Disclosures: Pfizer supported the study. Shaw is global head of translational clinical oncology at the Novartis Institutes for BioMedical Research. Please see the study for all other authors’ relevant financial disclosures.
November 18, 2020
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Lorlatinib extends PFS vs. crizotinib as first-line treatment in ALK-positive NSCLC

Disclosures: Pfizer supported the study. Shaw is global head of translational clinical oncology at the Novartis Institutes for BioMedical Research. Please see the study for all other authors’ relevant financial disclosures.
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Lorlatinib appeared to be an effective first-line therapy compared with crizotinib among patients with advanced ALK-positive non-small cell lung cancer, according to phase 3 study results published in The New England Journal of Medicine.

Researchers observed higher rates of grade 3 and grade 4 adverse events with lorlatinib (Lorbrena, Pfizer) due to the frequent occurrence of altered lipid levels.

Lorlatinib appeared to be an effective first-line therapy compared with crizotinib among patients with advanced ALK-positive NSCLC.
Lorlatinib appeared to be an effective first-line therapy compared with crizotinib among patients with advanced ALK-positive NSCLC.

Lorlatinib, a potent, brain-penetrant, third-generation ALK inhibitor, has been shown in preclinical and clinical studies to overcome all known ALK resistance mutations, according to Alice T. Shaw, MD, PhD, attending physician at the Center for Thoracic Cancers at Massachusetts General Hospital.

Alice T. Shaw, MD, PhD
Alice T. Shaw

“We had previously shown that lorlatinib is active in ALK-positive NSCLC after patients have failed first- and second-generation ALK inhibitors, and lorlatinib was FDA-approved in 2018 for ALK-positive patients who failed one or more ALK inhibitors,” Shaw told Healio. “In prior studies of previously treated patients, we had also shown that lorlatinib demonstrated remarkable activity in treating and controlling brain metastases. The compelling activity of lorlatinib in these patients led us to examine whether lorlatinib might be even more effective than current ALK-targeted therapies in the front-line, treatment-naive setting. Here, the hope was that lorlatinib would not only treat active disease, but also might prevent or significantly delay the onset of resistance, as well as prevent the development of brain metastases.”

The efficacy of lorlatinib vs. the first-generation ALK inhibitor crizotinib (Xalkori; Pfizer, EMD Serono) as initial treatment for advanced ALK-positive NSCLC had not been well-established.

For this reason, Shaw and colleagues conducted the CROWN study to compare outcomes of lorlatinib vs. crizotinib among 296 patients with previously untreated advanced ALK-positive NSCLC recruited from 104 medical centers across 23 countries.

Researchers randomly assigned participants to 28-day cycles of oral lorlatinib dosed at 100 mg daily (n = 149; median age, 61 years; 56% women; 48% white) or oral crizotinib dosed at 250 mg twice daily (n = 147; median age, 56 years; 62% women; 49% white).

PFS as assessed by blinded independent central review served as the primary endpoint. Independently assessed objective response and intracranial response served as secondary endpoints.

Researchers planned an interim efficacy analysis after approximately 133 expected disease progression or death events had occurred.

At 1-year follow-up, 78% (95% CI, 70-84) of patients in the lorlatinib group vs. 39% (95% CI, 30-48) in the crizotinib group remained alive without disease progression (HR = 0.28; 95% CI, 0.19-0.41). Median PFS had not been reached with lorlatinib compared with 9.3 months with crizotinib, corresponding to a 72% reduction in the risk for progression or death with lorlatinib.

“Second-generation ALK inhibitors have been compared with crizotinib in separate randomized phase 3 trials and, notably, the magnitude of benefit relative to crizotinib appears to be greatest for lorlatinib, as second-generation drugs have all been associated with an approximately 50% reduction in the risk of progression or death relative to crizotinib,” Shaw said.

Patients in the lorlatinib group had a higher objective response rate (76% vs. 58%; OR = 2.25; 95% CI, 1.35-3.89). In addition, more patients with brain metastases assigned lorlatinib experienced an intracranial response (82% vs. 23%; OR = 16.83; 95% CI, 1.95-3.89). Researchers additionally observed an intracranial complete response in 71% of patients with brain metastases who received lorlatinib.

Grade 3 to grade 4 adverse events occurred more frequently with lorlatinib (72% vs. 56%). However, slightly more patients assigned crizotinib discontinued treatment (9% vs. 7%). Common adverse events associated with lorlatinib included hyperlipidemia, edema, increased weight, peripheral neuropathy and cognitive effects.

“These data support the concept of using our best drug first to maximize the chance of highly durable remissions,” Shaw said. “In addition, as patients with ALK-positive NSCLC are known to be at high risk for CNS metastases, treating and preventing brain metastases is a critical priority. Patients treated with second-generation ALK inhibitors still relapse in the CNS, with CNS progression as a major cause of morbidity and mortality. Lorlatinib profoundly reduces the risk for CNS progression, which leads to longer PFS and likely improved quality of life.”

Although lorlatinib was not compared directly with alectinib (Alecensa, Genentech), the current first-line standard of care, Shaw said the strength of the CROWN data establishes lorlatinib as another potential first-line treatment option for patients with advanced ALK-positive NSCLC.

“The most important questions facing the field now have to do with detection of residual disease after initial [tyrosine kinase inhibitor] therapy, eradication of residual disease to further enhance durations of response, and development of rational combinations that can overcome and potentially prevent ALK-independent mechanisms of resistance,” she told Healio.

For more information:

Alice T. Shaw, MD, PhD, can be reached at Massachusetts General Hospital Cancer Center, 32 Fruit St., Boston, MA 02114; email: ashaw1@mgh.harvard.edu.