FDA Grants Priority Review to sNDA for Lorlatinib in Previously Untreated ALK+ NSCLC

Under the FDA’s Real-Time Oncology Review Pilot Program and Project ORBIS, the FDA is reviewing a supplemental new drug application for lorlatinib (Lorbrena) as a first-line treatment for patients with ALK-positive metastatic non–small cell lung cancer.

The FDA has accepted and granted priority review to the supplemental new drug application (sNDA) for the third-generation ALK inhibitor lorlatinib (Lorbrena) as a first-line treatment for patients with ALK-positive metastatic non–small cell lung cancer (NSCLC), according to Pfizer, the developer of the agent.1

The FDA is reviewing the sNDA under the FDA’s Real-Time Oncology Review pilot program and Project ORBIS, which enables concurrent submission and review to multiple international health authorities. A prescription drug user fee act (PDUFA) goal date for a decision has been set by the FDA for April 2021.

The sNDA is based on data gathered from the pivotal CROWN study (NCT03052608), which met its primary end point of improved progression-free survival (PFS) versus crizotinib (Xalkori) in patients with previously untreated advanced ALK-positive NSCLC. Results from the study were published in the New England Journal of Medicine and were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.2,3

“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 non­small cell lung cancer,” Chris Boshoff, MD, PhD, chief development officer of Oncology at Pfizer Global Product Development, said in a press release. “We look forward to working with the FDA to bring this treatment option to patients as quickly as possible.”

The randomized, open-label, parallel 2-arm, phase 3 trial enrolled a total of 296 individuals with previously untreated advanced ALK-positive NSCLC. Participants were randomized 1:1 to receive either lorlatinib monotherapy (n = 149) or crizotinib monotherapy (n = 147).

The study’s primary end point is PFS per blinded independent central review with secondary end points including PFS by investigator’s assessment, overall survival, objective response rate (ORR), intracranial objective response, and safety.

Results from an interim analysis found that at 12 months, the PFS rate was 78% (95% CI, 70%-84%) in the lorlatinib group and 39% (95% CI, 30%-48%) in the crizotinib group (HR, 0.28; 95% CI, 0.19-0.41; P <.001). The ORR was 76%(95% CI, 68%-83%) in the lorlatinib group versus 58% (95% CI, 49%-66%) in the crizotinib group. Intracranial response among those with measurable brain metastases was 82% (95% CI, 57%-96%) with lorlatinib, including 71% with an intracranial complete response, and 23% (95% CI, 5%-54%) with crizotinib.

Regarding safety, the most common adverse events (AEs) observed with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Notably, lorlatinib was associated with more grade 3/4 AEs than crizotinib (72% vs 56%, respectively), with altered lipid levels accounting for the greatest discrepancy between arms. Discontinuation of treatment due to AEs occurred in 7% and 9% of the patients, respectively.

Importantly, the FDA granted accelerated approval to lorlatinib in 2018 for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least 1 other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease based on efficacy end points of tumor response rate and duration of response. Data from the CROWN study is also intended to support the full approval for the use of lorlatinib for this indication.


1. Lorbrena (lorlatinib) sNDA in previously untreated ALK-positive lung cancer accepted for priority review by U.S. FDA. News release. Pfizer, Inc. Published December 28, 2020. Accessed January 4, 2020. https://www.pfizer.com/news/press-release/press-release-detail/lorbrenar-lorlatinib-snda-previously-untreated-alk-positive

2. 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

3. Solomon B, Bauer TM, De Marinis F, et al. Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): Results of the phase III CROWN study. Ann Oncol. 2020;31(suppl 4):LBA2. doi:10.1016/annonc/annonc325