there's a critical need for TKIs with good CNS activity. Vincent Lam, MD

Lorlatinib

Lorlatinib is a third-generation ALK inhibitor that was designed to cross the blood–brain barrier and to be capable of overcoming ALK resistance mutations.2 It was initially approved in the second-line setting for patients with ALK-positive mNSCLC on the basis of phase I/II results demonstrating systemic efficacy as well as intracranial activity, in patients with or without prior ALK TKI therapy.12 In the first-line setting, single-agent lorlatinib was compared to crizotinib in patients with ALK-positive mNSCLC in the phase III CROWN randomized clinical trial. At the time this global trial was initiated in February 2017, crizotinib was the global standard of care in this setting and thus was chosen as the study comparator. At the initial interim analysis by blinded independent central review (BICR), with 18-month follow-up, median progression-free survival was not reached (NR) with lorlatinib (95% confidence interval [CI] = NR–NR) compared to 9.3 months (95% CI = 7.6–11.1) with crizotinib; the hazard ratio (HR) for disease progression or death was 0.28 (95% CI = 0.19–0.41; P < .001).13 Objective response rates were 76% and 58%, respectively. These results led to the approval of lorlatinib as first-line therapy in adults with mNSCLC whose tumors are ALK-positive as detected by an FDA-approved test.14

A post hoc analysis (by BICR) with a 36-month follow-up found that the median progression-free survival was NR with lorlatinib. In patients without brain metastases at baseline (n = 218), the 12-month progression-free survival rate was 78% (95% CI = 69–85) with lorlatinib compared to 45% (95% CI = 34–55) with crizotinib (HR = 0.32; 95% CI = 0.20–0.49; P < .0001).15 At this time point, median progression-free survival was NR in lorlatinib-treated patients with and without baseline brain metastases, and intracranial efficacy was seen regardless of baseline brain metastases (see below).

In a subsequent post hoc analysis (median follow-up, 60 months), median progression-free survival, by investigator, was NR with lorlatinib compared to 9.1 months with crizotinib (HR = 0.19; 95% CI = 0.13–0.27). The 5-year progression-free survival rates per investigator assessment were 60% and 8%, respectively. Overall survival data are not yet mature; analyses are ongoing and will be presented in the future (Figure 1).16 The results of this unplanned, landmark investigator-assessed analysis are descriptive, and no formal hypothesis or statistical testing was performed. Overall, the CROWN 5-year data represent the longest progression-free survival observed with any single-agent targeted therapy for mNSCLC and across all metastatic solid tumors achieved to date.16

Figure 1. CROWN 5-Year Progression-Free Survivala 16

aPFS as determined by investigator assessment.
Abbreviations: CI =confidence interval; HR = hazard ratio; NR = not reached; PFS = progression-free survival.
Reprinted with permission from Solomon BJ, Liu G, Felip E, et al: Lorlatinib versus crizotinib in patients with advanced ALK-positive non–small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol 42:3400-3409, 2024.16 © American Society of Clinical Oncology.

The CROWN trial also demonstrated that lorlatinib is effective against pre-existing brain metastases and could delay development of new brain metastases. At the 5-year follow-up post hoc analysis, in patients with measurable baseline brain metastases (n = 18), the intracranial objective response rate by investigator assessment was 92% (95% CI = 62–100) with lorlatinib and 33% (95% CI = 4–78) with crizotinib. Considering patients with measurable and/or nonmeasurable brain metastases (n = 73), these values were 60% (95% CI = 42–76) and 11% (95% CI = 3–25), respectively. Median progression-free survival for patients with baseline measurable and/or nonmeasurable brain metastases was NR (95% CI = 32.9–NR) with lorlatinib and 6.0 months (95% CI = 3.7–7.6) with crizotinib. For those without baseline brain metastases, these values were NR (95% CI = 64.3–NR) and 10.8 months (95% CI = 9.0–12.8), respectively.16 “These results are remarkable,” noted Dr. Lam. “In the CROWN study, only 4 of the 114 patients without baseline brain metastases have developed brain metastasis, which highlights the ability of lorlatinib to protect the brain,” he said.

In the CROWN study, only 4 of the 114 patients without baseline brain metastases have developed brain metastasis, which highlights the ability of lorlatinib to protect the brain.Vincent Lam, MD

The cumulative incidence of CNS progression as assessed by investigators was also lower with lorlatinib in the CROWN trial. In the intention-to-treat population, the cumulative incidence of progression of brain metastases as first event at 36 months was 5% with lorlatinib compared to 64% with crizotinib in patients without baseline brain metastases. Median time to intracranial progression was NR (95% CI = NR–NR) with lorlatinib compared to 16.4 months (95% CI, 12.7–21.9) with crizotinib.16 These results suggest that lorlatinib could delay the onset of CNS metastases in this patient population.

Lorlatinib Safety

All ALK TKIs used for the treatment of ALK-positive mNSCLC are associated with toxicities, although they differ in their safety profiles.17 With lorlatinib, the most common (incidence ≥ 20%) adverse events and grade 3/4 laboratory abnormalities are edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough.14 Paresthesia and muscle weakness may occur but are generally mild. In the CROWN trial, treatment-emergent adverse events were consistent with those observed in other lorlatinib studies, and no new safety signals were noted with longer follow-up.18,19 At the 18-month interim analysis, the most common adverse events (any grade) in CROWN associated with lorlatinib were hypercholesterolemia (70%), hypertriglyceridemia (64%), edema (55%), increased weight (38%), peripheral neuropathy (34%), and cognitive impairment (21%); these adverse events occurred more frequently in the lorlatinib arm compared with the crizotinib arm.13 Grade 3/4 adverse events were more common with lorlatinib than crizotinib (72% vs 56%), primarily due to increased hyperlipidemia with the former agent. The most frequent grade 3/4 adverse events with lorlatinib consisted of elevated triglyceride (20%), increased weight (17%), hypercholesterolemia (16%), and hypertension (10%).

