Lorlatinib Improves PFS, Reduces CNS Progression in Advanced ALK+ NSCLC

Benjamin J. Solomon, MBBS, PhD

Lorlatinib (Lorbrena) improved progression-free survival (PFS) and reduced 12-month cumulative incidence of central nervous system (CNS) progression compared with crizotinib (Xalkori) in patients with advanced ALK-positive non–small cell lung cancer (NSCLC) irrespective of brain metastases at baseline.¹

In an ad hoc analysis of the phase 3 CROWN trial (NCT03052608), investigators found that, in patients with brain metastases (n = 78), first-line lorlatinib induced a 12-month PFS rate of 78% compared with 22% on crizotinib (HR, 0.20; 95% CI, 0.10-0.43; P < .0001) and 78% vs 45% (HR, 0.32; 95% CI, 0.20-0.49; P < .0001), respectively, for those without.

The median PFS for patients without brain metastases (n = 218) was not reached [NR] vs 7.2 months in favor of lorlatinib. Similarly, patients with brain metastases assigned to the ALK/ROS1 inhibitor had a superior median PFS compared with those who received crizotinib (NR vs 11.0 months).

In patients with baseline brain metastases who received lorlatinib without prior brain radiotherapy (n = 30), the 12-month PFS rate was 75% (95% CI, 55%-87%). The median PFS was NR in both prior brain radiotherapy subgroups.

“These additional post hoc analyses of data from the phase 3 CROWN study show that lorlatinib has potent and durable efficacy in patients with and without brain metastases at baseline, regardless of prior brain radiotherapy use,” lead author Benjamin J. Solomon, MBBS, PhD, and colleagues wrote in the article. “These additional post hoc analyses of data from the phase 3 CROWN study show that lorlatinib has potent and durable efficacy in patients with and without brain metastases at baseline, regardless of prior brain radiotherapy use.”

In March 2021, the FDA approved a supplemental new drug application for lorlatinib to expand the indication to include the frontline treatment of patients with ALK-positive NSCLC as detected by an FDA-approved test.² The European Commission approved lorlatinib monotherapy for adults with ALK-positive advanced NSCLC who did not receive a prior ALK inhibitor in January 2022.³ In previous data from the CROWN trial, the agent induced a 72% reduction in the risk of disease progression or death vs crizotinib; 78% (95% CI, 70%-84%) of those in the lorlatinib arm were alive without disease progression at 12 months vs 39% (95% CI, 30%-48%) of those in the crizotinib arm (HR, 0.28; 95% CI, 0.19-0.41; P < .001). Moreover, lorlatinib elicited an objective response rate (ORR) of 76% (95% CI, 68%-83%) vs 58% (95% CI, 49%-66%) with crizotinib.⁴

Notably, 82% (95% CI, 57%-96%) of 30 patients with measurable central nervous system (CNS) brain metastases at baseline who received lorlatinib achieved an intracranial response vs 23% (95% CI, 5%-54%) of those who were given crizotinib; 71% of patients in the investigative arm experienced an intracranial complete response vs 8% of those in the control arm.

In the global, randomized CROWN trial, eligible patients had histologically or cytologically confirmed, locally advanced or metastatic NSCLC with ALK positivity, and at least 1 extracranial measurable target lesion that had not been previously irradiated. Patients were required to have an ECOG performance status of 0 to 2, as well as acceptable bone marrow, pancreatic, renal, and liver function.

Those with asymptomatic treated or untreated CNS metastases were permitted to enroll. Patients who received prior systemic treatment for metastatic disease were not eligible.

A total of 296 participants were randomly assigned to 100 mg daily oral lorlatinib (n = 149) or twice-daily 250 mg oral crizotinib (n = 147). Treatment was continued until disease progression, death, withdrawn consent, or intolerable toxicity. Stratification factors included the presence of brain metastases (yes vs no) and ethnic group (Asian vs non-Asian). Crossover between the arms was not allowed.

Key end points included cumulative incidence of CNS progression and non-CNS progression as first progression event, intracranial complete response rate, duration of response (DOR), and safety

Thirty-eight (26%) patients in the lorlatinib arm had brain metastases at baseline, 8 (21%) of whom previously received brain radiotherapy. In the crizotinib arm, 40 (27%) patients had brain metastases according to BICR assessment, 10 (25%) of whom had received prior brain radiotherapy.

Eight percent of those in the lorlatinib arm previously received anticancer treatment vs 6% of those on the crizotinib arm; 6% and 7%, respectively, previously received brain radiotherapy, and 26% vs 27%, respectively, had brain metastases at baseline.

Twelve-month cumulative incidence rates of CNS progression were 7% with lorlatinib vs 72% with crizotinib in patients with baseline brain metastases (HR, 0.07; 95% CI, 0.02-0.24). In patients without baseline brain metastases, the 12-month cumulative incidence rates of CNS progression were 1% with lorlatinib and 18% with crizotinib (HR, 0.05; 95% CI, 0.01-0.42). Cumulative incidence of non-CNS progression was lower with lorlatinib than with crizotinib in patients with and without baseline brain metastases.

Twenty-three of 38 (61%) patients with any brain metastases assigned to lorlatinib had complete CNS responses vs 6 of 40 (15%) assigned to crizotinib. Among those with at least 1 measurable brain metastasis at baseline, 71% (12/17) of those assigned to lorlatinib and 8% (1/13) of those assigned to crizotinib had complete response.

Among patients with complete responses and measurable brain lesions at baseline, the median DOR was NR (range, 7.4-31.4 months) in the experimental group. Five of 12 patients (42%) had a DOR of 18 months or more. Most patients with intracranial complete responses assigned to lorlatinib were still in treatment at data cutoff.

References

1. Solomon BJ, Bauer TM, Ignatius Ou SH, et al. Post hoc analysis of lorlatinib intracranial efficacy and safety in patients with ALK-positive advanced non-small-cell lung cancer from the phase III CROWN study. J Clin Oncol. 2022;40(31):3593-3602. doi:10.1200/JCO.21.02278
2. US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. March 3, 2021. Accessed March 3, 2021. http://bit.ly/30e9cWU
3. European Commission approves LORVIQUA (lorlatinib) as a first-line treatment for ALK-positive advanced lung cancer. News release. Pfizer Inc. January 28, 2022. Accessed November 1, 2022. https://bit.ly/3ACOtxD
4. Shaw AT, Bauer TM, dr Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187