The following article features coverage from the European Society for Medical Oncology 2020 virtual meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Progression-free survival (PFS) was significantly prolonged in adult patients with ALK-positive advanced/metastatic non-small cell lung cancer (NSCLC) treated in the first-line setting with lorlatinib compared with crizotinib, according to results of an interim analysis of a phase 3 study (CROWN; Identifier: NCT03052608) presented at the European Society of Medical Oncology (ESMO) Virtual Congress 2020.1

Lorlatinib, a third-generation ALK inhibitor, is currently approved by the US Food and Drug Administration (FDA) for patients with ALK-positive metastatic NSCLC only following progression on at least 1 second-generation ALK inhibitor, ceritinib or alectinib, or the first-generation ALK inhibitor, crizotinib, plus 1 other ALK inhibitor.2

Reported here are the results of a planned interim analysis of a randomized, open-label study comparing loratinib with crizotinib in the first-line treatment of patients with advanced NSCLC.

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In this study, 149 and 147 treatment-naive patients with stage IIIB/IV ALK-positive NSCLC were assigned to the lorlatinib and crizotinib arms, respectively. Patients were stratified by ethnicity (Asian vs non-Asian) and whether or not central nervous system (CNS) metastases were present. Five patients in the crizotinib arm did not receive treatment.

The primary endpoint of the study was PFS by blinded independent central review (BICR).  PFS by investigator, overall survival (OS), objective response rate (ORR), safety, and quality of life were secondary endpoints, along with intracranial objective response rate (IC-ORR), duration of response (DR), intracranial duration of response (IC-DR), and intracranial time to progression by BICR.

At a median follow-up of 18.3 months for patients receiving lorlatinib and 14.8 months for those receiving crizotinib, the median PFS by BICR for lorlatinib was not estimable, while it was 9.3 months for patients treated with crizotinib (hazard ratio [HR], 0.28; 95% CI, 0.19-0.41; P <.001). This represents a 72% reduction in the risk of death or progression. In addition, the 12-month PFS rate was 78% and 39% for those receiving lorlatinib and crizotinib, respectively.

This PFS benefit of lorlatinib over crizotinib was observed across patient subgroups defined by age, sex, ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status, smoking status, and the presence or absence of CNS metastases, among others.   

The ORR rates by BICR were 76% and 58% in patients treated with lorlatinib and crizotinib, respectively, and, with exception of a 3% complete response (CR) rate in patients treated with lorlatinib, almost all responses were partial.

The median DR was not estimable in patients treated with lorlatinib and 11 months in those treated with crizotinib.  

IC-OR rates by BICR were 82% vs 23% for the 30 patients with measurable brain metastases at baseline treated with lorlatinib compared with crizotinib, respectively. A particularly notable finding: CR rates in this subgroup of patients were 71% for those receiving loratinib compared with 8% for patients treated with crizotinib.

Furthermore, loratinib improved time to progression of IC metastases compared with crizotinib with a HR of 0.07 (95% CI, 0.03-0.17; P <.001). There was a significantly greater improvement from baseline in global quality of life among patients treated with lorlatinib compared with those treated with crizotinib.

Intracranial response rates, or efficacy in the brain, compared with crizotinib, coupled with the hazard ratio of .28, make the results of the CROWN study quite compelling, according to Christine Lovly, MD, PhD, associate professor of medicine and coleader of the Translational Research and Interventional Oncology Program at Vanderbilt University Medical Center in Nashville, Tennessee, who led the discussion following the presentation of LBA2.

“These data indicate the ability of lorlatinib not only to delay progression of existing brain metastases, but also to prevent the development of new brain metastases in patients with ALK-positive NSCLC,” stated the presenting author, Benjamin Solomon, MBBS, PhD, medical oncologist and group leader of the Molecular Therapeutics and Biomarkers Laboratory at the Peter MacCallum Cancer Centre in Melbourne, Australia.

Data on OS were immature at the time of this interim analysis.

Regarding safety, the frequencies of grade 3/4 adverse events (AEs) were 72% in the lorlatinib arm and 56% in the crizotinib arm, among which hypercholesterolemia, hypertriglyceridemia, edema, weight gain, and reversible peripheral neuropathy were more common in patients receiving lorlatinib. In addition, there was evidence of some neurocognitive effects with lorlatinib.

We now have multiple options for first-line treatment of patients with ALK-positive lung cancer, said Dr Lovly. But she said to continue to “move the needle” toward understanding how to best deploy ALK TKI therapies, the focus going forward should be to make sure all patients undergo molecular testing for ALK rearrangements. A related goal is to increase representation in clinical trials that examine ALK aberrations. “We can develop wonderful drugs … but if we’re not actually testing for the markers, then we cannot deploy the drugs in the best fashion,” Dr Lovly said.

In his concluding remarks, Dr Solomon noted that “these results of the CROWN study support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC.”

Disclosures: Research funding for this study was provided by Pfizer Inc. Some of the authors disclosed financial relationships with the pharmaceutical industry. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of the ESMO Virtual Congress 2020 by visiting the conference page.


  1. 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. Presented at: European Society of Medical Oncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Abstract LBA2.
  2. Lorlatinib (Lorbrena®) [package insert]. New York, NY: Pfizer, Inc.; 2020.