Lorlatinib (Lorbrena) significantly improved progression-free survival (PFS) and intracranial response rates compared with the former standard of care, crizotinib (Xalkori), as first-line treatment for patients with advanced ALK-positive non–small-cell lung cancer (NSCLC), as reported in a planned interim analysis of the CROWN trial.
“Lorlatinib resulted in a significantly longer progression-free survival, significantly higher overall and intracranial response rates, and improved global quality of life compared to crizotinib as first-line treatment for ALK-positive NSCLC,” said lead investigator Benjamin Solomon, MBBS, PhD, FRACP, Medical Oncologist, Lung Service, Peter MacCallum Cancer Centre, Melbourne, Australia, who presented the results at the 2020 virtual meeting of the European Society for Medical Oncology (ESMO).
“Safety was similar to that reported in previous studies. These results support the use of lorlatinib as an effective first-line therapy for patients with advanced ALK-positive NSCLC,” Dr Solomon added.
“These are amazing data sets with absolutely astonishing results,” noted ESMO President Solange Peters, MD, PhD, Medical Oncologist, Centre Hospitalier Universitaire Vaudois, Lausanne University, Switzerland.
ALK rearrangements are found in an estimated 3% to 7% of NSCLC, primarily in smokers. Crizotinib was the first ALK inhibitor to be approved (in 2011) for the treatment of ALK-positive NSCLC, and it became the standard of care. Lorlatinib is a third-generation, highly potent ALK-tyrosine kinase inhibitor (TKI) with overall and intracranial activity in ALK-positive NSCLC. Lorlatinib was designed to treat central nervous system (CNS) metastases, a common site of metastasis in lung cancer, giving it an advantage over crizotinib.
CROWN is a randomized, phase 3 clinical trial comparing lorlatinib versus crizotinib in patients with stage IIIB/IV ALK-positive NSCLC and no previous treatment for metastatic disease. Patients with asymptomatic, treated or untreated CNS metastases were eligible for enrollment. A total of 296 patients from 104 study sites in 23 countries were randomized in a 1:1 ratio to receive lorlatinib 100 mg once daily (N = 149) or crizotinib 250 mg twice daily (N = 147). All patients underwent restaging computed tomography and brain imaging every 8 weeks.
The median follow-up for the primary end point of PFS was 18.3 months with lorlatinib and 14.8 months with crizotinib. The median PFS by blinded independent central review (BICR) was not reached in the lorlatinib group versus 9.3 months in the crizotinib group (P <.001). The 12-month PFS was 78% with lorlatinib and 39% with crizotinib.
The objective response rates by BICR were 76% with lorlatinib and 58% with crizotinib. Overall, 4 patients in the lorlatinib group had a complete response versus no patients in the crizotinib group. The median duration of response was not evaluable in the lorlatinib arm versus 11 months in the crizotinib arm. The median time to response was 1.8 months in each arm.
The overall survival was not evaluable in either group at this early time. However, a trend toward improved survival was observed with lorlatinib.
Delayed CNS Progression
“Lorlatinib has the ability to delay progression of existing brain metastases, and also to prevent development of new brain metastasis in patients with ALK-positive NSCLC,” Dr Solomon stated.
Among those with nonmeasurable brain metastasis, intracranial objective response by BICR was 66% in patients receiving lorlatinib and 20% in patients receiving crizotinib, and intracranial objective response was 82% and 23%, respectively.
The median time to CNS progression was not evaluable in the lorlatinib group versus 16.6 months in the crizotinib arm (P <.001).
“Lorlatinib was strategically designed to have activity against ALK and to be highly CNS-penetrant,” said invited discussant Christine M. Lovly, MD, PhD, Co-Leader, Translational Research and Interventional Oncology Program, Vanderbilt-Ingram Cancer Center, Nashville, TN.
Safety and tolerability were comparable with both treatments. Almost all patients in both groups had an adverse event of any grade. The rates of grade 3 and 4 adverse events were 72% in the lorlatinib arm and 56% in the crizotinib arm. Serious adverse events occurred in 34% and 27% of patients, respectively.
Fatal adverse events occurred in 7 patients in each treatment arm. Adverse events leading to treatment discontinuation occurred in 7% and 9% of patients, respectively, and temporary dose interruptions were required in 49% and 47%.
“Although grade 3 and 4 adverse events were more frequent with lorlatinib, the majority were laboratory abnormalities that were asymptomatic and readily managed,” Dr Solomon stated.
Adverse events that were more common with lorlatinib included hypercholesterolemia, elevated triglyceride levels, edema, weight gain, peripheral neuropathy, and cognitive effects. Diarrhea, fatigue, vision disorder, increased liver enzyme levels, and nausea and vomiting were more common with crizotinib.
According to global quality-of-life scores on the EORTC Quality of Life Questionnaire–Core Questionnaire 30, patients who received lorlatinib maintained quality of life throughout treatment, whereas quality of life worsened for those who received crizotinib.
Commenting on the different toxicity profiles, Dr Lovly said, “As we treat longer with these drugs, toxicity is important. In CROWN, hypercholesterolemia and triglyceridemia are exclusive to lorlatinib, and neurocognitive effects were seen with lorlatinib, although less commonly. It appears that any TKI will achieve high response rates and long progression-free survival, but that is not a cure.”
“Toxicity profiles will be important as well as mechanisms of resistance to lorlatinib as we figure out the optimal way to sequence the available ALK TKIs. We need more data, and we need data on combinations,” Dr Lovly observed.
“We look forward to seeing more data from this trial. Alectinib [Alecensa] had a progression-free survival of about 3 years, which was remarkable. We await the data on lorlatinib,” she said.