FDA Grants Priority Review to Frontline Lorlatinib for ALK+ Metastatic NSCLC

December 28, 2020 - The FDA has granted priority review to a supplemental new drug application for lorlatinib for use as a frontline treatment in patients with ALK-positive metastatic non–small cell lung cancer.

The FDA has granted priority review to a supplemental new drug application (sNDA) for lorlatinib (Lorbrena) for use as a frontline treatment in patients with ALK-positive metastatic non–small cell lung cancer (NSCLC).1

The application is based on findings from an interim analysis of the pivotal phase 3 CROWN trial (NCT03052608) in which the third-generation ALK TKI elicited higher overall and intracranial response rates vs crizotinib (Xalkori) in patients with ALK-positive disease; the agent also significantly improved progression-free survival (PFS).2

Specifically, the median PFS via blinded independent central review (BICR) with lorlatinib was determined to not be estimable (NE; 95% CI, NE-NE) vs 9.3 months with crizotinib (95% CI, 7.6-11.1); this translated to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.19-0.41; 1-sided P <.001).

Moreover, in patients with measurable brain metastases, the intracranial objective response rate (IC-ORR) was 82% with lorlatinib; this included a complete response (CR) rate of 71%. The agent was also found to result in a significant prolongation of time to IC progression compared with crizotinib.

Under the Prescription Drug User Fee Act, the FDA must make a decision on the sBLA by April 2021.

“The decision by the FDA to evaluate our application for [lorlatinib] under its innovative review pathways, which aim to speed up availability of potentially life-changing medicines, underscores the significance of the CROWN data and potential impact of [lorlatinib] as an initial therapy for people with ALK-positive advanced NSCLC,” Chris Boshoff, MD, PhD, chief development officer of Oncology, Pfizer Global Product Development, at Pfizer, stated in a press release. “We look forward to working with the FDA to bring this treatment option to patients as quickly as possible.”

In the phase 3 trial, investigators enrolled a total of 296 patients with ALK-positive NSCLC. Participants were randomized 1:1 to receive either lorlatinib at a daily dose of 100 mg (n = 149) or crizotinib at a twice-daily dose of 250 mg (n = 147). Stratification was based on brain metastases (yes vs no) and ethnicity (Asian vs non-Asian). No crossover between the 2 treatment arms was allowed and 5 patients on the control arm did not receive treatment.

To participate, patients had to be treatment naïve and have stage IIIB/IV disease, an ECOG performance status of 0-2, and at least 1 extracranial measurable target lesion per RECIST v1.1 criteria. No previous radiation was required, and patients who had asymptomatic treated or untreated central nervous systemic metastases were included.

The primary objective of the trial was PFS per BICR, while key secondary end points comprised investigator-assessed PFS, BICR- and investigator-assessed ORR, IC-ORR, duration of response (DOR), and IC-DOR via BICR, IC-time to progression per BICR, overall survival (OS), safety, and quality of life.

Additional results presented during the 2020 ESMO Virtual Congress demonstrated that the PFS rate at 12 months with lorlatinib, as evaluated by BICR, was 78% vs 39% with crizotinib. The median PFS per investigator assessment was NE vs 9.1 months with lorlatinib and crizotinib, respectively; this translated to a 79% reduction in the risk of disease progression or death (HR, 0.21; 95% CI, 0.14-0.31; 1-sided P <.001). At 12 months, the PFS rates in the investigational and control arms were 80% and 35%, respectively.

Notably, the PFS benefit per BICR was found to be upheld across all prespecified subgroups, including those with brain metastases (HR, 0.20).

The ORR per BICR with lorlatinib vs crizotinib was 76% and 58%, respectively (odds ratio [OR], 2.25; 95% CI, 1.35-3.89). The CR rates in the investigational and control arms was 3% vs 0%, respectively; the partial response rates were 73% vs 58%, respectively. Additionally, 13% of patients in the lorlatinib arm achieved stable disease vs 28% of those in the crizotinib arm. Disease progression was reported in 7% and 5% of those in the lorlatinib and crizotinib arms, respectively.

The median DOR was not determined to be evaluable in the lorlatinib arm, compared with 11.0 months in the crizotinib arm. In both treatment arms, the median time to response was 1.8 months.

Moreover, the IC-ORR per BICR was 66% and 20% of those in the lorlatinib and crizotinib arms, respectively, in those with measurable or nonmeasurable brain metastases at baseline (OR, 8.41; 95% CI, 2.59-27.23). In the investigative and control arms the IC-CR rates were 61% and 15%, respectively. In those with measurable brain metastases the IC-ORR rates were 82% vs 23%, respectively (OR, 16.83; 95% CI, 1.95-163.23). In this subgroup, the IC-CR rates were 71% vs 8%, respectively.

The median DOR was not evaluable with lorlatinib; in those with measurable/nonmeasurable brain metastases, the median DOR was 9.4 months in both and 10.2 months in the only-measurable brain metastases group with crizotinib.

The OS data are still immature; however, the median OS was not estimable in both treatment arms and favored lorlatinib (HR, 0.72; 95% CI, 0.41-1.25).

Regarding safety, toxicities reported with lorlatinib at more than 10% than with crizotinib included hypocholesterolemia, hypertriglyceridemia, edema, weight gain, peripheral neuropathy, and cognitive effects. Toxicities that were most commonly associated with crizotinib comprised diarrhea, nausea, vision disorder, vomiting, increased aspartate aminotransferase/alanine aminotransferase, and constipation.

Previously, in 2018, the FDA granted an accelerated approval to lorlatinib for use in patients with ALK-positive metastatic NSCLC after disease progression on 1 or more previous ALK-targeted TKIs or who experienced disease progression on alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK inhibitor treatment for metastatic disease. Data from CROWN will support the conversion to a full approval for the use of lorlatinib in this indication.


  1. Lorbrena (lorlatinib) sNDA in previously untreated ALK-positive lung cancer accepted for priority review by US FDA. News release. Pfizer Inc. December 28, 2020. Accessed December 28, 2020. http://bit.ly/3rAp5DK.
  2. Solomon B, Bauer T, de Marinis F, et al. Lorlatinib vs crizotinib in the first-line treatment of patients with advanced ALK-positive non–small cell lung cancer: results of the phase 3 CROWN study. Ann Oncol. 2020;31(suppl 4):S1180-S1181. doi:10.1016/j.annonc.2020.08.2282