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Patients with previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) experienced better outcomes with first-line lorlatinib (Lorbrena) versus crizotinib (Xalkori), regardless of whether they had brain metastases at baseline, according to an analysis of the study.

In a post-hoc efficacy analysis of the phase III trial, progression-free survival (PFS) significantly improved with lorlatinib among patients with brain metastases at baseline, with a median PFS not reached versus 7.2 months with crizotinib (HR 0.20, 95% CI 0.10-0.43, P<0.0001), reported Benjamin J. Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues.

At 12 months, the PFS rates in this subgroup were 78% versus 22%, respectively, they stated in the .

Patients without brain metastases at baseline also experienced a significant PFS improvement with lorlatinib (median not reached vs 11.0 months; HR 0.32, 95% CI 0.20-0.49, P<0.0001), with 12-month PFS rates of 78% and 45%.

Results from the main CROWN study showed that treatment with lorlatinib versus crizotinib reduced the risk of disease progression or death by 72% in patients with untreated advanced ALK-positive NSCLC, and demonstrated intracranial activity resulting in higher complete and partial intracranial response rates in patients with brain metastases. The study included 218 patients without brain metastases at baseline (111 assigned lorlatinib, 107 crizotinib), and 78 patients with brain metastases at baseline (38 assigned lorlatinib, 40 crizotinib).

Lorlatinib received in 2021 for this patient population.

In the current analysis, lorlatinib was associated with a lower cumulative incidence of central nervous system (CNS) progression versus crizotinib in patients with and without brain metastases at baseline.

Specifically, the 12-month cumulative incidence rates of CNS progression were 7% with lorlatinib and 72% with crizotinib in patients with baseline brain metastases (HR 0.07, 95% CI 0.02-0.24) and 1% with lorlatinib and 18% with crizotinib in patients without baseline brain metastases (HR 0.05, 95% CI 0.01-0.42).

"Furthermore, we demonstrate that, for some patients, CNS AEs [adverse events] can be managed either without any intervention or through appropriate dose modification," the authors wrote. "Our data support lorlatinib as first-line treatment in patients with advanced ALK-positive NSCLC with/without brain metastases."

Solomon and colleagues reported that complete CNS responses with lorlatinib were observed in 61% of patients with any brain metastases at baseline compared with 15% with crizotinib, while in patients with at least one measurable brain metastasis at baseline, 71% had complete responses with lorlatinib compared to 8% with crizotinib.

Median duration of response (DOR) with lorlatinib in patients with complete responses and measurable brain lesions at baseline was not reached (range: 7.4-31.4 months), with 83% of patients achieving a DOR ≥12 months, and 42% a DOR ≥18 months.

In an accompanying editorial, Maurice Pérol, MD, and Aurélie Swalduz, MD, both of the Léon Bérard Cancer Center in Lyon, France, pointed out that lorlatinib's toxicity profile "may make the physicians uncomfortable providing it as frontline therapy. The occurrence of CNS side effects should not be trivialized because of their potential impairment of the patients' quality of life that is becoming a key endpoint in the context of the prolongation of overall survival in ALK-positive advanced NSCLC."

However, Solomon's group noted that the "occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life."

"Today, the choice of the frontline treatment for advanced ALK-positive NSCLC is still a debate," they stated. "Until we know the true value of the duration of response and PFS of lorlatinib in the first-line setting, which remains the key to validate in ALK-positive NSCLC, the concept of using the most effective treatment first, the use of upfront brigatinib (Alunbrig) or alectinib (Alecensa) remains a reasonable option, especially since the mechanisms of resistance to frontline lorlatinib are largely unknown."

However, some patients clearly already benefit from lorlatinib in the first-line setting, such as those with initial CNS involvement, they added.

In the current study, 35% of patients had CNS AEs with lorlatinib compared with 11% of patients who received crizotinib. Most of the patients in each arm had a maximum CNS AE severity of grade 1. Five patients (29%) in the lorlatinib arm and four patients (27%) in the crizotinib arm had maximum severity of grade 2, and five (10%) in the lorlatinib arm had maximum severity of grade 3. There were no grade 4/5 CNS AEs.

At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved during the follow-up period. The latter made it difficult "to assess the full duration of all CNS AEs," which was a study limitation, the authors acknowledged.

Other limitations included the fact that CNS AEs can be difficult to assess so some events may have been underreported, and that "patients with and without reported CNS AEs experienced some decline in over time."

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