Lorlatinib Data Published in NEJM Underscore Benefits Over Crizotinib in ALK+ NSCLC

November 19, 2020
Kristi Rosa
Kristi Rosa

Managing Editor, OncLive®
Kristi Rosa joined MJH Life Sciences in 2016 and has since held several positions within the company. She helped launch the rapidly growing infectious disease news resource Contagion, strengthened the Rare Disease Report, of HCPLive, and now serves as the main digital news writer for OncLive. Prior to working at the company, she served as lead copywriter and marketing coordinator at The Strand Theater. Email: krosa@onclive.com

November 19, 2020 - Lorlatinib has been found to significantly prolong progression-free survival, elicit a higher overall and intracranial response, and improve quality of life compared with crizotinib in treatment-naïve patients with advanced ALK-positive non­–small cell lung cancer.

Lorlatinib (Lorbrena) has been found to significantly prolong progression-free survival (PFS), elicit a higher overall and intracranial response, and improve quality of life (QoL) compared with crizotinib (Xalkori) in treatment-naïve patients with advanced ALK-positive non­–small cell lung cancer (NSCLC), according to data from the phase 3 CROWN trial (NCT03052608) published in the New England Journal of Medicine.1

Results from a preplanned interim analysis showed that the median PFS per blinded independent central review (BICR) was not estimable (NE, 95% CI, NE-NE) with lorlatinib versus 9.3 months (95% CI, 7.6-11.1) with crizotinib; this translated to a 72% reduction in the risk of disease progression or death (hazard ratio [HR], 0.28; 95% CI, 0.19-0.41; one-sided P <.001).

“For nearly a decade, we have been committed to transforming the treatment of NSCLC through the development of innovative medicines like [lorlatinib], a third-generation ALK inhibitor specifically developed to inhibit the most common tumor mutations that drive resistance to current medications and to address brain metastases,” Chris Boshoff, MD, PhD, chief development officer of Oncology at Pfizer Global Product Development, stated in a press release.2

“The prolonged PFS and intracranial responses seen in the CROWN trial highlight the potential role for [lorlatinib] to significantly improve outcomes for people with previously untreated ALK-positive advanced NSCLC and we are pleased that these data will be reviewed as part of the FDA’s REAL-Time Oncology Review pilot program,” Boshoff added.

With regard to secondary end points, the overall survival (OS) data were not mature at the time of the analysis, although deaths occurred in a total of 51 patients in the intent-to-treat (ITT) population; 23 patients in the lorlatinib arm died versus 28 patients in the crizotinib arm. The HR for death was 0.72 (95% CI, 0.41-1.25) and the difference in OS between the 2 arms was not determined to be significant.

Moreover, lorlatinib elicited a confirmed objective response rate (ORR) of 76% (95% CI, 68-83) versus 58% (95% CI, 49-66) with crizotinib. Moreover, lorlatinib was found to have more intracranial activity versus crizotinib. Specifically, 96% (95% CI, 91-98) of patients on the lorlatinib arm were without central nervous system (CNS) progression at 12 months versus 60% (95% CI, 49-69) of those in the crizotinib arm (HR, 0.07; 95% CI, 0.03-0.17).

Among 30 patients with brain metastases, lorlatinib elicited an intracranial ORR of 82% (n = 14; 95% CI, 57-96) versus just 23% (n = 3; 95% CI, 5-54) with crizotinib. Intracranial complete response rates in the lorlatinib and crizotinib arms were 71% versus 8%, respectively.

In the global, randomized, phase 3 CROWN trial, investigators compared the safety and efficacy of lorlatinib and crizotinib in a total of 296 patients with advanced ALK-positive. NSCLC who had not received prior systemic therapy for metastatic disease.

To be eligible for enrollment, patients had to have histologically or cytologically confirmed locally advanced or metastatic NSCLC with ALK positivity determined via the Ventana ALK (D5F3) CDx immunohistochemical assay. Patients with asymptomatic treated or untreated CNS metastases were permitted for inclusion. Patients had to have at least 1 extracranial measurable target lesion; an ECOG performance status ranging from 0 to 2; and acceptable bone marrow, pancreatic, renal, and liver function.

In the trial, patients were randomized 1:1 to receive a 100-mg daily dose of oral lorlatinib or a 250-mg twice daily dose of oral crizotinib in 28-day treatment cycles. Participants were stratified based on brain metastases (yes or no) and ethnicity (Asian or non-Asian). Crossover between the treatment arms was not allowed. Treatment was administered until progressive disease, withdrawn consent, or intolerable toxicity. Patients were permitted to continue treatment after disease progression at the investigator’s discretion.

The primary end point of the trial was PFS, while key secondary end points comprised PFS per investigator assessment, OS, ORR, objective intracranial response, and safety.

The interim analysis was planned to be conducted after about 75% of 177 expected events of disease progression or death had been reported. Efficacy end points were evaluated in the ITT population and this was comprised of all patients who underwent randomization.

Between May 2017 and February 2019, 296 patients enrolled to the trial at 104 centers spanning 23 countries; 149 were randomized to receive lorlatinib, while 147 received crizotinib. Five patients enrolled to the crizotinib arm were not given treatment but were included in the ITT population.