At the CROWN 18-month interim analysis (median duration of treatment, 16.7 months), adverse events led to dose interruption in 49% of lorlatinib-treated patients, dose reduction in 21%, and discontinuation in 6.7%.14 At the 60-month analysis (median duration of treatment, 57.0 months), all-causality adverse events led to dose interruption in 62% of patients, dose reduction in 23%, and discontinuation in 11%.16 Lorlatinib dose reduction within the first 16 weeks of the CROWN trial did not seem to impact median progression-free survival or time to intracranial progression, though, a finding supported by another retrospective study.16,20

Increases in serum cholesterol and triglycerides commonly occur with lorlatinib, which may require initiation or dose escalation of a lipid-lowering agent. Providers should refer to recommendations for preferred statins—pitavastatin, pravastatin, or rosuvastatin—given their low involvement with specific CYP450 enzymes that can interact with lorlatinib.14,21,22

CNS adverse events can occur with lorlatinib treatment, including cognitive, mood, speech, and psychotic effects. These have been reported in both patients with and without brain metastases.14,23 In the CROWN 60-month analysis, among patients who received lorlatinib at 100 mg once daily, CNS adverse effects were observed in 42% of patients, the majority (86%) of which were grade 1/2 in severity.16

CNS adverse events are generally manageable with lorlatinib dose interruptions and reductions or the addition of concomitant medications. At the CROWN 18-month interim analysis, cognitive effects leading to dose reductions occurred in 2% of lorlatinib-treated patients and discontinuation in 1%.13 At the 36-month analysis, 62% of patients with CNS adverse events could be managed without intervention and 23% with dose modification (reduction and/or interruption); 2% of patients required treatment discontinuation.15 In the 60-month analysis, more than half of CNS adverse events did not require any pharmacological intervention, and 60% resolved with dose modification or interruption.24 “Neurocognitive effects generally occur relatively early in the course of lorlatinib therapy and can often be managed by dose interruption or reduction,” explained Dr. Lam.

Certain risk factors may be associated with development of neurocognitive adverse events with lorlatinib. In a study of lorlatinib-treated patients with NSCLC, factors associated with developing cognitive effects that were noted in one of two cohorts included brain metastasis, brain radiation, psychiatric disease, and use of psychoactive drugs.23 However, the number of patients experiencing specific neurocognitive adverse events was low, so these results should be confirmed in larger studies. Recommendations on the monitoring, evaluation, and management of selected CNS adverse events and other toxicities associated with lorlatinib have been published.14,21,22,25

The crux of lorlatinib management is typically dose manipulations, and most side effects resolve completely with a dose hold. Todd Bauer, MD

A recent publication outlines a pragmatic, patient-focused approach to lorlatinib-related toxicity assessment and management, based on the general framework of “prepare, monitor, manage, reassess” to facilitate prompt adverse event recognition and mitigation and aid in practical, actionable patient care.21 According to Todd Bauer, MD, of the Greco-Hainsworth Centers for Research/Tennessee Oncology, “The crux of lorlatinib management is typically dose manipulations, and most side effects resolve completely with a dose hold. While lorlatinib may require a little more time in clinic initially to adjust the dose, once it’s properly managed, patients can stay on the drug.”

Conclusion

The availability of next-generation ALK TKIs has significantly altered the first-line treatment landscape for patients with ALK-positive mNSCLC. Current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) indicate alectinib, brigatinib, and lorlatinib as preferred first-line treatment options (all NCCN Category 1) for patients with ALK-rearranged mNSCLC.26 Lorlatinib has demonstrated effective and durable disease control in this setting, with prolonged progression-free survival and intracranial time to progression compared to crizotinib observed in the CROWN trial in patients with and without intracranial disease. At the time of the 5-year analysis, the required number of overall survival events for a protocol-specified second interim analysis had not been met. Overall survival follow-up is currently ongoing in the CROWN trial, and results will be reported in the future. Treatment-related adverse events such as hyperlipidemia, weight gain, edema, peripheral neuropathy, and CNS effects commonly occur with lorlatinib, but these are considered to be manageable and usually respond to therapy management.

The demonstrated efficacy and safety of lorlatinib, including the long-term progression-free survival benefit and intracranial time to progression observed in the CROWN trial, support its use as first-line therapy in patients with ALK-positive mNSCLC. According to Dr. Lam, “With multiple TKI options available for ALK-positive mNSCLC, we can tailor our choice of therapy to meet the goals and individual needs of each patient. The CROWN results indicate that lorlatinib should be part of the discussion with all of our newly and recently diagnosed patients with ALK-positive mNSCLC.”

Disclosure

Dr. Lam reported a consulting or advisory role with Pfizer, Genentech/Roche, Seattle Genetics, AstraZeneca, Guardant Health, Takeda, Anheart Therapeutics, and Iovance Biotherapeutics; and institutional research funding from Bristol Myers Squibb, Merck, Seattle Genetics, and AstraZeneca.

Dr. Bauer reported employment with Tennessee Oncology; a consulting or advisory role with Pfizer, Bayer, Lilly, Sanofi, and AVEO; and speakers’ bureau participation with Bayer, and Lilly.

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