Lorlatinib Significantly Improves Progression-Free Survival in Advanced ALK+ NSCLC

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Treatment with lorlatinib induced a 72% reduction in the risk of progression or death compared with crizotinib in patients with previously untreated ALK-positive advanced non–small cell lung cancer.

Benjamin Solomon, MD

Benjamin Solomon, MD

Treatment with lorlatinib (Lobrena) induced a 72% reduction in the risk of progression or death compared with crizotinib (Xalkori) in patients with previously untreated ALK-positive advanced non–small cell lung cancer (NSCLC), according to findings from a planned interim analysis of the phase 3 CROWN study (NCT03052608).1

Lorlatinib led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with crizotinib according to a blinded independent central review (BICR), which was the primary end point of the study (HR, 0.28; 95% CI, 0.19-0.41; P <.001). Overall survival (OS), which was a secondary end point in the CROWN trial, was not yet mature at the time of the analysis.

“Biomarker-driven medicines have improved outcomes for people living with ALK-positive NSCLC, but innovative therapies are still needed to delay disease progression,” said Benjamin Solomon, MD, Department of Medical Oncology, Peter MacCallum Cancer Centre, in a statement.2 “The results from the CROWN trial demonstrate that LORBRENA 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.”

The third-generation ALK inhibitor, lorlatinib, has demonstrated antitumor activity in patients with ALK-positive NSCLC who have been previously treatment, but the efficacy of this therapy in the frontline setting for newly diagnosed patients remains unknown. This global randomized study aimed to explore the efficacy of lorlatinib compared with crizotinib in patients with advanced ALK-positive disease who have not received prior systemic therapy for metastatic disease (n = 296). The interim analysis was planned to evaluate the efficacy after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.

Patients were randomized 1:1 to receive either single-agent lorlatinib (n = 149) or crizotinib (n = 147). In addition to PFS per BICR and OS, the study is evaluating PFS based on investigator assessment, objective response rate (ORR), intracranial objective responses, and safety as secondary end points.

Disease progression or death occurred in 127 patients by the time of data cutoff, which included 41 patients (28%) in the lorlatinib arm and 86 (28%) in the crizotinib arm. Overall, 78% of patients were alive without disease progression at 1 year (95% CI, 70-84) with lorlatinib compared with 39% (95% CI, 30-48) in the control arm with crizotinib.

Objective responses were observed in 76% of the patients (95% CI, 63-83) in the lorlatinib arm versus 58% (95% CI, 49-66) in the crizotinib arm. Seventy percent of the patients in the lorlatinib arm and 27% in the control arm had a response that lasted at least 12 months, and similar responses were determined in an investigator assessment.

Among patients with central nervous system (CNS) metastases (n = 78), measurable or non-measurable, 66% of patients in the lorlatinib arm (95% CI, 49-80) and 20% in the control (95% CI, 9-36) had a confirmed intracranial response by BICR, while 61% and 15% had a complete intracranial response, respectively. Additionally, 72% of patients receiving lorlatinib and 0% receiving crizotinib had an intracranial response of at least 12 months.

Among the patients who had measurable brain metastases (n = 30), 82% in the lorlatinib arm (95% CI, 57-96) and 23% in the control arm (95% CI, 5-54) had an intracranial response, while 71% of the patients in the lorlatinib arm had an intracranial complete response.

Overall, 96% of patients in the lorlatinib group (95% CI, 91-98) and 60% in the control group (95% CI, 49-69) were alive at 12 months without CNS progression (HR, 0.07; 95% CI, 0.03-0.17). With adjustments for the competing risks of non-CNS progression and death, the cumulative incidence of CNS progression as the first event was significantly lower in patients who received lorlatinib compared with crizotinib, which was 3% versus 33% at 12 months, respectively (HR, 0.06; 95% CI, 0.02-0.18).

Although, OS data were not yet mature, the analysis showed that death occurred in 51 patients in the intention-to-treat population, which included 23 (15%) in the lorlatinib arm and 28 (19%) in the crizotinib arm, and the HR for death was 0.72 (95% CI, 0.41-1.25). The OS difference between groups was not significant.

In terms of safety, the most common AEs of any grade in the lorlatinib and control groups, respectively, included hypercholesterolemia (70% vs 4%) 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%). The changes in cognition, such as memory impairment and disturbance in attention, and amnesia, as well as the changes in mood, like anxiety, depression, and lability, were mostly grade 1 and reversible with a dose interruption.

Grade 3/4 AEs were observed in 72% of the lorlatinib group and 56% of the crizotinib group. In the lorlatinib arm, the most common grade 3/4 AEs included elevated triglyceride levels (occurring in 20%), increased weight (17%), elevated cholesterol levels (16%), and hypertension (10%), while the most common in the crizotinib arm were laboratory abnormalities.

Serious AEs occurred in 34% of the patients who received lorlatinib and 27% who received crizotinib. Fatal events were observed in 14 patients, including 7 (5%) from the lorlatinib arm and 7 (5%) in the control arm.

AEs that led to a dose interruption occurred in 49% of those in the lorlatinib arm and 47% in the crizotinib arm, while dose reductions occurred in 21% and 15%, respectively. AEs that led to discontinuation occurred in 7% of the lorlatinib arm and 9% of the crizotinib arm.

The FDA approved lorlatinib in 2018, for the treatment of patients with ALK-positive metastatic NSCLC whose disease progressed on crizotinib and at least 1 other ALK inhibitor, or whose disease progressed on alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease. This indication was granted in an accelerated approval based on the tumor response rate and duration of response. The CROWN study is a confirmatory trial for the conversion to a full approval of lorlatinib.2

References

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;383:2018-2029. 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. November 19, 2020. Accessed December 4, 2020. https://bit.ly/39IGXpB

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