Baseline characteristics were reported to be well balanced between the 2 treatment arms. Twenty-six percent of patients (n = 38) in the lorlatinib arm had CNS metastases at baseline versus 27% (n = 40) of those in the crizotinib arm. At data cutoff, 103 patients versus 31 patients in the lorlatinib and crizotinib arms, respectively, were still receiving treatment. The median duration of follow-up with regard to PFS was 18.3 months in the investigational arm versus 14.8 months in the control arm.

Of the 296 patients that comprised the ITT population, 127 experienced progressive disease or died by the time of data cutoff; 28% of these patients were in the lorlatinib arm (n = 41/149) and 59% were in the crizotinib arm (n = 86/147).

Notably, with regard to PFS, the HR favored lorlatinib over crizotinib across all prespecified patient subgroups analyzed. Moreover, a greater percentage of patients who received lorlatinib were progression free at 12 months compared with crizotinib per investigator assessment; these rates were 80% versus 35%, respectively (HR, 0.21; 95% CI, 0.14-0.31).

Additionally, in terms of responses, 70% of patients in the lorlatinib arm versus 27% of patients in the crizotinib arm experienced a response to treatment that persisted for at least 12 months per BICR. Similar responses were observed via investigator assessment.

In the 78 patients with CNS metastases at baseline, a significantly higher percentage of those who achieved a confirmed objective intracranial response per BICR was reported with lorlatinib versus crizotinib, at 66% versus 20%, respectively. Moreover, 61% of patients experienced a complete intracranial response in the lorlatinib arm versus just 15% in the crizotinib arm. Notably, 72% of patients who received lorlatinib experienced an intracranial response that lasted for at least 12 months compared with 0% of those who received crizotinib.

Additional results revealed that the cumulative incidence of CNS progression as the first event was substantially lower with lorlatinib versus crizotinib. At 12 months, the cumulative incidence of CNS progression at the first event in the investigational and control arms was 3% versus 33%, respectively (HR, 0.06; 95% CI, 0.02-0.18).

Of 296 patients, 291 received treatment with either agent. Seventy-six percent of patients on the lorlatinib versus 35% of patients on the crizotinib arm continued to receive treatment for at least 12 months. Moreover, 69% of patients in the investigational arm versus 22% of patients in the control were still receiving treatment at the time of data cutoff.

With regard to safety, any-grade toxicities that were more commonly reported with lorlatinib versus crizotinib were hypercholesterolemia (70% vs 4%, respectively), hypertriglyceridemia (64% vs 6%), edema (55% vs 39%), increased weight (38% vs 13%), peripheral neuropathy (34% vs 15%), cognitive effects (21% vs 6%), anemia (19% vs 8%), hypertension (18% vs 2%), mood effects (16% vs 5%), and hyperlipidemia (11% vs 0%). Changes and cognition and mood experienced were lorlatinib were mostly grade 1 in severity and were found to be reversible with dose interruption.

Seventy-two percent of patients who received lorlatinib experienced adverse effects (AEs) that were grade 3 or 4 in severity compared with 56% of those who were given crizotinib. The most commonly reported toxicities in the investigational arm included elevated triglyceride (20%), increased weight (17%), elevated cholesterol levels (16%), and hypertension (10%). In the crizotinib arm, most of these effects were laboratory abnormalities.

Thirty-four percent of patients in the lorlatinib arm versus 27% of those in the crizotinib arm experienced serious AEs. Fourteen patients on the trial experienced a toxicity that resulted in fatality; 7 patients were in the lorlatinib arm and 7 patients were in the crizotinib arm.

Moreover, 49% of patients in the experimental arm required a dose interruption versus 21% of those in the control arm; 21% versus 15%, respectively, of these patients required dose reductions. Seven percent of patients who received lorlatinib experienced toxicities that led to treatment discontinuation compared with 9% of those who were given crizotinib.

An analysis looking at patient-reported outcomes revealed that those who received lorlatinib experienced a substantially greater overall improvement from baseline in global QoL than those who were given crizotinib, with an estimated mean difference of 4.65 (95% CI, 1.14-8.16); however, this difference was not concluded to be clinically meaningful. These improvements were reported as early as cycle 2 of treatment and they were found to be maintained over time in the investigational arm.

“Biomarker-driven medicines have improved outcomes for people living with ALK-positive NSLC, but innovative therapies are still needed to delay disease progression,” Benjamin Solomon, MD, of the Department of Medical Oncology at Peter MacCallum Cancer Centre, stated in the release. “The results from the CROWN trial demonstrate that [lorlatinib] has the potential to be a practice-changing, first-line option, and we thank the many people and their families who participated in this trial.”


  1. Shaw AT, Bauer TM, de 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
  2. Results from phase 3 CROWN trial of Pfizer’s Lorbrena (lorlatinib) in previously untreated ALK-positive lung cancer published in the New England Journal of Medicine. News release. Pfizer Inc. November 19, 2020. Accessed November 19, 2020. https://bit.ly/2UK6OVn.